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Stopping Breast Cancer Metastasis in Its Tracks
9/19/2016

TAU researcher harnesses targeted delivery of microRNAs to primary tumors in mice to block the movement of cancer

A new Tel Aviv University study finds that combining genetic therapy with chemotherapy delivered to a primary tumor site is extremely effective in preventing breast cancer metastasis.

The research was led by Dr. Noam Shomron of TAU's Sackler School of Medicine in collaboration with Dr. Natalie Artzi of the Massachusetts Institute of Technology, and conducted by Dr. Shomron's students Avital Gilam and Dr. Daphna Weissglas and Dr. Artzi's student Dr. Joao Conde. Data on human genetics were provided by Prof. Eitan Friedman of TAU's Sackler Faculty of Medicine and Chaim Sheba Medical Center.

The research was published in the September 19, 2016, online issue of Nature Communications.

Stopping cancer at the turning point

One in eight women worldwide are diagnosed with breast cancer during their lifetimes. Breast cancer is the second leading cause of cancer death in women. The chance that a woman will die from breast cancer is about 1 in 36. Early detection, while increasingly common, is not sufficient to preventing metastasis, the lethal movement of cancerous cells from a primary tumor site to colonies in vital organs. About 80 percent of women with metastatic cancer die from the disease within just five years of being diagnosed.

"The situation is bleak. Death rates from breast cancer remain high and relatively unchanged despite advances in medicine and technology," said Dr. Shomron. "We wanted to find a way to stop metastasis from happening altogether. It's the turning point, where survival rates drop exponentially.

"Our mission was to block a cancer cell's ability to change shape and move. Cancer cells alter their cytoskeleton structure in order to squeeze past other cells, enter blood vessels and ride along to their next stop: the lungs, the brain or other vital organs. We chose microRNAs as our naturally-occurring therapy, because they are master regulators of gene expression."

Database, drugs and delivery

The researchers based their approach on the "3Ds" — database, drugs and delivery. The team began by exploring bioinformatics databases to investigate the span of mutations in a tumor and identify precisely which ones to target. The scientists then procured a naturally-occurring, RNA-based drug to control cell movement and created a safe nanovehicle with which to deliver the microRNA to the tumor site.

"We looked at mutations and polymorphisms that other researchers have ignored," said Dr. Shomron. "Mutations in the three prime untranslated regions (UTRs) at the tail end of a gene are usually ignored because they aren't situated within the coding region of the gene. We looked at the three UTR sites that play regulatory roles and noticed that mutations there were involved in metastasis."

Two weeks after initiating cancer in the breasts of their mouse "patients," the researchers injected into primary tumor sites a hydrogel that contained naturally occurring RNAs to target the movement of cancer cells from primary to secondary sites. Two days after this treatment, the primary breast tumors were excised.

The mice were evaluated three weeks later using CT imaging, flourescent labelling, biopsies and pathology. The researchers discovered that the mice that had been treated with two different microRNAs had very few or no metastatic sites, whereas the control group — injected with random scrambled RNAs — exhibited a fatal proliferation of metastatic sites.

From mice to humans

"We realized we had stopped breast cancer metastasis in a mouse model, and that these results might be applicable to humans," said Dr. Shomron. "There is a strong correlation between the effect on the genes in mouse cells and the effect on the genes in human cells. Our results are especially encouraging because they have been repeated several times at TAU and at MIT by independent groups."

The researchers are continuing their study of the effects of microRNAs on tumors within different microenvironments.

Watch Prof. Shomron’s TEDx talk about his research: https://www.youtube.com/watch?v=wAoZym_anr0

Induced Labor After Water Breakage Poses No Harm to Mothers or Their Babies, TAU Researchers Find
9/1/2016

Natural and induced deliveries following amniotic sac rupture share similar neonatal outcomes

A new Tel Aviv University study has determined that natural, spontaneous deliveries and induced deliveries following the rupture of the amniotic sac in the mother share similar neonatal outcomes, contradicting common wisdom.

"Induced labor — the process of jumpstarting delivery using prostaglandin — has gotten a bad rap. We found little justification for this" in the case of women whose water broke prematurely, said principal investigator Dr. Liran Hiersch, who led the study with Dr. Eran Ashwal, both of TAU's Sackler School of Medicine and the Helen Schneider Hospital for Women at Rabin Medical Center. "People have an idea that everything natural is better, including childbirth. But induction is not necessarily more dangerous for mother and child than Mother Nature herself."

The study was published on August 8, 2016, in the Archives of Gynaecology and Obstetrics.

Fears about induced labor are unjustified

Most expectant mothers are warned about artificially induced deliveries. These warnings counsel that induction may cause a low fetal heart rate, an increased risk of infection to mother and baby, and uterine rupture or excessive bleeding after delivery. "We have found that induction produces healthy mothers and infants, with risk factors similar to those of spontaneous deliveries," Dr. Hiersch said.

The researchers evaluated the perinatal outcome of 625 women admitted to Rabin Medical Center in Israel with prolonged (24-hour) premature rupture of membranes or water breakage. Women who did not exhibit the spontaneous onset of labor within 24 hours from the moment their water broke underwent prostaglandin induction. These were then compared to those women who did develop the spontaneous onset of labor within 24 hours of being admitted. No significant difference was found between the groups regarding maternal age, parity and obstetrical complications.

Women in the induction group were found to be at an increased risk for Caesarean section (CS), but researchers believe this was due mainly to blocked birth canals and not the induction itself.

Artificial induction is a possibility for all expectant mothers who have approached two weeks past their delivery date, who experience high blood pressure or diabetes, who have a uterine infection or who simply haven't experienced contractions despite their water having broken. These women are often hospitalized for 24 hours. But after 24 hours have passed without natural delivery, most medical professionals will induce labor artificially to reduce subsequent risks to mother and child.

Patients should be reassured

"There is a palpable fear among women who are waiting for the contractions to begin," said Dr. Hiersch. "They fear fetal distress, they fear infection, umbilical cord trouble, but we have found no basis for their fears. These mothers should be assured that induced labor poses no increased risk to the health of their babies and themselves."

"This study gives us, medical professionals, the reassurance we require to continue doing what we do. Hopefully, it will also reassure our patients, which is equally important," Dr. Hiersch concluded.

Dr. Hiersch is currently working on finding variables that predict which women may spontaneously go into labor following the premature rupture of membranes.

TAU Research Reveals How Melanoma Spreads to Other Organs in the Body
8/22/2016

Findings may lead to a cure for the deadly disease

In a landmark discovery, researchers at Tel Aviv University have unraveled the metastatic mechanism of melanoma, the most aggressive of all skin cancers.

According to a paper published today in the journal Nature Cell Biology, the scientists discovered that before spreading to other organs, a melanoma tumor sends out tiny vesicles containing molecules of microRNA. These induce morphological changes in the dermis in preparation for receiving and transporting the cancer cells. The researchers also found chemical substances that can stop the process and are therefore promising drug candidates.

"The threat of melanoma is not in the initial tumor that appears on the skin, but rather in its metastasis — in the tumor cells sent off to colonize in vital organs like the brain, lungs, liver and bones," said research leader Dr. Carmit Levy of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler School of Medicine. "We have discovered how the cancer spreads to distant organs and found ways to stop the process before the metastatic stage."

The TAU group worked in close collaboration with Prof. Jörg D. Hoheisel and Laureen Sander at the German Cancer Research Center (DKFZ) in Heidelberg, Dr. Shoshi Greenberger at the Sheba Medical Center at Tel HaShomer, Israel and Dr. Ronen Brenner at the Wolfson Medical Center in Holon, Israel. Lab research was led by Dr. Shani Dror of Dr. Levy's research group.

Morphological changes in the dermis

Melanoma, the most aggressive and lethal type of skin cancer, causes the death of one person every 52 minutes according to data from the Skin Cancer Foundation, and the number of diagnosed cases has been on the rise for the past three decades. Despite a range of therapies developed over the years, there is still no full remedy for this life-threatening disease. The new study proposes novel and effective methods for diagnosing and preventing this most deadly of skin cancers.

The researchers began by examining pathology samples taken from melanoma patients. "We looked at samples of early melanoma, before the invasive stage," Dr. Levy said. "To our surprise we found changes in the morphology of the dermis — the inner layer of the skin — that had never before been reported. Our next task was to find out what these changes were, and how they related to melanoma."

In the ensuing study, the group was able to discover and block a central mechanism in the metastasis of melanoma.

According to Dr. Levy, scientists have known for years that melanoma forms in the outer layer of the skin, the epidermis. At this early stage, the cancer is unable to send off colonizing cancer cells because it has no access to blood vessels — the highways that carry the cells to other parts of the body. With no blood vessels present in the epidermis, the tumor first needs to contact the abundant blood vessels running through the dermis. But how was the connection made?

"We found that even before the cancer itself invades the dermis, it sends out tiny vesicles containing molecules of microRNA," Dr. Levy said. "These induce the morphological changes in the dermis in preparation for receiving and transporting the cancer cells. It then became clear to us that by blocking the vesicles, we might be able to stop the disease altogether."

Transforming melanoma into a nonthreatening illness

Having discovered the mechanism, the researchers proceeded to look for substances that could intervene and block the process in its earliest stages. They found two such chemicals: one (SB202190) inhibits the delivery of the vesicles from the melanoma tumor to the dermis; and the other (U0126) prevents the morphological changes in the dermis even after the arrival of the vesicles. Both substances were tested successfully in the lab, and may serve as promising candidates for future drugs. In addition, the changes in the dermis, as well as the vesicles themselves, can be used as powerful indicators for early diagnosis of melanoma.

"Our study is an important step on the road to a full remedy for the deadliest skin cancer," said Dr. Levy. "We hope that our findings will help turn melanoma into a nonthreatening, easily curable disease."

TAU Researcher Awarded 2016 MetLife Foundation Prize
8/15/2016

Dr. Inna Slutsky receives illustrious award for outstanding research in the field of Alzheimer's disease

Photo: Dr. Inna SlutskyTel Aviv University's Dr. Inna Slutsky won the 2016 MetLife Foundation Promising Investigator Award in Medical Research for Alzheimer's Disease from the American Federation for Aging Research for her exemplary medical research in Alzheimer's disease. The award was presented on July 25, 2016, with the during the Alzheimer's Association International Conference in Toronto.

Dr. Slutsky, the first Israeli scientist to ever receive a MetLife Foundation Award, is a member of TAU's Department of Physiology and Pharmacology, Sackler Faculty of Medicine, and Sagol School of Neuroscience. She has focused her research on the breakdown of communication lines between brain cells in the pathology of Alzheimer's disease.

MetLife Foundation gave four awards this year, distributing a total of $350,000 to Dr. Slutsky; Guojun Bu, PhD, of the Mayo Clinic; Mia Kivipelto, MD, PhD, of Karolinska Institutet, Stockholm and Karolinska University Hospital, Stockholm; and John R. Cirrito, PhD, of Washington University School of Medicine. The awards recognize them as trail-blazing scientists who have made significant contributions to the understanding of Alzheimer's disease.

"Our Advisory Committee were so impressed by the potential impact of Dr. Slutsky and Dr. Cirrito's research that they granted them the Promising Investigator awards this year," said Dennis White, President and Chief Executive Officer, of MetLife Foundation at the awards ceremony.

"These four individuals have performed ground-breaking work, and the awards will help further their pioneering research," said past award recipient Dr. David M. Holtzman of Washington University School of Medicine during the ceremony. "Drs. Bu, Kivipelto, Slutsky, and Cirrito join a roster of past winners whose work has gone onto receive recognition in the field and beyond, including the Nobel Prize, the Potamkin Prize, and TIME Magazine's scientist of the year."

MetLife Foundation has been presenting these prestigious awards to outstanding researchers in the field of Alzheimer's disease for 30 years. Since 1986 it has granted more than $18 million to 88 awardees at 52 institutions in eight countries.

Brain’s Prefrontal Lobe Is Major Player in Parkinson’s Gait
8/10/2016

Cognitive functions play an active role in the gait pattern of Parkinson's patients, say TAU researchers

A new study by Tel Aviv University researchers demonstrates that the prefrontal cortex, the part of the brain associated with cognitive functions, plays a major role in "Parkinson's Gait." It suggests a radically new understanding of the mechanism underlying gait difficulties in people with Parkinson's disease (PD) and may lead to new therapeutic approaches.

The study was led by Prof. Jeffery Hausdorff of TAU's Sackler School of Medicine and Dr. Anat Mirelman of the Department of Neurology at TAU's Sackler School of Medicine, co-directors of the Center for the Study of Movement, Cognition and Mobility at the Tel Aviv Medical Center; and conducted in large part by Dr. Inbal Maidan of Tel Aviv Medical Center. The work was recently published in the journals Parkinsonism and Related Disorders and Neurorehabilitation and Neural Repair.

More than motor deficits involved

The ability to walk safely and independently is central to functional independence and quality of life. That ability is impaired in people with PD, rendering the most basic and commonplace tasks nearly impossible.

Researchers had previously theorized that motor deficits associated with PD were the direct cause of impaired walking, the reduced ability to multitask while walking, and the dangerous falls associated with the disease.

However, when TAU researchers asked patients to walk and complete another task — e.g., a verbal fluency task such as naming fruits or simple serial subtractions — at the same time, also called "dual tasking," the gait pattern of patients with PD became worse. They walked slower and with less stability. This suggested that cognitive resources were being used as they walked.

"Work by our group has demonstrated that cognitive control deficits play an active role in the walking difficulties experienced by many people with Parkinson's," said Prof. Hausdorff.

New pictures of the problem

The team used functional near infrared spectroscopy (fNIRS) to show that cognitive resources are utilized by PD patients much more often than by healthy individuals. "The advantage of fNIRS is that we can measure brain activation during actual walking," said Dr. Mirelman. "These results are consistent with our study using MRI that found brain activity in Parkinson's patients was activated in the prefrontal cortex even during 'imagined walking.'

"The overactivation of the prefrontal cortex has a two-pronged effect in Parkinson's patients," Dr. Mirelman continued. "Because the prefrontal cortex is 'saturated,' it is unable to perform other tasks, impairing gait and creating cognitive deficits. The debilitation is two-fold."

Even when patients were lying flat in the MRI and merely imagining themselves walking, there was a "ceiling effect" — they were unable to recruit additional cognitive resources to tackle more difficult tasks involved with walking. "The increased activation during normal walking curtails the ability of Parkinson's patients to recruit further cognitive resources during other challenging tasks," said Prof. Hausdorff. "It may even exacerbate the high risk of falling in these patients."

The team is now conducting research to better understand the underlying mechanisms of the brain activation pattern and therapeutic approaches that may improve gait and reduce the risk of falls. The information is critical to the design of appropriate therapies such as virtual reality or non-invasive brain stimulation to improve neural efficiency.

Novel Technology May Prevent Burn Scars
8/8/2016

Researchers at Tel Aviv and Harvard Universities develop method to control collagen-cell proliferation that produces scarring

A group of researchers from Tel Aviv University and Harvard University has devised a new non-invasive method to prevent burn scarring caused by the proliferation of collagen cells. They are using short, pulsed electric fields prevent the formation of burn-related hypertrophic scars — raised tissue caused by excessive amounts of collagen.

Research for the study was led by Dr. Alexander Golberg of TAU's Porter School of Environmental Studies, together with Dr. Martin Yarmush of the Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Burns Hospital in Boston. It was recently published in the Journal of Investigative Dermatology.

Ten percent of all unintentional-injury deaths are the result of fire-related burns, according to the World Health Organization. But even for those who survive the destruction of skin and tissue cells, the road to recovery is never ending. Post-burn scarring creates lifelong physical, psychological and social challenges.

Relieving lifelong suffering

"People don't die from scars, but they do suffer from them," said Dr. Golberg. "We believe that the technology we developed, called partial irreversible electroporation (pIRE), can be used to prevent debilitating burn scars from forming."

The non-invasive pIRE technique harnesses microsecond-pulsed, high-voltage, non-thermal electric fields to control the body's natural response to trauma — the proliferation of collagen cells that cause permanent scarring at the site of injury. The technique partially destroys cells in the wound with short, pulsed electric fields that cause irreversible damage to the collagen cells. But the researchers had to find a delicate balance so that the technique didn't create a new wound or "overheal" the existing wound, because scarring is the body's natural way of healing.

The researchers treated burn injuries in rats in five therapy sessions over six months, then assessed them using an imaging technique developed by Drs. Martin Villiger and Brett Bouma's group at the Wellman Center of Photomedicine at Massachusetts General. The researchers found a 57.9% reduction of the scar area in comparison with untreated scars.

Next step: Human clinical studies

"Surgical excision, laser therapy, electron-beam irradiation, mechanical compression dressing, silicone sheet application and other techniques have been tested to treat scars over the years," said Dr. Golberg, "but there have been only modest improvements in the healing outcomes among all these treatments.

"Scarring is a very complex process, involving inflammation and metabolism," said Dr. Golberg. "We have found a way to partially prevent scar formation in animal models. Next we need to raise funding to develop a device for the clinical study on humans."

The study was supported by the Shriners Foundation, which funds research on pediatric burns.

TAU Research Opens the "Black Box" of Malignant Melanoma
7/25/2016

Study pinpoints when melanoma cells metastasize to the brain months before they develop into fatal tumors

When malignant melanoma metastasizes to the brain, it is a death sentence for most patients. Metastatic melanoma is the deadliest of the skin cancers and the mechanisms that govern early metastatic growth and interactions of metastatic cells with the brain microenvironment remain shrouded in mystery.

A new Tel Aviv University study reveals a novel way of detecting brain micrometastases months before they transform into malignant inoperable growths. According to the research, micro-tumor cells hijack astrogliosis, the brain's natural response to damage or injury, to support metastatic growth. This knowledge may lead to the detection of brain cancer in its first stages and permit early intervention.

The study was led by Dr. Neta Erez of the Department of Pathology at TAU's Sackler Faculty of Medicine and published in Cancer Research.

Following the path to cancer

Dr. Erez and her team used mouse models to study and follow the spontaneous metastasis of melanoma in the brain. She and her partners recapitulated all the stages of metastasis: the initial discovery of melanoma in the skin, the removal of the primary tumor, the micrometastatic dissemination of cancer cells across the body, the discovery of a tumor and death.

The detection of metastasis depends on imaging techniques that still can't detect micrometastases. Melanoma patients whose initial melanoma was excised believe that everything is fine for months or years following the initial procedure.

But following the removal of the primary tumor, micrometastatic cells learn to communicate with cells in their new microenvironment in the brain — cells which are, at first, hostile to them. But eventually a tumor appears. These cells travelled across the body to the brain or other organs but were undetectable at the micro level. When they become detectable, it is too late for treatment.

Opening the "black box"

Dr. Erez calls the period of the initial growth of disseminated micrometastatic cells in distant organs the metastasis' "black box" — the history of melanoma in the brain. "We believe that we have found the tools to characterize this black box," said Dr. Erez. "And this is key to developing therapeutic approaches that may prevent brain metastatic relapse.

"Every organ in body has a defense system that detects intruders," said Dr. Erez. "Much of this is regulated by support cells in the brain. When there is tissue damage due to a stroke or viral infection, these cells are activated and induce an inflammatory response.

"At the earliest stages of metastasis, we already see astrogliosis and inflammation. The brain perceives the micrometastatic invasion as tissue damage, activating inflammation — its natural defense mechanism. We found that the inflammation unfortunately gets hijacked by tumor cells that are able to grow faster and penetrate deeper because the blood vessels in the brain are more permeable than in any other part of the body. We found that all of this happens very early on."

Dr. Erez is currently studying detailed molecular pathways in the brain's biological response to find a way to block the metastases. "We're hoping to develop the detection tools for humans that we developed in mice," said Dr. Erez. "We're also trying to find molecular targets that will allow us to prevent metastasis rather than trying to treat it."

Biological Mechanism Passes On Long-term Epigenetic "Memories"
3/28/2016

TAU researchers discover the on/off button for inheriting responses to environmental changes

According to epigenetics — the study of inheritable changes in gene expression not directly coded in our DNA — our life experiences may be passed on to our children and our children's children. Studies on survivors of traumatic events have suggested that exposure to stress may indeed have lasting effects on subsequent generations. But how exactly are these genetic "memories" passed on?

A new Tel Aviv University study pinpoints the precise mechanism that turns the inheritance of environmental influences "on" and "off." The research, published last week in Cell and led by Dr. Oded Rechavi and his group from TAU's Faculty of Life Sciences and Sagol School of Neuroscience, reveals the rules that dictate which epigenetic responses will be inherited, and for how long.

"Until now, it has been assumed that a passive dilution or decay governs the inheritance of epigenetic responses," Dr. Rechavi said. "But we showed that there is an active process that regulates epigenetic inheritance down through generations."

Passing stress from one generation to the next

Researchers have been preoccupied with how the effects of stress, trauma, and other environmental exposures are passed from one generation to the next for years. Small RNA molecules — short sequences of RNA that regulate the expression of genes — are among the key factors involved in mediating this kind of inheritance. Dr. Rechavi and his team had previously identified a "small RNA inheritance" mechanism through which RNA molecules produced a response to the needs of specific cells and how they were regulated between generations.

"We previously showed that worms inherited small RNAs following the starvation and viral infections of their parents. These small RNAs helped prepare their offspring for similar hardships," Dr. Rechavi said. "We also identified a mechanism that amplified heritable small RNAs across generations, so the response was not diluted. We found that enzymes called RdRPs are required for re-creating new small RNAs to keep the response going in subsequent generations."

Most inheritable epigenetic responses in C.elegans worms were found to persist for only a few generations. This created the assumption that epigenetic effects simply "petered out" over time, through a process of dilution or decay.

"But this assumption ignored the possibility that this process doesn't simply die out but is regulated instead," said Dr. Rechavi, who in this study treated C.elegans worms with small RNAs that target the GFP (green fluorescent protein), a reporter gene commonly used in experiments. "By following heritable small RNAs that regulated GFP — that 'silenced' its expression — we revealed an active, tuneable inheritance mechanism that can be turned 'on' or 'off.'"

The scientists discovered that specific genes, which they named "MOTEK" (Modified Transgenerational Epigenetic Kinetics), were involved in turning on and off epigenetic transmissions.

"We discovered how to manipulate the transgenerational duration of epigenetic inheritance in worms by switching 'on' and 'off' the small RNAs that worms use to regulate genes," said Dr. Rechavi. "These switches are controlled by a feedback interaction between gene-regulating small RNAs, which are inheritable, and the MOTEK genes that are required to produce and transmit these small RNAs across generations.

"The feedback determines whether epigenetic memory will continue to the progeny or not, and how long each epigenetic response will last."

A comprehensive theory of heredity?

Although their research was conducted on worms, the team believes that understanding the principles that control the inheritance of epigenetic information is crucial for constructing a comprehensive theory of heredity for all organisms, humans included.

"We are now planning to study the MOTEK genes to know exactly how these genes affect the duration of epigenetic effects," said Leah Houri-Zeevi, a PhD student in Dr. Rechavi's lab and first author of the paper. "Moreover, we are planning to examine whether similar mechanisms exist in humans."

Cyborg Cardiac Patch May Treat the Diseased Heart
3/14/2016

TAU researchers combine electronics with living tissues to create a self-regulating cardiac patch

More than 25% of the people on the national US waiting list for a heart will die before receiving one. Despite this discouraging figure, heart transplants are still on the rise. There just hasn't been an alternative. Until now.

The "cyborg heart patch," a new engineering innovation from Tel Aviv University, may single-handedly change the field of cardiac research. The bionic heart patch combines organic and engineered parts. In fact, its capabilities surpass those of human tissue alone. The patch contracts and expands like human heart tissue but regulates itself like a machine.

The invention is the brainchild of Prof. Tal Dvir and PhD student Ron Feiner of TAU's Department of Biotechnology, Department of Materials Science and Engineering, and Center for Nanoscience and Nanotechnology. Their study was published today in the journal Nature Materials.

Science fiction becomes science fact

"With this heart patch, we have integrated electronics and living tissue," Dr. Dvir said. "It's very science fiction, but it's already here, and we expect it to move cardiac research forward in a big way.

"Until now, we could only engineer organic cardiac tissue, with mixed results. Now we have produced viable bionic tissue, which ensures that the heart tissue will function properly."

Prof. Dvir's Tissue Engineering and Regenerative Medicine Lab at TAU has been at the forefront of cardiac research for the last five years, harnessing sophisticated nanotechnological tools to develop functional substitutes for tissue permanently damaged by heart attacks and cardiac disease. The new cyborg cardiac patch not only replaces organic tissue but also ensures its sound functioning through remote monitoring.

"We first ensured that the cells would contract in the patch, which explains the need for organic material," said Dr. Dvir. "But, just as importantly, we needed to verify what was happening in the patch and regulate its function. We also wanted to be able to release drugs from the patch directly onto the heart to improve its integration with the host body."

For the new bionic patch, Dr. Dvir and his team engineered thick bionic tissue suitable for transplantation. The engineered tissue features electronics that sense tissue function and accordingly provide electrical stimulation. In addition, electroactive polymers are integrated with the electronics. Upon activation, these polymers are able to release medication, such as growth factors or small molecules on demand.

Cardiac therapy in real time

"Imagine that a patient is just sitting at home, not feeling well," Dr. Dvir said. "His physician will be able to log onto his computer and this patient's file — in real time. He can view data sent remotely from sensors embedded in the engineered tissue and assess exactly how his patient is doing. He can intervene to properly pace the heart and activate drugs to regenerate tissue from afar.

"The longer-term goal is for the cardiac patch to be able to regulate its own welfare. In other words, if it senses inflammation, it will release an anti-inflammatory drug. If it senses a lack of oxygen, it will release molecules that recruit blood-vessel-forming cells to the heart."

Dr. Dvir is currently examining how his proof of concept could apply to the brain and spinal cord to treat neurological conditions.

"This is a breakthrough, to be sure," Dr. Dvir said. "But I would not suggest binging on cheeseburgers or quitting sports just yet. The practical realization of the technology may take some time. Meanwhile, a healthy lifestyle is still the best way to keep your heart healthy."

Image caption: A remotely regulated living bionic heart. The engineered tissue is comprised of living cardiac cells, polymers, and a complex nanoelectronic system. This integrated electronic system provides enhanced capabilities, such as online sensing of heart contraction, and pacing when needed. In addition, the electronics can control the release of growth factors and drugs, for stem cell recruitment and to decrease inflammation after transplantation. Credit: Tel Aviv University.

Mutated Gene Associated With Colon Cancer Discovered in 18th-Century Hungarian Mummy
2/29/2016

TAU finding suggests genetic predisposition to cancer already existed in pre-modern era

The modern plagues of obesity, physical inactivity and processed food have been definitively established as modern causes of colon cancer. Researchers have also associated a mutation of the Adenomatous polyposis coli (APC) gene with the deadly disease. But which came first? Is colon cancer a lethal product of modernity? Or is this an open-and-shut case of DNA gone awry?

A new Tel Aviv University discovery suggests that a genetic predisposition to colorectal cancer preceded the advent of modernization — and, in a bizarre twist, they discovered this evidence in an 18th-century Hungarian mummy.

The research team was led by Dr. Rina Rosin-Arbesfeld of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine and Dr. Ella H. Sklan of the same department, together with Prof. Israel Hershkovitz and Michal Feldman of the Department of Anatomy and Anthropology at the Sackler Faculty. The findings were published February 10, 2016, in the journal PLOS ONE.

Meeting the mummies

In 1995, more than 265 mummies were excavated from sealed crypts in the Dominican church in Vác, Hungary. These crypts were used continuously from 1731 to 1838 for the burial of middle-class families and clerics and provided ideal conditions for the natural mummification of corpses — low temperatures, constant ventilation and low humidity. Some 70% of the bodies found had been completely or partially mummified.

The preservation of the tissue samples and abundant archival information about the individuals buried in the crypts attracted researchers from around the world, all of whom where interested in conducting their own morphological and genetic studies of the human remains.

"Colorectal cancer is among the most common health hazards of modern times," Dr. Rosin-Arbesfeld explains. "And it has a proven genetic background. We wanted to discover whether people in the past carried the APC mutation — how common it was, and whether it was the same mutation known to us today. In other words: Is the increase in the incidence of cancer the result of man's manipulation of nature alone?

"After hearing that tuberculosis had been discovered in the corpses, I was interested in seeking out a number of gene mutations known to be associated with colorectal cancer," Dr. Rosin-Arbsefeld says.

A new area for cancer research

The researchers used genetic sequencing to identify mutations in APC genes that were isolated from the mummies. "Mummified soft tissue opens up a new area of investigation," Prof. Hershkovitz says. "Very few diseases attack the skeleton, but soft tissue carries evidence of disease. It presents an ideal opportunity to carry out a detailed genetic analysis and test for a wide variety of pathogens."

"Our data reveal that one of the mummies may have had a cancer mutation. This means that a genetic predisposition to cancer may have already existed in the pre-modern era," Dr. Sklan says. "But we've found this mutation in only one individual so far. Additional studies with a larger sample size should be conducted in order to draw more meaningful conclusions."

The researchers are currently establishing a specialized lab at TAU for ancient DNA research.

Photo caption: A Hungarian mummy's genes are helping scientists better understand the causes of colorrectal cancer. Photo courtesy Tel Aviv University.

New Therapeutic Pathway May Keep Cancer Cells Turned "Off"
2/23/2016

TAU researchers offer proof of concept for new nanomedicine designed to inhibit tumor growth by keeping cancer dormant

Osteosarcoma is a cancer that develops in the bones of children and adolescents. It is one of the most aggressive cancers, with only a 15 per cent, five-year survival rate when diagnosed in an advanced metastatic stage. There are approximately 800 new cases diagnosed each year in the US, and no viable treatments.

A new Tel Aviv University study offers tangible hope of a therapeutic pathway to keep osteosarcoma lesions dormant. It also provides the fundamental basic-science for novel nanomedicines tailored to maintain cancer cells in an asymptomatic state.

The proof of concept was pioneered by Prof. Ronit Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology at TAU's Sackler Faculty of Medicine and Head of TAU's Cancer Angiogenesis and Nanomedicine Laboratory. The study is the fruit of a five-year collaboration between Prof. Satchi-Fainaro's team, led by TAU PhD student Galia Tiram, and the laboratories of Rainer Haag and Marcelo Calderón of Berlin's Frei University. It was recently published in the journal ACS Nano.

Finding the switch for cancer cells

"We want to keep the cancer 'switch' turned off," said Prof. Satchi-Fainaro. "Once osteosarcoma metastasizes away from the primary tumor site, there is no effective treatment, just different ways of prolonging life.

"A 1993 article in the New England Journal of Medicine by William C. Black and H. Gilbert Welch about dormant tumor lesions discovered in the autopsies of people who were considered healthy until their accident-related deaths provided the basis for our research. We decided to investigate osteosarcoma recurrence, with an eye toward the potentially therapeutic value of dormancy."

Osteosarcoma tumors may return with a vengeance, even if they're caught early and excised from a primary site. In the case of "minimal residual disease," cancerous cells left after surgery in a localized spot suddenly "turn on," and the disease reappears. In the other case of "dormant micrometastatic lesions," mini-tumors undetected by current imaging technologies suddenly reemerge as large macro-metastases, primarily in the lungs.

"We wanted to understand what causes the cancer cells to 'switch on' in these cases," said Prof. Satchi-Fainaro. "As long as cancer cells remain asymptomatic and dormant, cancer is a manageable disease. Many people live with thyroid lesions without their knowledge, for example. Ours is a very optimistic approach, and we believe it could apply to other cancers as well."

A circuit-breaker for cancer cells?

Prof. Satchi-Fainaro and her team of researchers used mice to create model pairs of osteosarcoma tumor tissues (part "silent" cancer, part "progressive" cancer) and observed their different characteristics. "We wanted to examine what was different, because we knew that if we could understand their genesis, then we could understand what kept the tumor tissue dormant," said Prof. Satchi-Fainaro. "If we could inhibit the growth of cancer, we could target it and keep it dormant."

The researchers sequenced microRNAs in the tissue and found three microRNAs that were expressed in low levels in the aggressive tumor tissue and in high levels in the dormant tumor tissue. They then inserted the microRNA into the tumor tissues in a petri dish and observed a reduced malignant potential, demonstrated by decreased ability of the cancer cells to communicate with the normal cells present in the microenvironment.

"We saw that the osteosarcoma cells treated with the selected microRNAs were unable to recruit blood vessels to feed their growth," said Prof. Satchi-Fainaro. "In order to keep these microRNAs stable in the blood, we needed to encapsulate them in a nanoparticle that circulates in healthy blood vessels, but that disembark and deliver the drug therapy at the leaky blood vessels that exist at tumor sites. We designed a nanomedicine that would have a special activation method at the tumor site in the target cell.

"The mice treated with the nanomedicine lived for six months, which is the equivalent of 25-odd human years," she reported. "This makes us very optimistic. If we cannot teach tumor cells to be normal, we can teach them to be dormant."

According to Prof. Satchi-Fainaro, there is major potential for this therapeutic approach. She and her team are currently exploring other tumor types and also plan to move the current research into clinical trials. "This has huge potential, because the insertion of microRNA affects many, many genes — making it that much more difficult for cancer to avoid them and compensate for their loss with an alternative pathway," she concludes. "I hope our findings will apply to other tumor types as a universal approach to treating cancer."

New RNA Letter Regulates Gene Expression
2/16/2016

TAU, Sheba Medical Center, University of Chicago discovery brings RNA to the fore of epigenetics

DNA, RNA, protein — the end. Or is it? Until recently, the pattern used to encode genetic information into our cells was considered to be relatively straightforward: four letters (A,G,C,T) for DNA and four (A,G,C,U) for RNA. This equation, however, turned out to be oversimplified — RNA was holding out.

A new study published in Nature by a team of Tel Aviv University, Sheba Medical Center, and University of Chicago scientists finds that RNA, considered the DNA template for protein translation, often appears with an extra letter — and this letter is the regulatory key for control of gene expression. The discovery of a novel letter marking thousands of mRNA transcripts will offer insight into different RNA functions in cellular processes and contributions to the development of disease.

"Epigenetics, the regulation of gene expression beyond the primary information encoded by DNA, was thought until recently to be mediated by modifications of proteins and DNA," said Prof. Gidi Rechavi, Djerassi Chair in Oncology at TAU's Sackler Faculty of Medicine and head of the Cancer Research Center at Sheba Medical Center. "The new findings bring RNA to a central position in epigenetics."

The research, led jointly by Prof. Rechavi and Prof. Chuan He, John T. Wilson Distinguished Service Professor in Chemistry and Investigator of the Howard Hughes Medical Institute at the University of Chicago, and conducted by a team of researchers at TAU, Sheba, and Chicago, represents a breakthrough in understanding how RNAs are regulated.

"This discovery further opens the window on a whole new world of biology for us to explore," said Prof. He. "These modifications have a major impact on almost every biological process."

The number of modified nucleotides (letters) in RNA is 10 times larger than that of the letters found in DNA. But what accounts for the evolutionary drive for a large RNA alphabet? RNA molecules have a wide variety of functions, including storage of genetic information as well as catalytic, structural, and regulatory activities. This is in contrast to the important but one-dimensional function of DNA in encoding genetic information.

"The 140 or so different modifications that decorate RNA increase significantly the vocabulary of RNA and enable the various types of RNA, including mRNA, rRNA, tRNA, siRNA, miRNA and, lncRNA, to implement their versatile activities," said Prof. Rechavi.

Prof. Rechavi's group, led by Dan Dominissini and Sharon Moshkovitz, began exploring the landscape of chemical modifications of messenger RNA (mRNA) four years ago through a specific modification: the addition of a methyl group in position 6 of Adenosine (m6A) in mRNA. The research team then showed that this modification is specific to unique regions of the mRNA molecules and that the modification can be "read" by specific proteins. They also showed that this modification is dynamic and responds to environmental stimuli.

These findings complemented the identification by Prof. He's University of Chicago group at the time of an enzyme (FTO) that removes the m6A marks from mRNA. The demonstration of a reversible process that decorates mRNA and affects its stability, translatability, splicing, and localization established a new field of RNA "epigenetics" known as "epitranscriptomics."

In their new study, the researchers unraveled a new dynamic modification of mRNA — the methylation of position 1 of Adenosine (m1A). Importantly, this modification was shown to be localized in a telltale position near the start of protein translation and linked to increased protein synthesis. Thousands of genes are decorated by this modification, allowing cells to regulate the expression of proteins needed for key biological processes.

"We expect disruption of this new regulatory mechanism to be associated with disease states such as cancer and neurodegenerative disorders," said Prof. Rechavi.

The research groups are currently studying the cellular processes involved in "writing" and "erasing" m1A, as well as the biochemical pathways regulated by this new RNA modification. In the future, they plan to explore the role of m1A methylation in embryonic development and its involvement in cancer and neurodegenerative disorders.

The study was supported by the Kahn Family Foundation, the Sagol Neuroscience Network, the National Institutes of Health, Howard Hughes Medical Institute, Flight Attendant Medical Research Institute, Israel Science Foundation, Israeli Centers of Excellence Program, Ernest and Bonnie Beutler Research Program, Chicago Biomedical Consortium, and the Damon Runyon Cancer Research Foundation.

Necessity, the Mother of Participation
2/16/2016

TAU researchers find link between maternal satisfaction and involvement of autistic children in daily activities

Mothers of children with Autism Spectrum Disorder (ASD) often experience stress and suffer from sleep deprivation. Sacrifices almost always follow as they abandon professional careers and personal ambitions, believing that care for their children "comes first."

But is maternal abandonment of aspirations and interests really beneficial for the ASD child? A new Tel Aviv University study finds that a mother's positive attitude to involvement in everyday activities and a sense of competency in the performance of parental tasks accounts for a significant proportion of her children's successful participation in day-to-day activities.

The research was led jointly by Dr. Orit Bart and Dr. Michal Avrech Bar of the Department of Occupational Therapy at the Stanley Steyer School of Health Professions at TAU's Sackler Faculty of Medicine, and conducted by TAU master's student Limor Shelef. It was published in the journal Research in Autism Spectrum Disorders.

Like mother, like child

"The study has shown that when a mother feels competent and productive, she performs better as a mother," said Dr. Bart, who has been conducting ASD research for 10 years. "This satisfaction is as important for children as it is for mothers themselves. If a mother engages every day in a variety of personal and professional occupations and gains a sense of personal satisfaction from that engagement, this alone positively affects her child's participation in everyday activities.

"Our intention was to determine what might improve ASD children's participation in everyday activities from showering and brushing teeth to after-school activities and playing with friends," Dr. Bart said. "We focused on a unique perspective — the relationship between the mother's participation and her child's participation."

Dr. Bart and Dr. Avrech Bar, whose specialty is motherhood and maternal health, created a model of child participation that included first and foremost the severity of autism and then several variables connected to the mother, i.e. maternal "self-efficacy" (i.e., how competent she feels as a mother).

The researchers invited 30 mothers of children with ASD and 30 mothers of children aged 4-6 with typical development to participate in the study. The mothers completed questionnaires regarding their children's participation in life, their own active participation in life, and their sense of maternal self-efficacy. While the severity of autism was found to be a predictor in 20 percent of child participation, a significant proportion — 30 percent — was found to correlate with a mother's robust participation in life and high sense of self-efficacy.

Take time for yourself

"Our conclusions are clear," said Dr. Avrech Bar. "Mothers need to focus on themselves, to take care of themselves — their own careers, education, and leisure. Don't give up your own interests and occupational aspirations. This might adversely affect your own health and well-being and your child's. There is a clear lesson here: If you participate meaningfully in life, it is likely that your child will participate too."

The researchers are currently preparing a family-centered approach to ASD intervention that includes close attention to mothers' self-efficacy and participation in a variety of activities to promote their children's participation.

"Today the mother is still the main caregiver but this is starting to change," said Dr. Bart. "Intuitively, I believe this kind of research may benefit fathers as well."

Novel Neuroprotective Therapy Found to Enhance Memory
2/11/2016

TAU researcher's novel peptide, developed to treat neuroprotective protein deficiencies, reveals significant gender differences

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, is frequently mutated in children on the autism spectrum. In older men and women, ADNP expression in the blood is correlated with cognition and further altered in Alzheimer's disease. While the three-to-one ratio of autism in boys to girls is well known, as is the greater number of female Alzheimer's patients than male Alzheimer's patients, the reasons for these phenomena — and the theory that men and women may have different brain constitutions — remain in hot dispute.

New research from Tel Aviv University highlights the neuroprotective potential of SKIP, a four-amino-acid peptide ADNP-replacement therapy developed at the university, and the marked difference in the nerve cell communication in male and female mice. If researchers come to understand how ADNP — an activity-related neuroprotective protein that is a major regulatory gene — acts differently in males and females, drugs for potential therapeutics can be optimized to treat both autism and Alzheimer's disease.

The research was led by Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler Faculty of Medicine and a member of TAU's Adams Super Center for Brain Studies and the Sagol School of Neuroscience. It was recently published in Molecular Psychiatry.

The difference between men and women?

"We found a clear difference in ADNP's effect on male and female mice," Prof. Gozes said. "The movement of transported material through nerve cells in the brains of the tested mice was slower in males. This information is critical, because it can be used to design more efficient and successful clinical trials for neurological drug candidates, and hopefully develop precise therapies for ADNP-related diseases or conditions with special attention to gender differences."

Prof. Gozes and her team examined the behavioral response of ADNP-deficient and normal male and female mice to different cognitive challenges and social situations. They worked with the Bioinformatics Unit, the NMR Laboratory, the Alfredo Federico Strauss Center for Computational Neuroimaging and Genomic Centers at TAU and the Technion — Institute of Technology to harness state-of-the-art technology that led to the new understanding of molecular mechanisms underlying differences in the male and female mouse brain.

Prof. Gozes has been instrumental in drawing attention to the proteins that bind microtubules — tubes within nerve cells that maintain cellular shape and serve as "train tracks" for movement of biological material through the brain. In this study, Prof. Gozes and her team observed mice in which SKIP was introduced and witnessed accelerated microtubular function in both males and females, using MRI imaging. The pace of neural transport in mice that inhaled magnesium was found to be significantly slower in males.

"The loss of protective proteins exposes cells to physical damage that eventually destroys them," said Prof. Gozes, whose previous research on NAP, a snippet of ADNP, has been proven in multiple studies to protect cognitive functioning. "The new protein-protectant drug candidate SKIP, which is half the size of NAP, was found to increase and repair blocked nerve-cell transport and normalize it."

Social behaviors

Male and female reactions were different in social situations, too. "SKIP was found to normalize mouse reactions in social situations," said Prof. Gozes. "Normal male and female mice behaved very differently: Females were infrequently drawn toward new mice, whereas males were more frequently drawn to new mice. ADNP-deficient male and female mice both preferred the company of familiar mice. After SKIP was introduced, by intranasal administration, we saw that the female and male mice behaved like the ADNP-intact mice.

"When clinicians treat patients, they must look at gender," Prof. Gozes concluded. "There may be a gender difference in the way certain nerves behave and the way the nerve cells communicate. ADNP is involved in this process. There are differences between the way men and women react to their environments, and differences at the molecular level may indicate that indeed there are differences between the very way men and women think."

SKIP (Prof. Gozes, PI) was licensed by Tel Aviv University's technology-transfer company, Ramot, to Coronis Partners Ltd., a specialty pharma company that is currently conducting a financing round for its clinical development.

Research Discovers Neuroprotective Protein in Blood is Biomarker of Alzheimer's Disease
2/8/2016

TAU, Harvard, Technion team suggests a routine blood test can reveal Alzheimer's risk and IQ measurements

Medical professionals have to conduct a long series of tests to assess a patient's memory impairment and cognitive skills, functional abilities, and behavioral changes to accurately diagnose Alzheimer's disease. They also have to execute costly brain imagining scans and even, sometimes, invasive cerebral spinal fluid tests to rule out other diseases. The process is laborious at best — and subjective at worst.

A new discovery by Tel Aviv University, Technion (Rambam Medical Center), and Harvard University researchers takes the medical community a leap forward in the process of effectively screening and diagnosing Alzheimer's disease. The new study, published in the Journal of Alzheimer's Disease, proposes a new biomarker for cognitive aging and Alzheimer's disease: activity-dependent neuroprotective protein (ADNP), the levels of which can be easily monitored in routine blood tests. The study also found that ADNP levels tested in the blood correlate with higher IQ in healthy older adults.

The research was led by Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and former director of the Adams Super Center for Brain Studies at TAU's Sackler Faculty of Medicine and a member of TAU's Sagol School of Neuroscience, conducted by TAU PhD student Anna Malishkevich and spearheaded by Dr. Gad Marshall, Dr. Aaron Schultz, and Prof. Reisa Sperling of Harvard University, and Prof. Judith Aharon-Peretz of Rambam Medical Center – The Technion Institute of Technology.

A step to early intervention

Significant increases in ADNP RNA levels were observed in patients ranging from mild cognitive impairment (MCI) to Alzheimer's dementia. ADNP levels tested in plasma and serum samples, as well as white blood cell RNA levels, distinguished among cognitively normal elderly, MCI, and Alzheimer's dementia participants.

For the purpose of the cross-sectional study, the investigators analyzed blood samples taken from 42 healthy adults, MCI patients, and Alzheimer's disease patients at Rambam Medical Center in Israel. After comparing the ADNP expression in the blood samples, the researchers prepared plasma samples and once again compared the protein levels.

"This study has provided the basis to detect this biomarker in routine, non-invasive blood tests, and it is known that early intervention is invaluable to Alzheimer's patients," said Prof. Gozes. "We are now planning to take these preliminary findings forward into clinical trials — to create a pre-Alzheimer's test that will help to tailor potential preventative treatments."

Builds on original research

This new research is based on Prof. Gozes' earlier investigation of neuronal plasticity and nerve cell protection at the molecular, cellular, and system level, and her discovery of novel families of proteins, including ADNP, associated with cross-communication among neural nerve cells and their support cells.

Prof. Gozes focused on the potential utility of blood ADNP levels as an Alzheimer's biomarker. "The more ADNP RNA found in the blood cells, the fewer aggregates found in the brain of elderly cognitively normal individuals," said Prof. Gozes. "Interestingly, we also found that the more ADNP in the serum, the higher the person's IQ level."

These findings are corroborated by a separate study by an independent group that found that the ADNP protein is present in lesser quantities in serum samples from select mild Alzheimer's disease patients. However, in Prof. Gozes' studies, which approach advanced Alzheimer's disease patients, the ADNP mRNA levels in white blood cells dramatically rose above the levels measured in cognitively normal individuals. This finding suggests that dramatically increased ADNP mRNA blood levels in Alzheimer's patients may be either insufficient or damaging.

"We have found a clear connection between ADNP levels in the blood and amyloid plaques in the brain," said Prof. Gozes. "Our study is the first to assess ADNP in elderly individuals at risk for Alzheimer's disease, and its results open the door for further validation in larger, more informative studies."

The researchers are currently exploring larger clinical trials to better determine the ability of ADNP to predict cognitive decline and disease progression.

Targeting the Mind/Body Connection in Stress
2/4/2016

TAU researchers combine genetic testing and brain imaging to determine vulnerability to stress

Our ability to cope with stress depends on how efficiently our body and mind regulate their response to it. Poor recovery from extremely stressful encounters can trigger post-traumatic stress disorder (PTSD), depression, or even chronic somatic dysfunction (such as pain and fatigue) in some people. Insight into the multi-level sequence of events — from cellular changes to brain function, emotional responses, and observed behavior — will help medical professionals make more informed decisions concerning interventions.

A new Tel Aviv University study published in PLOS One provides it. Researchers have used cutting-edge genetic research and brain imaging technologies to determine that the brain function responsible for regulating our stress response intertwines with molecular regulatory elements to produce a personal profile of resilience to stress. Their findings may lead to a future blood test that would facilitate preventive or early intervention in professions prone to high stress or trauma (combat soldiers and policemen, for example).

The research was led jointly by Prof. Talma Hendler of TAU's Sagol School of Neuroscience and the Director of the Functional Brain Center at Tel Aviv Sourasky Medical Center and Dr. Noam Shomron of TAU's Sagol School of Neuroscience and Sackler School of Medicine. Research for the study was conducted by TAU doctoral students Dr. Sharon Vaisvaser and Dr. Shira Modai.

The biological complexity of stress

"We can't look at one measurement at one point in time and think we have the whole picture of the stress response," Prof. Hendler explained. "This is perhaps the first study to induce stress in the lab and look at resulting changes to three levels of the stress response — neural (seen in brain imaging), cellular (measured through epigenetics), and experience (assessed through behavioral report)."

"We found that vulnerability to stress is not only related to a predisposition due to a certain gene," said Dr. Shomron. "The relevant gene can be expressed or not expressed according to a person's experience, environment, and many other context-related factors.

"This type of interaction between the environment and our genome has been conceptualized lately as the 'epigenetic process.' It has become clear that these processes are of an utmost importance to our health and well being, and are probably, in some cases, above and beyond our predispositions."

The research for this study was conducted on 49 healthy young male adults. Researchers integrated the analysis of fMRI images of brain function during an acute social stress task and also measured levels of microRNAs — small RNAs that exert potent regulatory effects — obtained in a blood test before and three hours after the induced stress. Dr. Vaisvaser explains, "Twenty minutes after the stress drill ended, we had two groups: the sustainers, those still stressed, and the recovered, those no longer stressed. The sustainers either didn't go back to baseline or took much longer to do so."

The researchers found that a specific alteration in the expression of the microRNA miR-29c was greater among the stress sustainers, implying a marker of slow recovery. Intriguingly, this change corresponded with modified connectivity of a major stress regulation node in the brain, the vento-medial prefrontal cortex (vmPFC).

The researchers were able to interpret functions in the brain through RNA molecules tested in the blood. They found that miR-29c played a mediating role, linking the enhancement of vmPFC connectivity with the anterior insula, a core node in the saliency network, sustaining the feeling of stress.

From basic research to practical treatment

"We all need to react to stress; it's healthy to react to something considered a challenge or a threat," said Prof. Hendler. "The problem is when you don't recover in a day, or a week, or more. This indicates your brain and'or body do not regulate properly and have a hard time returning to homeostasis (i.e., a balanced baseline). We found that this recovery involves both neural and epigenetic/cellular mechanisms, together contributing to our subjective experience of the stress.

"Knowing the brain metric that corresponds to such genetic vulnerability will make it possible to develop a personalized plan for brain-guided treatment based on a blood test."

"If you can identify through a simple blood test those likely to develop maladaptive responses to stress, you can offer a helpful prevention or early intervention," Dr. Shomron added.

"Conducting a collaborative interdisciplinary study is a great challenge," said Dr. Vaisvaser. "But the challenge is worth it, opening up new ways of looking at dynamics between concurrent factors contributing to the overall experience of stress."

The researchers are currently taking the study forward to look for the dynamic oscillations in the epigenetic markers of people suffering from stress disorders to confirm whether they can be modified via brain-targeted treatments.

Insulin-like Growth Factor Linked to Hippocampal Hyperactivity in Alzheimer's Disease
2/1/2016

TAU researchers find IGF-1 receptor plays critically important role regulating the transfer of information within neural circuits

The mechanisms underlying the stability and plasticity of neural circuits in the hippocampus, the part of the brain responsible for spatial memory and the memory of everyday facts and events, has been a major focus of study in the field of neuroscience. Understanding precisely how a "healthy" brain stores and processes information is crucial to preventing and reversing the memory failures associated with Alzheimer’s disease (AD), the most common form of late-life dementia.

Hyperactivity of the hippocampus is known to be associated with conditions that confer risk for AD, including amnestic mild cognitive impairment. A new Tel Aviv University study finds that the insulin-like growth factor 1 receptor (IGF-1R), the "master" lifespan regulator, plays a vital role in directly regulating the transfer and processing of information in hippocampal neural circuits. The research reveals IGF-1R as a differential regulator of two different modes of transmission — spontaneous and evoked — in hippocampal circuits of the brain. The researchers hope their findings can be used to indicate a new direction for therapy used to treat patients in the early stages of Alzheimer's disease.

The study was led by Dr. Inna Slutsky of TAU's Sagol School of Neuroscience and Sackler School of Medicine and conducted by doctoral student Neta Gazit. It was recently published in the journal Neuron. "People who are at risk for AD show hyperactivity of the hippocampus, and our results suggest that IGF-1R activity may be an important contributor to this abnormality," Dr. Slutsky concluded.

Resolving a controversy

"We know that IGF-1R signaling controls growth, development and lifespan, but its role in AD has remained controversial," said Dr. Slutsky. "To resolve this controversy, we had to understand how IGF-1R functions physiologically in synaptic transfer and plasticity."

Using brain cultures and slices, the researchers developed an integrated approach characterizing the brain system on different scales — from the level of protein interactions to the level of single synapses, neuronal connections and the entire hippocampal network. The team sought to address two important questions: whether IGF-1Rs are active in synapses and transduce signalling at rest, and how they affect synaptic function.

"We used fluorescence resonance energy transfer (FRET) to estimate the receptor activation at the single-synapse level," said Dr. Slutsky. "We found IGF-1Rs to be fully activated under resting conditions, modulating release of neurotransmitters from synapses."

While acute application of IGF-1 hormone was found to be ineffective, the introduction of various IGF-1R blockers produced robust dual effects — namely, the inhibition of a neurotransmitter release evoked by spikes, electrical pulses in the brain, while enhancement of spontaneous neurotransmitter release.

A test for Alzheimer's?

"When we modified the level of IGF-1R expression, synaptic transmission and plasticity were altered at hippocampal synapses, and an increase in the IGF-1R expression caused an augmented release of glutamate, enhancing the activity of hippocampal neurons," said Gazit.

"We suggest that IGF-1R small inhibitors, which are currently under development for cancer, be tested for reduction aberrant brain activity at early stages of Alzheimer's disease," said Dr. Slutsky.

The researchers are currently planning to study how IGF-1R signaling controls the stability of neural circuits over an extended timescale.

Dr. Irena Vertkin, Dr. Ilana Shapira, Edden Slomowitz, Maayan Sheiba and Yael Mor of Dr. Slutsky's lab at TAU, and Martin Helm and Prof. Silvio Rizzoli of the University of Göttingen in Germany, contributed to this research.

Post-term Delivery Raises Risk of Complications and Illness for Newborns
1/19/2016

TAU researcher finds infants born past 42 weeks are far more likely to be admitted to neonatal ICU

While pregnancy is considered full-term at 40 weeks, only some 5 percent of women actually give birth on their predetermined due date. Most OBGYNs recommend more frequent and more vigilant monitoring after 40 weeks and sometimes the artificial induction of labor. But many pregnant women refuse induction due to the risk of stress to the fetus or increased likelihood of requiring a caesarean section.

A new Tel Aviv University study has found that post-term deliveries, even among low-risk pregnancies, are associated with increased short-term risks to newborns, including illnesses and infections, which land them twice as frequently in Neonatal Intensive Care Units (NICUs). The study isolates the post-term due date as a single, influential risk factor for the first time.

The research was led by Dr. Liran Hiersch of TAU's Sackler Faculty of Medicine and Rabin Medical Center in Israel, together with Prof. Nehama Linder, also of Sackler and director of Rabin Medical Center's Department of Neonatology, and Dr. Nir Melamed of Rabin Medical Center. It was published in December in the Archives of Disease in Childhood, Fetal and Neonatal Edition.

Countering fear with fact

"There are women who refuse induction of labor, even more than two weeks past their due date," said Dr. Hiersch. "Without the relevant data, it is difficult for doctors to convince them otherwise. Maybe now, with this research and further studies in hand, we can convince them that even though their pregnancies had experienced no complications — and they are being monitored, say, every three days — they're potentially risking infection, illness and other unforeseen complications by refusing medical intervention."

Dr. Hiersch and his team examined the electronic records of all women who delivered babies at Rabin Medical Center over a five-year period. They extracted the records of approximately 23,500 women with a single fetus and without pregnancy complications who delivered at 39-44 weeks of gestation. Then they compared the neonatal outcomes of three groups: neonates born at 39-40 weeks; neonates born at 41 weeks; and neonates born at 42 weeks and later, or "post-date pregnancies."

"Although previous studies demonstrated an increased risk of complications for newborns born in the post-term period, most of these studies included women with pregnancy-related complications, such as small fetuses, hypertension and diabetes mellitus," said Dr. Hiersch. "The isolated effect of the prolonged pregnancy could not be determined. For this reason, we included in our analysis only women with low-risk pregnancies in order to more clearly determine the effect of gestational age at delivery on neonatal outcome."

The researchers only addressed women who gave birth to live infants, excluding all cases of still-borns, in order to effectively isolate the influence of time of delivery on the infant. They found that infants born past 42 weeks had approximately twice the risk of contracting infections, experiencing respiratory difficulties and being admitted to NICUs than those born at 39-40 weeks.

A warning to new mothers

"Our study implies that even in otherwise low-risk pregnancy, it is advisable not to postpone delivery beyond 42 weeks," said Dr. Hiersch. "Therefore, it is reasonable to offer induction of labor to women reaching that time of pregnancy and maybe a little earlier."

In the study, the researchers addressed the complications that occur immediately following birth. They are now exploring a larger study that addresses whether post-term deliveries put infants at risk for developmental difficulties later in life.

New Microscopy May Identify Best Sperm Cells
1/13/2016

TAU researcher's cutting-edge innovation pinpoints top candidates for assisted reproductive technology

Watch a video with Dr. Shaked

Photo: Dr. Natan ShakedMore than 10% of American women aged 15-44 struggle to conceive or maintain full-term pregnancies, according to the Centers for Disease Control and Prevention (CDC). Assisted reproductive technology (ART), through which eggs are fertilized with sperm in a lab and then returned to a woman's uterus, is often the last resort for reproductively-challenged couples. But the physical, emotional, and financial toll they exact is high because the success rates of ART treatments are low — only 20-30%, according to the CDC.

New microscopic technology from Tel Aviv University promises to be a game-changer in the field of reproductive assistance. A team of TAU scientists have devised a new method of microscopy allowing scientists to perform clinical sperm analysis without the use of staining, which can affect the viability of sperm samples.

Sperm cells are nearly transparent under standard microscopy methods. Their optical properties differ only slightly from those of their surroundings, resulting in a weak image contrast. Sperm cells cannot be stained, if fertilization is the goal, because the process might damage the resulting fetuses. The challenge is to pinpoint strong sperm candidates without staining, while still being able to characterize their viability.

The research, recently published in Fertility and Sterility, was led by Dr. Natan Shaked, PhD, of the Department of Biomedical Engineering at TAU's Faculty of Engineering and his masters student, Dr. Miki Hifler, MD. Sperm cells for the study were obtained from the Male Fertility Clinic at Chaim Sheba Medical Center in Israel.

Improving the picture

There are two effective ART methods available today. The first is in vitro fertilization (IVF), in which a woman is treated with drugs that cause her ovaries to produce multiple eggs. These are placed in a Petri dish with a man's sperm for fertilization for three to five days, then implanted in the woman's uterus. The second is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected into a mature egg and then transferred to a woman's uterus. Dr. Shaked’s method is applicable to both methods, but is especially helpful in ICSI.

"Until now, clinicians have chosen the 'best' sperm according to their speed, but speed is not necessarily an indicator of DNA quality," Dr. Shaked says. "Some of the best sperm candidates are slow or even immobile because their tails have malfunctioned. If we can better determine the full structure and composition of the sperm, the success rate of ART treatments will be higher. Success means more births without congenital defects. In cases where sample staining is impossible — such as in vitro fertilization and ICSI — our device provides a promising new direction."

A black box for better screening

His new device, a small "black box" attached to an existing microscope, is smaller, cost-effective, and easier to align than conventional interferometric imaging methods. It is joined to new automated software that produces a thickness map of the sample and other physical parameters to evaluate the sperm's viability in real time and, at a cost of only $1,000, can be used in any doctor's office already outfitted with a conventional microscope.

Dr. Shaked believes his new imaging process, which harnesses phase imaging methods to record the passage of light through a sample to assess its thickness, can quantify the quality of sperm used in ART, leading to more successful ART treatments.

The new method was developed with the support of Ramot, TAU's technology transfer company The team recently submitted their patent on the technology and are poised to begin clinical trials next year on IVF patients in Israel.

Photo: Dr. Natan Shaked, Tel Aviv University

Smokers Diagnosed with Pneumonia Found to Have Higher Risk of Lung Cancer
1/7/2016

TAU study says nearly 10 percent of smokers hospitalized for pneumonia are diagnosed with lung cancer within one year

Lung cancer is the leading cause of cancer mortality in the United States, with a five-year survival rate of just 17 percent. Smoking causes approximately 85 percent of all lung cancer cases, only 15 percent of which are diagnosed at an early stage. Most efforts to obtain early diagnosis have been unsuccessful, largely due to the highly aggressive nature of the disease.

A new study from Tel Aviv University and Rabin Medical Center researchers proposes that screening heavy smokers admitted to the hospital with community-acquired pneumonia could facilitate the early diagnosis of lung cancer and thereby reduce the incidence of mortality. Heavy smokers who are diagnosed with pneumonia are one of the highest lung cancer risk groups — and therefore should be considered for early screening by chest-computer tomography.

The research was led by Daniel Shepshelovich, MD, of TAU's Sackler Faculty of Medicine and Rabin Medical Center and was recently published in the American Journal of Medicine.

An early warning system

"Lung cancer is truly aggressive," said Dr. Shepshelovich. "The only chance of recuperation is if it's caught before it begins to cause any symptoms at all. The idea is to find the tumor well in advance. Previous studies have shown that a low-dose radiation CT scan conducted once a year on heavy smokers has the potential to lower lung cancer mortality rates. But this requires huge resources, and we still don't know how it will perform in real-world conditions, outside of strictly conducted clinical trials.

"We want to develop a more realistic and cost-effective strategy targeting a particularly high-risk population," he said.

Dr. Shepshelovich and his team examined the files of 381 admissions of heavy smokers with community-acquired pneumonia — a form of pneumonia contracted by a person with little contact with the health care system — at Rabin Medical Center between 2007-2011. They reviewed every patient's medical file for patient demographics, smoking history, lung cancer risk factors and the anatomical location of the pneumonia. The data was then crosschecked with the database at Israel's National Cancer Registry for new diagnoses of cancer.

The researchers found that out of 381 admissions of heavy smokers with pneumonia, 31 — 9 percent, a figure that surprised the researchers — were diagnosed with lung cancer within a year of being hospitalized. Lung cancer incidence was found to be significantly higher in patients admitted with upper lobe pneumonia (23.8%). They also found that the lung cancer was located in the lobe affected by pneumonia in 75.8% of cases.

"We discovered that smokers hospitalized with pneumonia are diagnosed with cancer after the infection because often the cancer masquerades as pneumonia, physically obstructing the airway and creating such an infection," said Dr. Shepshelovich. "Considering that only 0.5-1% of smokers without pneumonia have a chance of being diagnosed with lung cancer every year, the fact that 9% of our study group developed lung cancer is alarming."

Extending the lives of cancer patients

"The current diagnostic methods in place — chest X-rays, sputum cytology — sometimes find the cancerous tumors, but they do not change mortality rates," Dr. Shepshelovich said. "In other words, people are aware that they have cancer for longer periods of time, but do not recover. This is not a solution.

"Smokers admitted to the hospital with pneumonia should be considered for chest-computer tomography," he continued. "Only 15 percent of lung cancer cases are detected at an early stage. We want to increase that number in order to reduce mortality or, at the very least, extend lives."

The researchers are currently considering a larger nationwide retrospective study on the subject.

Novel RNA Delivery System May Treat Incurable Blood Cancers
1/5/2016

TAU researchers develop unique system to deliver therapy at site of Mantle Cell Lymphoma

With a median survival rate of just five to seven years, Mantle Cell Lymphoma (MCL) is considered the most aggressive known blood cancer — and available therapies are scarce. Three thousand Americans are diagnosed with MCL every year, and despite progress in personalized therapies to treat metastases elsewhere in the body, systemic therapeutic drug delivery to cancerous blood cells continues to challenge the world of cancer research.

A new study by Tel Aviv University researchers offers tangible hope of curing the currently incurable blood cancer — and others like it. The revolutionary system was found to successfully halt the proliferation of a cancer-related protein in white blood cells in both animal models and samples taken from MCL patients.

The research was led by Prof. Dan Peer of TAU's Department of Cell Research and Immunology and conducted by TAU PhD students Shiri Weinstein and Itai Toker, in collaboration with Prof. Pia Raanani of Rabin Medical Center and Prof. Arnon Nagler of Sheba Medical Center. The study was published in the early edition of the Proceedings of the National Academy of Sciences USA (PNAS).

A "Zip code identifier" system for cancer drug delivery

"MCL has a genetic hallmark," said Dr. Peer. "In 85 percent of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression — a 3,000- to 15,000-fold increase — of Cyclin D1, a protein that controls the proliferation of cells. Downregulation of Cyclin D1 using siRNAs is a potential therapeutic approach to this malignancy."

The research validates a novel strategy developed two years ago in Dr. Peer's lab that involved small interfering RNAs (siRNAs). The radical new delivery system harnesses nanoparticles coated with "GPS" antibodies that navigate toward the location of the cancerous cells, where they then offload Cyclin D1-blockers in the form of siRNAs.

For the purpose of the research, the scientists designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that were taken up by human MCL cells in the bone marrow of affected mice. When loaded with siRNAs against Cyclin D1, the targeting LNPs induced gene silencing in MCL cells and prolonged the survival of tumor-bearing mice with no observed adverse effects.

"In MCL, Cyclin D1 is the exclusive cause of the over-production of B Lymphocytes, the cells responsible for generating antibodies," said Dr. Peer. "This makes the protein a perfect target for RNA therapy by siRNAs. Normal, healthy cells don't express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty Cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off."

The new research highlights the therapeutic potential of Cyclin D1 therapy in MCL and presents a novel RNA delivery system that opens new therapeutic opportunities for treating MCL and other similar B-cell malignancies.

Making cancer personal

"This research makes a definite contribution to the revolution of personalized medicine, whereby you tailor the drug based on the genetic profile of patient," said Dr. Peer. "In this case, MCL is a disease with a specific genetic hallmark, so you can sequence the patient to identify the mutation(s), and design RNA blockers to be placed inside a nanovehicle.

"While the targeting antibodies — the 'GPS' — can be used to target many different B-cell malignancies, the drug itself is designed to silence this specific disease. However, the delivery system can be used to accommodate any disease with a genetic profile. This could be the future. We are seeing it happen before our very eyes."

The research was supported in part by the National Institutes of Health, The Israel Cancer Association, The Leona M. and Harry B. Helmsley Charitable Trust, the Lewis Trust and the Dotan Center for Haematological Research at TAU. The researchers intend to take the study further and translate these findings into clinical trials pending additional funding.

Rapid Eye Movements in Sleep Reset Dream "Snapshots"
8/12/2015

TAU, UCLA researchers find eye movements during REM sleep reflect brain activity patterns associated with new images

Rapid Eye Movement (REM) sleep, the period in which we experience vivid dreams, was discovered by scientists in the 1950s. Because REM sleep is associated with dreaming, on the one hand, and eye movement, on the other, it has been tempting to assume that each movement of the eye is associated with a specific dream image. But despite decades of intense research by leading international scientists, this intuitive hypothesis has remained unproven.

A new study based on rare neuronal data offers the first scientific evidence of the link between rapid eye movement, dream images, and accelerated brain activity. When we move our eyes in REM sleep, according to the study, specific brain regions show sudden surges of activity that resemble the pattern that occurs when we are introduced to a new image — suggesting that eye movements during REM sleep are responsible for resetting our dream "snapshots."

The research, published this week in Nature Communications, was led by Dr. Yuval Nir of Tel Aviv University's Sackler Faculty of Medicine in collaboration with TAU's Prof. Itzhak Fried, also of UCLA and Tel Aviv Medical Center; Thomas Andrillon of the Laboratoire de Sciences Cognitives et Psycholinguistique in Paris; and Dr. Giulio Tononi and Dr. Chiara Cirelli of the University of Wisconsin-Madison.

Deep down in the brain

"Our goal was to examine what happens deep in the human brain during REM sleep, specifically when rapid eye movements occur," said Dr. Nir. "Prof. Fried's trailblazing research with epilepsy patients at UCLA offered a unique opportunity to collect the necessary data — the activity of neurons located deep inside the human brain."

The research for the study was conducted on 19 epileptic patients at the UCLA Medical Center, who required invasive monitoring of brain activity prior to potential surgical excision of seizure-causing areas of the brain. Electrodes were implanted deep inside the patients' brains to monitor their brain activity over the course of 10 days. These electrodes were able to provide the rare data needed to prove the link between eye movements, dream imagery, and brain activity.

"We focused on the electrical activities of individual neurons in the medial temporal lobe, a set of brain regions that serve as a bridge between visual recognition and memories," said Dr. Nir. "Prof. Fried's prior research had shown that neurons in these regions become active shortly after we view pictures of famous people and places, such as Jennifer Aniston or the Eiffel Tower — even when we close our eyes and imagine these concepts."

In addition to monitoring the patients' brain activity via intracranial electrodes, the researchers also recorded scalp EEG, muscle tone, and eye movements to identify periods of REM sleep and detect the precise moment of each rapid eye movement.

Images, awake and asleep

"The electrical brain activity during rapid eye movements in sleep were highly similar to those occurring when people were presented with new images," said Dr. Nir. "Many neurons — including those in the hippocampus — showed a sudden burst of activity shortly after eye movements in sleep, typically observed when these cells are 'busy' processing new images."

"The research findings suggest that rapid eye movements represent the moment the brain encounters a new image in a dream, similar to the brain activity exhibited when one encounters visual images while awake," Prof. Fried said.

"How and why eye movements occur are important," said Dr. Nir. "And these moments represent privileged windows of opportunity for the study of brain activity."

A Single Interrupted Pregnancy May Impact Later Deliveries, New TAU Research Finds
8/11/2015

Researchers say only one incident of abortion or miscarriage can have repercussions for subsequent pregnancies

It has been well established that women who have had several abortions or miscarriages are likely to face a slightly higher risk of complications in subsequent pregnancies. They may experience vaginal bleeding during early pregnancy, preterm birth, low fetal birth weight, and placenta-related complications. Women with a medical history of several interrupted pregnancies are usually advised to take extra precautions to ensure healthy full-term pregnancies later in life.

New Tel Aviv University research published in the Journal of Maternal-Fetal and Neonatal Medicine finds that a single incidence of abortion or miscarriage alone has the potential to impact subsequent pregnancies in a woman's life. The study suggests that women who have experienced a single pregnancy loss are about 30 percent more likely to suffer complications in subsequent pregnancies than women who have never miscarried or had a single abortion.

According to the research, women who have experienced a single first-trimester interruption at one point in their medical history run a higher risk of requiring labor inductions and caesarean sections and of experiencing retained placentas. The study was led by Dr. Liran Hiersch and Prof. Yariv Yogev of TAU's Sackler Faculty of Medicine and the Helen Schneider Hospital for Women at Rabin Medical Center, Petah Tikva, Israel.

Earlier studies flawed, researchers say

In their retrospective analysis of 15,000 deliveries at Rabin Medical Center over the last five years, the researchers compared the pregnancy outcomes of nulliparous women (who experienced a single previous first-trimester interruption) with those of primigravidas (women in their first pregnancies who had neither prior deliveries nor abortions).

According to the researchers, previous studies exploring the effect of a single pregnancy loss on subsequent pregnancy outcome were based on incorrect assumptions. They compared outcomes between women who never gave birth before and those whose first pregnancy ended in a normal delivery, for example.

"A history of normal pregnancy is considered protective from adverse outcomes, so this group already had an advantage over those who had pregnancy loss in their past," said Dr. Hiersch, who assessed only those women who delivered their first infants and compared them with those who had only one or no pregnancy loss in their past. "This, I believe, was the main advantage of the methodology of our study in comparison to previous reports.

"It is important to emphasize that a single pregnancy loss is a very common event during a woman's reproductive years. In most cases it has no effect on future fertility or pregnancy outcome," Dr. Hiersch continued. "In addition, although we found that a single early pregnancy loss was associated with an increased risk for subsequent adverse pregnancy outcome, the effect was mild. Our findings should be taken into account together with other parameters when assessing the risk for adverse outcome."

"We hope this study will be incorporated in the usual risk assessments," said Dr. Hiersch. "Doctors should know there is another element to factor in when assisting a woman before labor." The researchers are currently planning to conduct a major prospective study on the subject.

TAU Researcher Discovers Trigger of Deadly Melanoma
8/3/2015

Study pinpoints cause of melanoma transformation within the epidermis

Skin cancer is the most common of all cancers, and melanoma, which accounts for 2% of skin cancer cases, is responsible for nearly all skin cancer deaths. Melanoma rates in the US have been rising rapidly over the last 30 years, and although scientists have managed to identify key risk factors, melanoma's modus operandi has eluded the world of medical research.

A new Tel Aviv University study published in Molecular Cell sheds light on the precise trigger that causes melanoma cancer cells to transform from non-invasive cells to invasive killer agents, pinpointing the precise place in the process where “traveling” cancer turns lethal. The research was led by Dr. Carmit Levy of the Department of Human Genetics and Biochemistry at TAU's Sackler School of Medicine and conducted by a team of researchers from TAU, the Technion Institute of Technology, the Sheba Medical Center, the Institut Gustave Roussy and The Hebrew University of Jerusalem.

If melanoma is caught in time, it can be removed and the patient's life saved. But once melanoma invades the bloodstream, turning metastatic, an aggressive treatment must be applied. When and how the transformation into aggressive invasion took place was until now a mystery.

Understanding the skin

"To understand melanoma, I had to obtain a deep understanding about the structure and function of normal skin," said Dr. Levy, "Melanoma is a cancer that originates in the epidermis, and in its aggressive form it will invade the dermis, a lower layer, where it eventually invades the bloodstream or lymph vessels, causing metastasis in other organs of the body. But before invading the dermis, melanoma cells surprisingly extend upward, then switch directions to invade.

"It occurred to me that there had to be a trigger in the microenvironment of the skin that made the melanoma cells 'invasive,'" Dr. Levy continued. "Using the evolutionary logic of the tumor, why spend the energy going up when you can just use your energy to go down and become malignant?"

After collecting samples of normal skin cells and melanoma cells from patients at hospitals around Israel, the researchers mixed normal and cancerous cells and performed gene analysis expression to study the traveling cancer's behavior. They found that, completely independently of any mutation acquisition, the microenvironment alone drove melanoma metastasis.

"Normal skin cells are not supposed to 'travel,'" said Dr. Levy. "We found that when melanoma is situated at the top layer, a trigger sends it down to the dermis and then further down to invade blood vessels. If we could stop it at the top layer, block it from invading the bloodstream, we could stop the progression of the cancer."

A new way of saving lives

The researchers found that the direct contact of melanoma cells with the remote epidermal layer triggered an invasion via the activation of "Notch signaling," which turns on a set of genes that promotes changes in melanoma cells, rendering them invasive. According to the study, when a molecule expressed on a cell membrane — a spike on the surface of a cell, called a ligand — comes into contact with a melanoma cell, it triggers the transformation of melanoma into an invasive, lethal agent.

"When I saw the results, I jumped out of the room and shouted, 'We got it!'" Dr. Levy said. "Now that we know the triggers of melanoma transformation and the kind of signalling that leads to that transformation, we know what to block. The trick was to solve the mystery, and we did. There are many drugs in existence that can block the Notch signalling responsible for that transformation. Maybe, in the future, people will be able to rub some substance on their skin as a prevention measure."

Dr. Levy is continuing to explore the research with the end goal of providing medical professionals with another tool of analysis of different stages of melanoma. "Melanoma is a cancer with a very long gestation period," said Dr. Levy. "If you can provide a simple kit with precise answers, you can catch it at the beginning stage and hopefully save lives."

Diabetics Who Skip Breakfast Provoke Hazardous Blood Sugar Spikes
7/28/2015

Type-2 diabetics who "fast" until noon risk day-long consequences, says TAU researcher

More and more Americans on-the-go are skipping the "most important meal of the day," not eating until lunch. This tendency to miss breakfast has already been linked to the growing epidemic of obesity and cardiovascular problems in the US — and it may put the health of diabetics at risk as well.

Very little was known regarding the effect of skipping breakfast on the health of diabetics — until now. A new Tel Aviv University study reveals the substantial impact of skipping breakfast on type-2 diabetics. "Fasting" until noon triggers major blood sugar spikes (postprandial hyperglycemia) and impairs the insulin responses of type-2 diabetics throughout the rest of the day, researchers say.

The study was conducted by TAU's Prof. Daniela Jakubowicz and Prof. Julio Wainstein of the Wolfson Medical Center's Diabetes Unit, Prof. Oren Froy of the Hebrew University of Jerusalem, and Prof. Bo Ahrén of Lund University in Sweden. It was recently published in Diabetes Care and presented at the American Diabetes Association meeting in Boston in June 2015.

The most important meal for diabetics?

"Despite the fact that many studies have previously demonstrated the benefits of a high-caloric breakfast for weight loss and to regulate the glucose metabolism, very little was known regarding the effect of skipping breakfast on glycemic spikes after meals throughout the entire day," said Prof. Jakubowicz. "It is quite remarkable that, for type-2 diabetic individuals, the omission of breakfast is associated with a significant increase in all-day blood sugar spikes and of HbA1C, which represents average blood glucose levels over the preceding three months."

The clinical study was conducted on 22 type-2 diabetics who averaged 56.9 years old, with a mean Body Mass Index of 28.2 kg/m2. Over the course of two days, the participants consumed precisely the same number of calories and the same balanced meal — milk, tuna, bread, and a chocolate breakfast bar — for lunch and dinner. The only difference was that one day they ate breakfast and the second day they fasted until lunch.

"We theorized that the omission of breakfast would not be healthy, but it was surprising to see such a high degree of deterioration of glucose metabolism only because the participants did not eat breakfast," said Prof. Jakubowicz. The researchers found that participants experienced extraordinary glucose peaks of 268 mg/dl after lunch and 298 mg/dl after dinner on days they skipped breakfast, versus only 192 mg/dl, and 215 mg/dl after eating an identical lunch and dinner on days they ate breakfast.

"This means that reducing the amount of starch and sugars in lunch and dinner will have no effect on reducing elevated glucose levels if diabetic individuals also skip breakfast," said Prof. Jakubowicz.

Improving the "memory" of beta cells

According to the researchers, pancreatic beta cells which produce insulin lose their "memory" due to the prolonged period between one evening's dinner and the next day's lunch. In other words, they "forget" their vital role. Therefore it takes additional time after lunch for the beta cells to recover, causing small and delayed insulin responses and resulting in an exaggerated elevation of blood glucose levels throughout the day. Another factor is that fasting until lunch increases the fatty acids in our blood, which renders insulin ineffective in reducing blood glucose levels.

"In light of our study, we highly recommend that type-2 diabetics not skip breakfast, because it causes major damage to the beta cell function and leads to high sugar levels, even if they don’t overeat at lunch and dinner," said Prof. Jakubowicz. The researchers are planning to conduct a similar study on type-1 diabetics, who require daily insulin treatment.

The Medical Odyssey of an Undiagnosed Child
7/21/2015

Discovery by TAU, Antwerp University researchers of the mutations of a neuroprotective protein finds expression in the story of a 7-year-old patient

Children born with ADNP-related autism syndrome suffer from a heart-breaking combination of ambiguous developmental problems injurious to both their physical health and cognitive functioning. For parents, the mystery surrounding their infants' suffering can be even more agonizing than the syndrome itself, which has no known cure.

Recent research from Tel Aviv University and the University of Antwerp is easing some of that agony. Activity-dependent neuroprotective protein (ADNP), discovered by TAU's Prof. Illana Gozes 15 years ago, has now been shown by Prof. Frank Kooy at the University of Antwerp to be mutated in autism, causing developmental and cognitive delays, speech and feeding difficulties, heart abnormalities, and a laundry list of other debilitating symptoms.

"Nothing is as frightening as having a son with an unknown medical/genetic condition," writes Sandra Bedrosian Sermone, the mother of Tony, a child with the syndrome, in a recent Journal of Molecular Neuroscience article. "What does this mean? Will he be normal? Can they fix this? Will he die? Is his twin brother OK? Was this because of me? It was agonizing waiting to get the results of that first genetic test. But the call came, and it would be the first of many in this journey of an undiagnosed child."

A 15-year-old breakthrough

Prof. Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and former director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of TAU's Sagol School of Neuroscience, first discovered ADNP as well its crucial role in brain formation, learning, and memory. For 15 years, she has been leading the crusade to understand ADNP and to develop a drug reversing the effects of ADNP deficiencies, which have been linked to schizophrenia, Alzheimer's disease, and dementia, among other neurological and psychiatric diseases.

Tony was diagnosed at the age of five with a new mutation of ADNP previously seen in only 10 other children around the world. The family's "aha" moment, as Sermone calls it, occurred after complete exome sequencing conducted at Duke University revealed the specific genetic mutation.

While the diagnosis was a blow to Sermone and her family, knowledge is power. Through Sermone's Facebook page, more and more people have gained awareness of the syndrome and its probable cause. "Our journeys have all been different in ways, but identical in others," writes Sermone. "[My son] has earned the name 'Superman,' because he is the strongest, toughest, sweetest little man on the planet, and he is helping other children every day by being a part of this new genetic testing and syndrome research with the team and doctors who discovered it."

Creating public awareness

According to Prof. Gozes, who is intimately familiar with Tony's case and that of other ADNP children, greater public awareness of the syndrome will more likely lead to the development of more appropriate care in the future.

"I hope it will become a routine screening in the future for undiagnosed cases that come to the clinic," said Prof. Gozes. "Teaming up with Prof. Kooy's Cognitive Genetics group in Antwerp and other leading researchers around the world will promote our understanding. Early diagnosis is key so these children can obtain the right training and the right help, and so the parents don't feel so alone in the world. The more we understand about the mutation, the better we can understand why on earth the gene is susceptible to mutations."

No Bones About It: Cannabis May Be Used to Treat Fractures
7/16/2015

TAU researcher finds non-psychotropic compound in marijuana can help heal bone fissures

Cannabis — marijuana, hashish — was used as a go-to medical remedy by societies around the world for centuries. But the therapeutic use of marijuana was banned in most countries in the 1930s and '40s due to a growing awareness of the dangers of addiction. The significant medical benefits of marijuana in alleviating symptoms of such diseases as Parkinson's, cancer, and multiple sclerosis have only recently been reinvestigated.

A new study published in the Journal of Bone and Mineral Research by Tel Aviv University and Hebrew University researchers explores another promising new medical application for marijuana. According to the research, the administration of the non-psychotropic component cannabinoid cannabidiol (CBD) significantly helps heal bone fractures. The study, conducted on rats with mid-femoral fractures, found that CBD — even when isolated from tetrahydrocannabinol (THC), the major psychoactive component of cannabis — markedly enhanced the healing process of the femora after just eight weeks.

The research was led jointly by Dr. Yankel Gabet of the Bone Research Laboratory at the Department of Anatomy and Anthropology at TAU's Sackler Faculty of Medicine and the late Prof. Itai Bab of Hebrew University's Bone Laboratory.

Undeniable clinical potential

The same team, in earlier research, discovered that cannabinoid receptors within our bodies stimulated bone formation and inhibited bone loss. This paves the way for the future use of cannabinoid drugs to combat osteoporosis and other bone-related diseases.

"The clinical potential of cannabinoid-related compounds is simply undeniable at this point," said Dr. Gabet. "While there is still a lot of work to be done to develop appropriate therapies, it is clear that it is possible to detach a clinical therapy objective from the psychoactivity of cannabis. CBD, the principal agent in our study, is primarily anti-inflammatory and has no psychoactivity."

According to Dr. Gabet, our bodies are equipped with a cannabinoid system, which regulates both vital and non-vital systems. "We only respond to cannabis because we are built with intrinsic compounds and receptors that can also be activated by compounds in the cannabis plant," he said. The researchers found that the skeleton itself is regulated by cannabinoids. Even the addition of a non-psychogenic compound acting outside of the brain can affect the skeleton.

Separating the components out

"We found that CBD alone makes bones stronger during healing, enhancing the maturation of the collagenous matrix, which provides the basis for new mineralization of bone tissue," said Dr. Gabet. "After being treated with CBD, the healed bone will be harder to break in the future."

The researchers injected one group of rats with CBD alone and another with a combination of CBD and THC. After evaluating the administration of THC and CBD together in the rats, they found CBD alone provided the necessary therapeutic stimulus.

"We found CBD alone to be sufficiently effective in enhancing fracture healing," said Dr. Gabet. "Other studies have also shown CBD to be a safe agent, which leads us to believe we should continue this line of study in clinical trials to assess its usefulness in improving human fracture healing."

High-pressure Oxygen Can Effectively Treat Fibromyalgia
7/14/2015

TAU study finds new treatment for pain syndrome reduces or eliminates need for medication

Fibromyalgia is almost impossible to diagnose. The chronic pain syndrome strikes an estimated 1 in 70 Americans, most of them women. The disorder is often triggered by head trauma, a neurological infection, or severe emotional stress, and is characterized by symptoms such as musculoskeletal pain, fatigue, memory loss and mood swings. Fibromyalgia is often mistaken for other culprits and most patients suffer months, even years, of unrelenting pain before being properly diagnosed. And once diagnosed, patients enjoy little respite because few therapies have been found to be effective in assuaging its symptoms.

A new study published in PLoS ONE by Tel Aviv University researchers may turn the tide. The research found that women with fibromyalgia were able to drastically reduce, or even eliminate, their use of pain medication following hyperbaric oxygen treatment. The study was led by the late Prof. Eshel Ben-Jacob of TAU's School of Physics and Astronomy and Rice University's Center for Theoretical Biological Physics, Dr. Shai Efrati of TAU's Sagol School of Neuroscience and Assaf Harofeh Medical Center, and Prof. Dan Buskila from Soroka Medical Center, and was conducted by a team of scientists from TAU, Rice University, Assaf Harofeh Medical Center, Ben-Gurion University, and Tel Aviv Sourasky Medical Center.

The TAU researchers believe they have also identified the primary factor causing fibromyalgia: the disruption of the brain mechanism for processing pain. "As a physician, the most important finding for me is that 70 percent of the patients could recover from their fibromyalgia symptoms," said Dr. Efrati. "The most exciting finding for the world of research, however, is that we were able to map the malfunctioning brain regions responsible for the syndrome."

A high-pressure solution

Hyperbaric oxygen chambers expose patients to pure oxygen at higher-than-atmospheric pressures and are commonly used to treat patients with embolisms, burns, carbon monoxide poisoning, and decompression sickness.

The clinical trial, which exposed participants to two months of hyberbaric oxygen therapy, found significant changes in the brain activity and symptoms of 70 percent of participants. The trial involved 60 women who had been diagnosed with fibromyalgia at least two years earlier. Half of the 48 patients who completed the therapy received 40 hyperbaric oxygen treatments — 90-minute treatments exposing patients to pure oxygen at twice the atmospheric pressure, five days a week over the course of two months.

The successful treatment enabled patients to drastically reduce or even eliminate their use of pain medications. "The intake of the drugs eased the pain but did not reverse the condition. But hyperbaric oxygen treatments did reverse the condition," said Dr. Efrati, who added that the findings warrant further study.

Getting to the root of the problem

"The results are of significant importance," Dr. Efrati said. "Hyperbaric oxygen treatments are designed to address the actual cause of fibromyalgia — the brain pathology responsible for the syndrome. It means that brain repair, including neuronal regeneration, is possible even for chronic, long-lasting pain syndromes, and we can and should aim for that in any future treatment development."

The researchers did find some discrepancies among patients with different fibromyalgia catalysts. When fibromyalgia was triggered by a traumatic brain injury, for example, they witnessed a complete resolution without any need for further treatment. But when the trigger was attributed to other causes, such as fever-related diseases, patients required periodic maintenance therapy.

The researchers are continuing to conduct comprehensive studies on the renewal of brain tissue under hyperbaric conditions.

Great Strides: Smartphone App May Prevent Dangerous Freezing of Gait in Parkinson’s Patients
6/25/2015

Joint TAU/European Union project focuses on major cause of disability

Many patients in the latter stage of Parkinson's disease are at high risk of dangerous, sometimes fatal, falls. One major reason is the disabling symptom referred to as Freezing of Gait (FoG) — brief episodes of an inability to step forward that typically occurs during gait initiation or when turning while walking. Patients who experience FoG often lose their independence, which has a direct effect on their already degenerating quality of life. In the absence of effective pharmacological therapies for FoG, technology-based solutions to alleviate the symptom and prolong the patients' ability to live independently are desperately being sought.

CuPID is a project three years in the making and the product of an eight-member European Union-funded consortium including researchers at Tel Aviv University. It strives to provide personalized rehabilitation for patients with Parkinson's disease who experience FoG or other gait disturbances. CuPID is a home-based, personalized rehabilitation tool in the form of a smartphone app that harnesses wearable sensors, audio biofeedback, and external cueing to provide intense motivational training tailored to each patient. The results are monitored remotely by medical professionals, who provide quality care while enhancing patient compliance.

The CuPID app just completed its pilot run and is being fine-tuned for more widespread use. It utilizes small sensors placed on a patients' shoes that measure a person’s gait in "real-time." If certain deviations from a pre-set norm emerge, an audio message alerts the patient to change his or her walking pattern immediately to avoid a dangerous situation.

"FoG is a leading cause of disability in patients with Parkinson's disease," said Prof. Jeffrey Hausdorff of TAU's Sackler Faculty of Medicine and the Center for Movement, Cognition, and Mobility at Tel Aviv Sourasky Medical Center (TASMC). Prof. Hausdorff is the lead investigator on the Israeli team. "It often occurs during 'walking transitions' associated with turning, starting, stopping, and moving in open spaces. It can also occur when people approach narrow spaces, such as doors or elevators, and in crowded places. Recognizing such situations is a very powerful key for prevention — and this is one of the features of this program."

Prof. Hausdorff and his team at Tel Aviv Medical Center conducted a pilot study on 40 subjects: 20 patients with Parkinson's disease who used the CuPid app and 20 patients who carried out conventional exercises and did not use the app. The results are promising and the investigators are currently exploring the possibility of a larger follow-up study to further demonstrate the app's efficacy.

Repairing a "short circuit"

Dr. Anat Mirelman, also of TAU and TASMC, co-directed the project. She explained that FoG episodes resemble a short circuit in the brain, rendering it unable to generate the appropriate stepping pattern, often leaving the patient in an untenable and frustrating situation. The app is designed to circumvent that difficulty.

"There are two modes to the app," said Dr. Mirelman. "The first improves the overall gait pattern — 'keep it up, you are walking well,' says a virtual physical therapist — and the positive feedback while walking actually helps the patient emotionally as well as functionally. If the gait pattern needs adjustments, the app will let the user know. The second mode helps patients avoid and free themselves of FoG if they are already stuck. We believe, and we have already seen in clinical trials here at the hospital, that this has the potential to improve the quality of life for these patients quite dramatically.

"FoG reduces patients' independence. Patients become afraid of walking by themselves and this leads to self-imposed restrictions in mobility," Dr. Mirelman continued. "When their feet get stuck to the ground, their bodies lunge forward — it's very frightening. People often end up in wheelchairs, and this is a vicious cycle, as it places more reliance on the assisted-living infrastructure."

"The program now integrates the expertise of a patient's physical therapist, who establishes what is considered a patient's 'normal' or 'strong' walking pattern," said Prof. Hausdorff. "It's unobtrusive and has the potential to reduce dependence on Parkinson's medication that has detrimental side effects. How much or how often the app is used depends on how advanced the disease is, but since the system is so small and non-invasive, it can be used just about anywhere. It's exciting to think of the potential of long-term use."

Programming DNA to Reverse Antibiotic Resistance in Bacteria
6/4/2015

TAU researcher's novel strategy may sensitize bacteria to antibiotics to selectively kill antibiotic-resistant bacteria

At its annual assembly in Geneva last week, the World Health Organization approved a radical and far-reaching plan to slow the rapid, extensive spread of antibiotic resistance around the world. The plan hopes to curb the rise caused by an unchecked use of antibiotics and lack of new antibiotics on the market.

New Tel Aviv University research published in PNAS introduces a promising new tool: a two-pronged system to combat this dangerous situation. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine, is based on bacterial viruses called phages, which transfer "edited" DNA into resistant bacteria to kill off resistant strains and make others more sensitive to antibiotics.

According to the researchers, the system, if ultimately applied to pathogens on hospital surfaces or medical personnel's hands, could turn the tide on untreatable, often lethal bacterial infections. "Since there are only a few pathogens in hospitals that cause most of the antibiotic-resistance infections, we wish to specifically design appropriate sensitization treatments for each one of them," Prof. Qimron says. "We will have to choose suitable combinations of DNA-delivering phages that would deliver the DNA into pathogens, and the suitable combination of 'killing' phages that could select the re-sensitized pathogens."

Reprogramming the system

"Antibiotic-resistant pathogens constitute an increasing threat because antibiotics are designed to select resistant pathogens over sensitive ones," Prof. Qimron says. "The injected DNA does two things: It eliminates the genes that cause resistance to antibiotics, and it confers protection against lethal phages.

"We managed to devise a way to restore antibiotic sensitivity to drug-resistant bacteria, and also prevent the transfer of genes that create that resistance among bacteria," he continues.

Earlier research by Prof. Qimron revealed that bacteria could be sensitized to certain antibiotics — and that specific chemical agents could "choose" those bacteria more susceptible to antibiotics. His strategy harnesses the CRISPR-Cas system — a bacterial DNA-reprogramming system Prof. Qimron pioneered — as a tool to expand on established principles.

According to the researchers, "selective pressure" exerted by antibiotics renders most bacteria resistant to them — hence the epidemic of lethal resistant infections in hospitals. No counter-selection pressure for sensitization of antibiotics is currently available. Prof. Qimron's strategy actually combats this pressure — selecting for the population of pathogens exhibiting antibiotic sensitivity.

"We believe that this strategy, in addition to disinfection, could significantly render infections once again treatable by antibiotics," said Prof. Qimron.

Prof. Qimron and his team are now poised to apply the CRISPR/phage system on pseudomonas aeruginosa — one of the world's most prevalent antibiotic-resistant pathogens involved in hospital-acquired infections — and to test whether bacterial sensitization works in a more complex microbial environment: the mouse cage.

Eyes Sealed Shut: Seamless Closure of Surgical Incisions
6/2/2015

TAU researcher brings groundbreaking fiber-optic laser system to the world of corneal transplants

Some 30,000 years ago, prehistoric man wielded animal bones as needles to suture otherwise lethal wounds. This tactic has been used, and improved upon, over time and remains the basis of surgical procedures conducted today. Even with radical new surgical techniques, which rely on metallic and polymeric staples or chemical adhesives to seal incisions, infection and permanent scarring remain major concerns. The success of any wound closure is entirely dependent on the physician's skill set alone.

Prof. Abraham Katzir, Head of the Applied Physics Group at Tel Aviv University's School of Physics and Astronomy, has spent much of his career honing a technique he devised called "laser welding," by which incision edges are heated in a precisely controlled manner for optimal wound closure. Now a study recently published in the Journal of Biomedical Optics explores a radical new application of this technique — sealing corneal transplants.

A corneal transplant can restore vision in people suffering from corneal conditions, such as bulging corneas, Fuchs' dystrophy, thinning corneas, corneal scarring caused by infection or injury, cataracts, corneal swelling, corneal ulcers, or complications caused by previous eye surgery. "Every year, for 50,000 Americans on the verge of losing their sight, corneal transplants are the only option. It is a torturous procedure followed by many months of painful recovery caused by sutures left in the eye," said Prof. Katzir. "Using our special optical fiber, we were able to seamlessly bond corneal tissue without causing damage to the surrounding eye or leaving lingering stitches."

An innovative fiber

"A surgeon needs great skill to perform internal stitching, to bond tiny blood vessels or to mend cuts on the skin almost without a trace," said Prof. Katzir. "Therefore, there has been great interest in the medical community in levelling the playing field, devising new technology that all surgeons — even those without years upon years of suturing experience — can use."

Prof. Katzir's group at TAU developed unique optical fibers made of silver halides that are transparent in the infrared. Such fibers deliver an infrared laser beam, which carefully heat the approximated edges of an incision spot by spot. Simultaneously, the same fiber delivers infrared light from the heated spot to an infrared detector, which monitors the temperature at each spot, much like an ear thermometer. This makes it possible to heat each spot to a desirable temperature (e.g. 140-150 degrees F), which creates a strong bond without causing thermal damage.

"The most important aspect of our technique is temperature," said Prof. Katzir. "Take an egg, for example. If you cook it at 70-80 degrees F, nothing happens. However, if you fry it at 250 degrees F, you destroy it altogether. At an intermediate temperature, however, one gets a hard-boiled egg. The same goes for laser bonding, where heating at an intermediate temperature, under precise controls, ensures strong bonding without scarring."

Prof. Katzir and his team, in collaboration with surgeons from Tel Aviv Medical Center and Sheba Medical Center, conducted corneal transplant experiments in eyes taken from deceased cows and pigs. They used the fiber-optic laser system to achieve a permanent tight seal with minimal thermal damage to the surrounding eye tissue. Conducting biopsies on the eyes, the researchers found neither leaks nor signs of overheating.

A broad range of applications

Based on these results, Prof. Katzir has received approval to conduct corneal transplant experiments on live animal models. In parallel, he is applying his technique to endoscopic surgeries.

"This least invasive surgery is the way the medical world is moving," said Prof. Katzir. "One of the most difficult tasks facing surgeons is the closure of incisions in such surgeries. Our technique is based on thin and flexible optical fibers that can be inserted through the endoscope to facilitate laser bonding within the body. This new technique is poised to be a major player in such surgeries and in the fast growing field of robotic surgery in particular."

In clinical trials conducted recently by members of Prof. Katzir's group and by general surgeons on incisions in the skins of 10 human patients, wounds treated with the fiber-optic laser technique successfully healed, with almost no scar tissue. "There are endless applications for the fiber-optic laser system," said Prof. Katzir. "Plastic surgery, urology, ENT, brain surgery, emergency medicine, battlefield wounds — the possibilities are truly endless. I hope that we will be able to apply our innovative technology to some of these fields."

A “Super-Cool” Way to Deliver Drugs
5/6/2015

TAU researchers discover the secret to substances that can be engineered to "freeze" at a specific time

Water, when cooled below 32°F, eventually freezes — it's science known even to pre-schoolers. But some substances, when they undergo a process called "rapid-freezing" or "supercooling," remain in liquid form — even at below-freezing temperatures.

The supercooling phenomenon has been studied for its possible applications in a wide spectrum of fields. A new Tel Aviv University study published in Scientific Reports is the first to break down the rules governing the complex process of crystallization through rapid-cooling. According to the research, membranes can be engineered to crystallize at a specific time. In other words, it is indeed possible to control what was once considered a wild and unpredictable process — and it may revolutionize the delivery of drugs in the human body, providing a way to "freeze" the drugs at an optimal time and location in the body.

The study was led jointly by Dr. Roy Beck of the Department of Physics at TAU's School of Physics and Astronomy and Prof. Dan Peer of the Department of Cell Research and Immunology at TAU's Faculty of Life Sciences, and conducted by TAU graduate students Guy Jacoby, Keren Cohen, and Kobi Barkai.

Controlling a metastable process

"We describe a supercooled material as 'metastable,' meaning it is very sensitive to any external perturbation that may transform it back to its stable low-temperature state," Dr. Beck said. "We discovered in our study that it is possible to control the process and harness the advantages of the fluid/not-fluid transition to design a precise and effective nanoscale drug encapsulating system."

For the purpose of the study, the researchers conducted experiments on nanoscale drug vesicles (fluid-filled sacs that deliver drugs to their targets) to determine the precise dynamics of crystallization. The researchers used a state-of-the-art X-ray scattering system sensitive to nanoscale structures.

"One key challenge in designing new nano-vesicles for drug delivery is their stability," said Dr. Beck. "On the one hand, you need a stable vesicle that will entrap your drug until it reaches the specific diseased cell. But on the other, if the vesicle is too stable, the payload may not be released upon arrival at its target."

"Supercooled material is a suitable candidate since the transition between liquid and crystal states is very drastic and the liquid membrane explodes to rearrange as crystals. Therefore this new physical insight can be used to release entrapped drugs at the target and not elsewhere in the body's microenvironment. This is a novel mechanism for timely drug release."

All in the timing

The researchers found that the membranes were able to remain stable for tens of hours before collectively crystallizing at a predetermined time.

"What was amazing was our ability to reproduce the results over and over again without any complicated techniques," said Dr. Beck. "We showed that the delayed crystallization was not sensitive to minor imperfection or external perturbation. Moreover, we found multiple alternative ways to 'tweak the clock' and start the crystallization process."

The researchers are investigating an appropriate new nano-capsule capable of releasing medication at a specific time and place in the body. "The challenge now is to find the right drugs to exploit our insights for the medical benefit of patients," said Dr. Beck.

Nail Biters, Beware: Teeth Grinding Is Next
5/5/2015

TAU research finds social anxiety increases the risk of bruxism, tooth erosion, and jaw pain

Anxiety disorders affect approximately one in six adult Americans, according to the National Institute of Mental Health. The most well-known of these include panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and social anxiety disorder. But what of brief bouts of anxiety caused by stressful social situations?

A new study by Tel Aviv University researchers, published recently in the Journal of Oral Rehabilitation, finds that anxiety experienced in social circumstances elevates the risk of bruxism — teeth grinding which causes tooth wear and fractures as well as jaw pain. According to the research, led by Dr. Ephraim Winocur of the Department of Oral Rehabilitation at TAU's School of Dental Medicine and conducted by TAU doctoral student Roi Skopski in collaboration with researchers at Geha Mental Health Center in Petah Tikva, Israel, interaction with people is likely to trigger bruxism in the socially anxious.

"This is not a dental problem, but one with clear dental consequences," said Dr. Winocur. "If we are aware, then we can bring it into consciousness. Psychiatrists can identify patients predisposed to bruxism and can try to help prevent it, and dental experts will immediately know what to treat."

The researchers assessed 75 men and women in their early 30s using questionnaires. One group of 40 people had social phobia, characterized by excessive fear in social situations. Just under half of the group members were on antidepressant drugs — selective serotonin reuptake inhibitors (SSRIs). A control group of 35 did not have social phobia. All the subjects underwent psychiatric and dental exams. Bruxism symptoms and oral habits, such as gum chewing, nail biting, and small jaw movements with no tooth contact ("jaw play"), were all assessed.

Although antidepressant drugs have previously been linked to bruxism, this study found no association. However, moderate-to-severe dental wear was found in 42.1% of the social phobia subjects and 28.6% of controls. The rate of jaw play was 32.5% in the phobia group and 12.1% in controls. Symptoms of awake bruxism were reported by 42.5% of social phobia patients and by 3% of controls.

"Interaction with people seems to be necessary to trigger bruxism in socially anxious people," said Dr. Winocur. "By treating social anxiety, we will be able to treat bruxism as well." Dr. Winocur is currently researching the effect of post-traumatic stress disorders on sleep and awake bruxism.

Bacterial "Memory" Targets Invading Viruses
4/16/2015

TAU researchers uncover mechanism that defends bacteria from an autoimmune attack

One of the immune system's most critical challenges is to differentiate between itself and foreign invaders — and the number of recognized autoimmune diseases, in which the body attacks itself, is on the rise. But humans are not the only organisms contending with "friendly fire."

Even single-celled bacteria attack their own DNA. What protects these bacteria, permitting them to survive the attacks?

A new study published in Nature by a team of researchers at Tel Aviv University and the Weizmann Institute of Science now reveals the precise mechanism that bacteria's defense systems use to target invading viruses, protecting their own infrastructures. According to the study, led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine and Prof. Rotem Sorek of the Weizmann Institute's Molecular Genetics Department and conducted by TAU graduate student Moran Goren and Weizmann graduate student Asaf Levy, bacteria adopt two unique strategies to produce an appropriate, targeted response to foreign invaders — at minimal damage to their own DNA.

Thanks for the memories?

"Bacteria defend themselves from viral attacks thorough a defense system called 'CRISPR-Cas,'" said Prof. Qimron. "This system is adaptive, meaning it can 'memorize' a virus by sampling pieces of its DNA, and consequently launch an attack against the virus in future encounters. It was a mystery how bacteria are able to avoid attacking themselves and preferentially target viruses. But, it was only logical that the avoidance would be developed during the early 'memorization' stage of this mechanism rather than in the latter stages of attack."

A virus kills a cell by harnessing a host cell's replication machinery to make copies of itself. Years ago, Prof. Qimron pioneered studies on the memorization mechanism of CRISPR-Cas, which protects the bacterial host by inserting a short sequence of invading viral DNA straight into the bacterial genome to "remember" the infection. Bits of the viral DNA stored in special sections of the genome were found to form immune memory. In subsequent infections, the CRISPR system used these genetic sequences to create short strands of RNA that exactly fit the genetic sequence of the virus. Once protein complexes attached to the RNA identified the viral DNA, they destroyed the invading virus.

"We knew there had to be a sophisticated mechanism in place. Otherwise the bacteria, which tend to destroy its more plentiful viral invaders, would succumb to attacks, which is usually not the case," said Prof. Qimron.

Making a monkey out of DNA

Qimron's and Sorek's groups teamed up to pinpoint the precise mechanism by recording and analyzing tens of millions of memorization events against foreign DNA by the CRISPR-Cas system. The researchers injected plasmids — short, circular pieces of DNA that mimic foreign DNA — into bacteria. Two proteins, Cas1 and Cas2, were found to be responsible for acquiring pieces of plasmid DNA and avoiding bacterial DNA. In other words, the CRISPR system successfully memorized the foreign DNA for future attack, while the self-bacterial DNA was only rarely memorized.

"We can possibly use this knowledge to protect a DNA piece from attack," said Prof. Qimron. "The CRISPR-Cas system has been used in many applications, including the manipulation of DNA to generate a genetically engineered monkey. It is considered one of the most promising tools of future medicine."

The researchers are currently studying the molecular details of the memorization mechanism.

Your Better Half (by Half?): Improving Your Fitness May Improve Your Spouse's
4/7/2015

TAU researcher finds the "power of the couple" has potential to get both partners moving

With obesity on the rise in households across America, the demand for weight-loss treatments, personal trainers, and lifestyle coaches is amping up. But when it comes to physical fitness, the best incentive to get in shape might be the very person sitting across from you at the dinner table.

New research finds that exercising isn't only good for you — it's also good for your spouse. According to Dr. Silvia Koton of the Department of Nursing in the Stanley Steyer School of Health Professions at Tel Aviv University's Sackler Faculty of Medicine, lead investigator Dr. Laura Cobb, and their colleagues at the Johns Hopkins Bloomberg School of Public Health, if one spouse improves his or her exercise regimen, the other spouse is much more likely to follow suit. The study, presented last month at the American Heart Association's EPI/Lifestyle 2015 Scientific Sessions in Baltimore, suggests that a better approach to helping people boost their physical activity might be to coach married couples together instead of individually.

"It was well known that spouses exhibit similar risky behaviors like smoking and drinking, but it wasn't clear how an individual's level of physical activity was influenced by changes in his or her spouse's level of physical activity," said Dr. Koton. "Our study tells us that spouses can have a positive impact on one another in terms of staying fit and healthy over time."

A healthy partnership

For the purpose of the study, the researchers examined records from the Atherosclerosis Risk in Communities (ARIC) Study, which in 1987 began following a group of 15,792 middle-aged adults from communities in Maryland, North Carolina, Minnesota, and Mississippi. Dr. Koton and her colleagues analyzed data from two medical visits conducted roughly six years apart. At each visit, the researchers asked 3,261 spouse pairs about their physical activity levels.

The Physical Activity Guidelines for Americans, established by the U.S. Department of Health and Human Services, recommends that adults should exercise at a moderate intensity for a minimum of 150 minutes per week or at a vigorous intensity for at least 75 minutes per week. During the first visit, 45% of husbands and 33% of wives met these recommendations. Six years later, they found that when a wife met recommended levels of exercise at the first visit, her husband was 70 percent more likely to meet those levels at subsequent visits than those whose wives were less physically active. Likewise, when a husband met recommended exercise levels, his wife was 40% more likely to meet the levels at follow-up visits.

"Our findings suggest that physical activity promotion efforts should consider targeting couples," said Dr. Koton. The study of theoretical models and mechanisms, which may explain changes in the levels of physical activity in couples over time, is a promising area for future research, she says.

A Breakfast of Champions for Diabetics
3/16/2015

TAU researcher says high-energy breakfast and modest dinner can control dangerous blood sugar spikes all day

Our modern epidemic of obesity has led to an alarming rise in the incidence of diabetes. More than 382 million people on the planet suffer from diabetes, predominantly type-2 diabetes. For these people, blood sugar surges — glucose spikes after meals — can be life threatening, leading to cardiovascular complications.

A new Tel Aviv University study published in Diabetologia proposes a new way to suppress deadly glucose surges throughout the day — eating a high-caloric breakfast and a more modest dinner. According to TAU's Prof. Daniela Jakubowicz and Dr. Julio Wainstein of the Wolfson Medical Center's Diabetes Unit, Prof. Oren Froy of the Hebrew University of Jerusalem, and Prof. Bo Ahrén of Lund University in Sweden, the combined consumption of a high-energy breakfast and a low-energy dinner decreases overall daily hyperglycaemia in type-2 diabetics.

"We found that by eating more calories at breakfast, when the glucose response to food is lowest, and consuming fewer calories at dinner, glucose peaks after meals and glucose levels throughout the day were significantly reduced," said Prof. Jakubowicz.

All in the timing

The new study was conducted on eight men and 10 women aged 30-70 with type-2 diabetes. Patients were randomized and assigned either a "B diet" or "D diet" for one week. The B diet featured a 2946 kilojoule (kj) breakfast, 2523 kj lunch, and 858kj dinner, and the D diet featured a 858 kj breakfast, 2523 kj lunch, and 2946 kj dinner. Both diets contained the same total energy measured in kilojoules, a food energy measurement similar to a calorie, but were consumed at different times through the day, with the larger meal taking place during breakfast in the B diet. The larger meal included two slices of bread, milk, tuna, a granola bar, scrambled egg, yoghurt and cereal; the smaller meal contained sliced turkey breast, mozzarella, salad and coffee.

Patients consumed their diets at home for six days before the day of testing. On the seventh day, each group consumed their assigned meal plan at the clinic, and blood samples were collected just before breakfast and at regular intervals after the meal. Blood sampling was repeated at the same intervals after lunch and dinner. Post-meal glucose levels were measured in each participant, as well as levels of insulin, c-peptide (a component of insulin), and glucagon-like-peptide 1 hormone (GLP-1, also known as incretin: an indicator of glucose metabolism that stimulates insulin release). Two weeks later, patients switched to the alternate diet plan, and the tests were repeated.

The results of the study showed that post-meal glucose elevations were 20% lower and levels of insulin, C-peptide, and GLP-1 were 20% higher in participants on the B diet compared with those on the D diet.

What — and when — to eat

Despite the fact that both diets contained the same calories, blood glucose levels rose 23 percent less after the lunch preceded by a large breakfast.

"By demonstrating that a diet of high-energy breakfasts and more modest dinners is more effective in lowering overall daily post-meal glucose surges, we suggest that such a regimen is a powerful therapeutic approach for improving glycemic control and may potentially reduce cardiovascular complications in type- 2 diabetics," said Prof. Jakubowicz. "It is not enough to tell the diabetic patient what he or she should or should not eat. It is more important to emphasize that a more advantageous meal schedule should be followed."

The researchers are currently engaged in an extended study of the benefits of high-energy breakfast and reduced-calorie dinners over time.

A Real Eye-Opener: Narcolepsy Bears Classic Autoimmune Hallmarks
3/9/2015

TAU researcher finds an autoimmune process plays major role in triggering neurological disorder

Narcoleptics suffer from bouts of sleepiness and sleep attacks, which impair their ability to function in daily life. But the precise cause of narcolepsy has long eluded scientists, and the cure for the devastating neurological disorder afflicting an estimated three million people worldwide — and one in 3,000 Americans — remains at bay.

A new study published in Pharmacological Research by the world's leading autoimmune disease expert, Tel Aviv University's Prof. Yehuda Shoenfeld, finds that narcolepsy bears the trademarks of a classic autoimmune disorder and should be treated accordingly. The research, led by Prof. Shoenfeld, the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at TAU's Sackler Faculty of Medicine and Head of Zabludowicz Center for Autoimmune Diseases at Chaim Sheba Medical Center, Tel Hashomer, and conducted by doctoral student María-Teresa Arango, points to a particular autoimmune process as the trigger for the specific loss of orexin neurons, which maintain the delicate equilibrium between sleep and wakefulness in the brain.

Not just the genes

"Narcolepsy is interesting, because although it has been considered to be strictly genetic, it is induced by environmental factors, such as a burst of laughter or stress," said Prof. Shoenfeld. "Narcolepsy is devastating to those suffering from it and debilitating to children, in particular. There is no known therapy to treat it."

Narcolepsy first strikes people aged 10 to 25, plaguing them for life. Narcoleptics may experience any or all of the following symptoms: falling asleep without warning, anywhere, anytime, making it difficult to concentrate and fully function; excessive daytime sleepiness; the sudden loss of muscle tone; slurred speech or weakness of most muscles for a few seconds or a few minutes; a temporary inability to move or speak while falling asleep or upon waking; and hallucinations.

Prof. Shoenfeld first became interested in the subject after an avalanche of narcolepsy diagnoses swept Finland in 2009 following the administering of the H1N1 flu vaccine. "Following the H1N1 vaccine, 16 times the average incidence of narcolepsy was reported," said Prof. Shoenfeld.

Prof. Shoenfeld discovered that a group of researchers from the Sleep Control Project at the Tokyo Metropolitan Institute of Psychiatry in Japan had published a study on an autoantibody presence attacking tribbles, small granules in our brains containing regulatory orexin neurons, which maintain the balance between sleep and wakefulness in the brain.

Fingering the culprit

"In patients and animals that develop narcolepsy, we have seen an evident depletion of orexin in the brain, and therefore a lack of balance, and later attacks of narcolepsy," said Prof. Shoenfeld. "Why is the orexin disappearing? We think the culprit is an autoimmune reaction — the binding of autoantibodies to the tribble granules to destroy them."

For the purpose of the new study, Prof. Shoenfeld and his team collaborated with the Japanese research group led by Dr. Makoto Honda to isolate the specific antibodies. These antibodies were then injected directly into laboratory mice. Ms. Arango monitored their behavior for several months, tracking their sleep patterns. "What we saw was an increased number of sleep attacks and irregular patterns of sleep in mice," said Prof. Shoenfeld. "Mice fall asleep like dogs, circling around before going to sleep. Suddenly, in this experiment, the mice just dropped off to sleep and then, just two minutes later, woke up as though nothing had happened.

"Our hope is to change the perception and diagnosis of narcolepsy, to define it as the 81st known autoimmune disease, because a better understanding of the mechanism causing this disease, which debilitates and humiliates so many people, will lead to better treatment and, maybe one day, a cure," Prof. Shoenfeld says. He is currently collaborating with Dr. Honda and his team to locate the area of the brain to which the targeting autoantibodies bind.

Neuron Groups, Not Single Cells, Maintain Brain Stability
3/2/2015

TAU researchers find neural networks preserve memories better than individual neurons

To compensate for erratic shifts and spikes in its neuronal communications, the brain relies on the stabilizing mechanism called "homeostasis" — the ability to maintain relatively stable equilibrium between different elements of its composition — to preserve overall network function. Disruptions in stability cause disorders such as epilepsy, but precious little is known about this macro-level regulatory phenomenon.

A new study published in eLife by Dr. Inna Slutsky of Tel Aviv University's Sackler Faculty of Medicine and TAU's Sagol School of Neuroscience finds that homeostatic regulation occurs mainly in groups of neurons rather than in the individual neurons themselves. Contradicting established assumptions, Edden Slomowitz and Boaz Styr, doctoral students in Dr. Slutsky's laboratory, discovered that single brain cells, on an individual basis, were unable to autonomously stabilize "spikes" in neuron communication over long periods. "Spikes" or "firing," as they are also known, are neurons' response to stimulation; they relay messages to the rest of the body.

"Neurological and psychiatric disorders often see similar or overlapping neurological symptoms, and the failure of the neuronal homeostatic system may lead to these common endpoints," said Dr. Slutsky. "Understanding the principles and mechanisms involved in neuronal homeostasis may lead to new approaches in the treatment of these and other brain disorders like Alzheimer's disease."

Seeking stability in a constantly changing environment

The brain's ability to adapt to a constantly changing environment and to form and store memories is due to the extreme flexibility, or plasticity, of its neural network. But the extreme plasticity of the brain also makes it inherently prone to instability and subsequent illnesses and disorders.

"Through homeostasis, organisms are able to maintain a stable internal environment," said Slomowitz. "One common example is the secretion of insulin in response to a meal to keep blood sugar levels within the normal range. While there was evidence to support the theory that there were homeostatic mechanisms at work in the brain to stabilize neuronal activity, it was unclear which precise properties were regulated."

For the purpose of the study, Slomowitz grew a neural network on an array of electrodes and recorded the activity of single individual neurons in the network. He then applied a drug which severely inhibited neural activity. In collaboration with Prof. Eli Nelken of Hebrew University and Dr. Michael Slutsky of Mantis Vision, Slomowitz found that the network returned to its original firing rate over the course of two days despite the continued presence of the drug — and even though the firing rates and patterns of individual neurons did not reflect homeostatic tendencies.

"These results were unexpected and contradicted the current dogma in the field stating that individual neurons can regulate their own firing rates in an autonomous manner," said Dr. Slutsky.

The trade-off of population stability

Following up, Styr repeated the experiment in the lab using calcium imaging, which can monitor the activity of visually identifiable neurons. The calcium images revealed similar results, bolstering the conclusion that homeostasis occurs at the level of neuron populations, not on a cell-by-cell basis.

The team also examined the ability of the network to differentiate between low- and high-frequency spikes, a capability critical for short-term memory. They found this detection was severely compromised two days after the introduction of the drug, even though network firing rates and patterns had been homeostatically restored.

"Our study demonstrates that neurons in a neural network act synergistically in order to keep the population spiking rates and patterns in a constant physiological range," said Dr. Slutsky. "This may occur at the cost of a diminished ability to form new memories, a process which may underlie the loss of short-term memory observed in brain diseases such as Alzheimer’s disease. This understanding may bring us one step closer to the understanding of the processes that precede cognitive decline in neurodegenerative disorders."

Together, Nanotechnology and Genetic Interference May Tackle “Untreatable” Brain Tumors
2/24/2015

TAU researchers' groundbreaking strategy stops brain tumor cell proliferation with targeted nanoparticles

There are no effective available treatments for sufferers of Glioblastoma multiforme (GBM), the most aggressive and devastating form of brain tumor. The disease, always fatal, has a survival rate of only 6-18 months.

Now a new Tel Aviv University study may offer hope to the tens of thousands diagnosed with gliomas every year. A pioneer of cancer-busting nanoscale therapeutics, Prof. Dan Peer of TAU's Department of Department of Cell Research and Immunology and Scientific Director of TAU's Center for NanoMedicine has adapted an earlier treatment modality — one engineered to tackle ovarian cancer tumors — to target gliomas, with promising results.

Published recently in ACS Nano, the research was initiated by Prof. Zvi R. Cohen, Director of the Neurosurgical Oncology Unit and Vice Chair at the Neurosurgical Department at Sheba Medical Center at Tel Hashomer. The Israeli Cancer Association provided support for this research.

Trying a new approach to gliomas

"I was approached by a neurosurgeon insistent on finding a solution, any solution, to a desperate situation," said Prof. Peer. "Their patients were dying on them, fast, and they had virtually no weapons in their arsenal. Prof. Zvi Cohen heard about my earlier nanoscale research and suggested using it as a basis for a novel mechanism with which to treat gliomas."

Dr. Cohen had acted as the primary investigator in several glioma clinical trials over the last decade, in which new treatments were delivered surgically into gliomas or into the surrounding tissues following tumor removal. "Unfortunately, gene therapy, bacterial toxin therapy, and high-intensity focused ultrasound therapy had all failed as approaches to treat malignant brain tumors," said Dr. Cohen. "I realized that we must think differently. When I heard about Dan's work in the field of nanomedicine and cancer, I knew I found an innovative approach combining nanotechnology and molecular biology to tackle brain cancer."

Dr. Peer's new research is based on a nanoparticle platform, which transports drugs to target sites while minimizing adverse effects on the rest of the body. Prof. Peer devised a localized strategy to deliver RNA genetic interference (RNAi) directly to the tumor site using lipid-based nanoparticles coated with the polysugar hyaluronan (HA) that binds to a receptor expressed specifically on glioma cells. Prof. Peer and his team of researchers tested the therapy in mouse models affected with gliomas and control groups treated with standard forms of chemotherapy. The results were, according to the researchers, astonishing.

"We used a human glioma implanted in mice as our preclinical model," said Prof. Peer. "Then we injected our designed particle with fluorescent dye to monitor its success entering the tumor cells. We were pleased and astonished to find that, a mere three hours later, the particles were situated within the tumor cells."

A safer, more promising approach

Rather than chemotherapy, Prof. Peer's nanoparticles contain nucleic acid with small interference RNAs, which silence the functioning of a key protein involved in cell proliferation. "Cancer cells, always dividing, are regulated by a specific protein," said Prof. Peer. "We thought if we could silence this gene, they would die off. It is a basic, elegant mechanism and much less toxic than chemotherapy. This protein is not expressed in normal cells, so it only works where cells are highly proliferated."

100 days following the treatment of four injections over 30 days, 60 percent of the afflicted mice were still alive. This represents a robust survival rate for mice, whose average life expectancy is only two years. The control mice died 30-34.5 days into treatment.

"This is a proof of concept study which can be translated into a novel clinical modality," said Prof. Peer. "While it is in early stages, the data is so promising — it would be a crime not to pursue it."

Crowdfunding Helps Solve Rare Disease Mystery
2/10/2015

TAU researcher identifies novel genetic mutations through DNA sequencing of afflicted child and family

Rare diseases — those that affect fewer than one in 200,000 people — are often identified early in life. Some 30 percent of children afflicted by these "orphan diseases" do not live to see their fifth birthday. While the US Orphan Drug Act of 1983 was written into law to promote research on the topic, the cost of identifying the source and progression of these diseases remains prohibitive for many families.

But there is hope for them in our Internet age. Researchers at Tel Aviv University recently concluded a successful experiment to identify a novel genetic mutation as the source of a specific rare disease, and their experiment was supported through crowdfunding — contributions from a large number of individuals over the Internet.

In the study, led by Dr. Noam Shomron of TAU's Sackler Faculty of Medicine and published recently in the Journal of Genetics and Genomics, analysis of DNA sequencing of a three-year-old girl and her family revealed a novel mutation that causes mental retardation and severe developmental delays in children. Research for the study was conducted by TAU doctoral student Ofer Isakov together with Dr. Dorit Lev and Dr. Esther Lishinsky of Wolfson Medical Center.

A roadmap to hope

"How does it help to know?" said Dr. Shomron. "It's the missing piece of the genetic puzzle, eliminating from the picture all other diseases that are known to cause death at an early age and allowing the parents to connect with families with similar problems or mutations to build a lifelong support network. The parents can connect with scientists working in the field to learn about advancements. In some cases, a change in lifestyle, drug therapy, and physiotherapy can help their child's situation. Finally, by knowing what to look for, the parents can feel free to have more children as long as they screen for the identified mutation.

"By knowing a child's DNA, you also unlock a family secret that can possibly reflect on cousins, siblings and so on. It goes around and around in a circle — who else is carrying this gene?"

The power of the crowd

"Parents look to comprehensive genetic analysis, like the one we carried out, when they don't know where else to look," said Dr. Shomron. "They are desperate to understand why their children are sick, and the medical community is challenged to identify the source of the suffering. By travelling through the complete human genome, we are able to locate, map, and analyze mutations involved in triggering certain rare diseases.

"Crowdfunding provides the means for economically disadvantaged patients to pursue a genetic diagnosis for their ailment. Our project reached its financial goal of $5,000 within 50 days. We were pleased, to say the least. Crowdfunding is a simple and efficient solution for families with rare genetic diseases who lack private or outside funding sources."

The study harnessed whole exome sequencing (WES) to identify the genetic cause of a three-year-old girl's involuntary eye movements, small-sized head, involuntary muscle contraction, developmental delay, and progressive neurological decline. The patient had a healthy brother and there was no recent family history of neurological disorders. Although she had smiled at six weeks, laughed at three months, and reached for toys at four months, over the next two years her motor functions had degenerated and she was unable to produce words. She could neither sit nor stand unassisted and she walked only with aids. At the age of 33 months, there was no progress. Extensive medical testing produced no answers. Desperate to understand what was happening to their daughter, the parents sought answers through genetic sequencing.

But because WES costs around $1,500 per individual, and the DNA of the patient and her parents had to be sequenced as well, the price of the project came to $4,500. Due to the high expense, Dr. Shomron sought to raise the necessary funds from individual donors over the Internet. The platform they used was that of Rare Genomics Institute (RGI; at http://raregenomics.org/), which specializes in this kind of fundraising in the US. Dr. Shomron opened the Israeli branch of RGI to cater to the local rare genetic mutation population.

Dr. Shomron is continuing his research on gene mutations to help other families struggling with rare diseases.

Acute Psychological Stress Reduces Ability to Withstand Physical Pain
2/5/2015

New TAU study exposes damaging effect of psychosocial stress on the body's pain modulation capabilities

Traffic slows to a crawl, then a stop. You are trapped in a bottleneck nightmare, and late for a meeting. The stress takes a toll on you psychologically — but your body is at risk as well, according to a Tel Aviv University researcher.

A new study by Prof. Ruth Defrin of the Department of Physical Therapy at TAU's Sackler Faculty of Medicine published in the journal PAIN finds that acute psychosocial stress has a dramatically deleterious effect on the body's ability to modulate pain. Prof. Defrin, together with TAU doctoral student Nirit Geva and Prof. Jens Pruessner of McGill University, applied acute stress tests on a large group of healthy young male adults to evaluate the behavior of the body's pain modulation mechanisms prior to and after the induction of stress.

The researchers found that although pain thresholds and pain tolerance seemed unaffected by stress, there was a significant increase in pain intensification and a decrease in pain inhibition capabilities.

Doing the math

For the purpose of the study, 29 healthy men underwent several commonly accepted pain tests to measure their heat-pain thresholds and pain inhibition, among other factors. In one test, for example, subjects were asked to signal the moment a gradually increasing heat stimulus became painful to identify their respective pain thresholds. They underwent a series of pain tests before and immediately after exposure to the Montreal Imaging Stress Task (MIST), a computer program of timed arithmetic exercises, designed to induce acute psychosocial stress.

In a way, the stress test is a psychological trick. MIST provides live feedback on submitted responses, registering only 20-45% of the responses as correct, whether or not a submitted response is the right answer. Because the subject has been previously informed that the average participant tends to score 80%–90%, he is reminded of his "poor performance" but has no way of improving his score, despite his best efforts. This provides the "stress" element of the experiment.

"To further test the effect of stress on pain, we divided the group according to stress levels," said Prof. Defrin. "We found that not only does psychosocial stress reduce the ability to modulate pain, the changes were significantly more robust among subjects with stronger reaction to stress ('high responders'). The higher the perceived stress, the more dysfunctional the pain modulation capabilities became. In other words, the type of stress and magnitude of its appraisal determine its interaction with the pain system.

"We know from our previous studies and studies of others that chronic stress is far more damaging than acute stress, associated not only with dysfunctional pain modulation capabilities but also with chronic pain and systemic illnesses," said Prof. Defrin.

Defining stress

"Stress is defined as a sense of uncontrollability and unpredictability, precisely like being stuck in traffic where you are helpless and have no control over the situation," said Prof. Defrin. "Stress can have positive repercussions in a challenging work environment, for example, but overall it has primarily negative effects."

The results were also somewhat surprising. "We were sure we would see an increased ability to modulate pain, because you hear anecdotes about people who are injured during fighting or sports having greater pain modulation," said Prof. Defrin. "But we were surprised to find quite the opposite. While there was no visible effect of acute stress on the subject's pain threshold or tolerance, pain modulation decreased in a very dramatic way.

"Modern life exposes individuals to many, recurrent stressful situations," Prof. Defrin observes. "While there is no way to predict the type of stress we will feel under different circumstances, it is advisable to do everything in our power — adopt relaxation and stress reduction techniques as well as therapy — to reduce the amount of stress in our lives."

Protective Brain Protein Reveals Gender Implications for Autism, Alzheimer’s Research
2/3/2015

TAU study finds a mutated gene is expressed differently in male and female brains

For parents of children struggling with autism, the dearth of information is heartbreaking. Medical professionals are hard put to answer the primary questions: Who is autistic? What causes autism? What treatments are available? The situation is similar for Alzheimer's patients and relatives, who are helpless before the aggressive disease devouring a sufferer's identity.

A new study by Tel Aviv University's Prof. Illana Gozes, published in Translational Psychiatry, may offer insight into the pathology of both autism and Alzheimer's by revealing that different activities of certain proteins in males and females cause gender-specific tendencies toward these diseases. While the three-to-one ratio of autism in boys to girls is well known, as is the greater number of female Alzheimer's patients, the reasons for these phenomena are less clear.

According to Prof. Gozes, "If we understand how ADNP, an activity-related neuroprotective protein which is a major regulatory gene, acts differently in males and females, we can try to optimize drugs for potential future therapeutics to treat both autism and Alzheimer’s disease."

Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler Faculty of Medicine, a member of TAU's Adams Super Center for Brain Studies and the Sagol School of Neuroscience. Research for the study was conducted by graduate students Anna Malishkevich, Noy Amram, and Gal Hacohen-Kleiman, in collaboration with post-doctoral fellow Dr. Iddo Magen, and staff scientist Dr. Eliezer Giladi, all of TAU.

The gender factor

For the purpose of the new study, Prof. Gozes and her team examined the behavioral response of male and female mice, both ADNP-altered and normal, to different cognitive challenges and social situations. To do so, they removed one copy of the ADNP gene — which regulates over 400 proteins involved in development — from some mice, and then examined their respective responses to unfamiliar objects, odors, and other mice.

Their results revealed sex-specific learning and memory differences in the mice, reflecting hippocampal expression changes in ADNP, resulting in ADNP-controlled autism and in genes which indicate a risk for Alzheimer's disease. For example, ADNP-deficient male mice exhibited deficiencies in object recognition and social memory, whereas ADNP-altered female mice were more socially deficient compared to the non-altered females.

Providing new hope?

"ADNP may be new to the world of autism, but I have been studying it for 15 years," said Prof. Gozes. "Its gender-dependent expression changes male and female chemical tendencies toward different neurological disorders. Male and female mice may look the same and their brains may look the same, but they are not. When the expression of ADNP is different, it may cause different behaviors and different cognitive abilities.

"This study emphasizes the need to analyze men and women separately in clinical trials to find cures for diseases because they may respond differently," she concludes.

Prof. Gozes hopes the new study will prompt further research into the drug Davunetide (NAP) as a means of treating social and cognitive deficits with special attention to gender differences. Prof. Gozes discovered Davunetide (NAP), a snippet of ADNP, by looking at the nerve cell protective activity of ADNP fragments. Proof-of-concept clinical studies performed in adults have shown that Davunetide protects memory in patients suffering from the mild cognitive impairment that precedes Alzheimer's disease as well as functional activity in schizophrenia patients.

New Protein Detonates “Invincible” Bacteria from Within
1/27/2015

TAU researchers identify protein capable of neutralizing antibiotic-resistant bacterial cells

Antibiotic-resistant infections are on the rise, foiling efforts to reduce death rates in developing countries where uncontrolled use of antibiotics and poor sanitation run amok. The epidemic of "superbugs," bacteria resistant to antibiotics, knows no borders — presenting a clear and present danger around the globe.

A groundbreaking discovery from Tel Aviv University researchers may strengthen efforts by the medical community to fight this looming superbug pandemic. By sequencing the DNA of bacteria resistant to viral toxins, TAU researchers identified novel proteins capable of stymieing growth in treacherous antibiotic-resistant bacteria.

The research, published last month in PNAS, was led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine and conducted primarily by TAU researcher Shahar Molshanski-Mor.

Fighting from within

"Because bacteria and bacterial viruses have co-evolved over billions of years, we suspected the viruses might contain precisely the weapons necessary to fight the bacteria," Prof. Qimron said. "So we systematically screened for such proteins in the bacterial viruses for over two and a half years."

Using high-throughput DNA sequencing, the researchers located mutations in bacterial genes that resisted the toxicity of growth inhibitors produced by bacterial viruses. In this way, the team identified a new small protein, growth inhibitor gene product (Gp) 0.6, which specifically targets and inhibits the activity of a protein essential to bacterial cells.

The inhibitor was found to cripple the activity of a protein vital to bacterial cells — a protein that maintains the bacterial cell structure. Malfunction of this bacterial protein consequently resulted in the rupture and consequent death of the bacterial cell.

Technology and collaboration

"The new technology and our new interdisciplinary collaboration, drawing from bioinformatics and molecular biology, promoted our study more than we could have anticipated," said Prof. Qimron. "We hope our approach will be used to further identify new growth inhibitors and their targets across bacterial species and in higher organisms."

The researchers are continuing their study of bacterial viruses in the hope of identifying compounds and processes that facilitate improved treatment of antibiotic-resistant bacteria using yet uncharacterized bacterial viruses' proteins. They believe that further basic knowledge on bacterial viruses biology will eventually lead to unexpected breakthroughs in the fight against antibiotic-resistant bacteria.

TAU’s Prof. Yosef Shiloh Receives First Olav Thon Foundation Prize
1/21/2015

Norway's largest charitable foundation bestows cash prize for TAU cancer geneticist's research on cell survival and DNA stability

Prof. Yosef ShilohNorway's largest charitable organization, the Olav Thon Foundation, which invests heavily in medical research, awarded its first international research award in the medical and natural sciences to Tel Aviv University's Prof. Yosef Shiloh and Prof. Judith Campisi of the Buck Institute for Research on Aging, California. The prize money, NOK 5,000,000 (approximately $660,000), was split between the two winners.

Prof. Shiloh, the Myers Professor of Cancer Genetics and Research Professor of the Israel Cancer Research Fund at TAU's Sackler School of Medicine, was recognized for his pioneering research on the mechanisms that maintain the survival of human cells and the stability of human genetic material.

A member of the Israel National Academy of Sciences and Humanities, Prof. Shiloh was a recipient of the prestigious Israel Prize (considered "Israel's Nobel") in Life Sciences in 2011, the 2011 American Association of Cancer Research G.H.A. Clowes Award, and the 2005 EMET Prize in Life Sciences.

"A prize means scientific recognition," said Prof. Shiloh. "Scientists do not work in order to get prizes or any other monetary benefits, but the award of a prize means that our work is recognized by our colleagues, and this is probably the true reward of a scientist."

Unraveling the genome

Prof. Shiloh has spent much of his career investigating the processes that maintain genome stability and the defense mechanisms against substances that damage our DNA. He has investigated how the harmful effects of such substances can be countered and offered insights into how mammalian cells react to DNA damage produced by environmental factors, such as radiation and carcinogenic chemicals.

According to the Foundation, "The laureates have provided us with new insights into the molecular basis of aging, aging-related diseases, and cellular degenerative processes."

Prof. Shiloh has dedicated most of his scientific career to understanding the genomic instability syndrome, ataxia-telangiectasia (A-T). (Watch a video on Prof. Shiloh’s research.) He began his work on A-T while working on his PhD thesis, and this quest culminated in 1995 with the identification of the responsible gene, ATM, in his lab. He and his team have since been engaged in exploring its function, its mode of action, and its many roles in cellular metabolism.

Prof. Shiloh obtained his BSc degree at the Technion Institute of Technology and his PhD in Human Genetics at The Hebrew University of Jerusalem. A Fogarty Fellow at the National Institutes of Health, Prof. Shiloh also studied at Harvard Medical School, the University of Michigan, and New York University Medical Center.

In addition to his research, Prof. Shiloh devotes considerable time to giving popular scientific lectures to the general public and high school students on the medical, social, and ethical implications of the genome revolution and its effect on cancer research and therapy.

Smoke Signals: New Evidence Links Air Pollution to Congenital Defects
12/22/2014

TAU study examines effect of air pollution on pregnancies

The health effects of air pollution are a major concern for urban populations all over the world. Children, the elderly, and people with impaired respiratory systems (such as asthmatics) tend to be especially sensitive to the impact of exposure to ozone, nitrogen dioxide, sulphur dioxide, and particulate matter.

A recent study by Tel Aviv University researchers provides new evidence linking high exposure to air pollution to an increased risk of congenital malformations. The research, published in Environmental Research, was led by Prof. Liat Lerner-Geva of TAU's Sackler Faculty of Medicine and School of Public Health and the Gertner Institute for Epidemiology and Health Policy Research, Dr. Adel Farhi of the Gertner Institute for Epidemiology and Health Policy Research, in collaboration with Prof. Itzhak Benenson of TAU's Department of Geography and Human Environment and Prof. Yinon Rudich of the Weizmann Institute of Science. The nationwide study is the first to assess the association between different modes of conception — assisted reproductive technology (ART) versus spontaneous conception (SC) — and the risks of exposure to air pollution to each.

"Our results suggest that exposure to higher levels of air pollution during pregnancy is associated with various adverse pregnancy outcomes," said Prof. Lerner-Geva. "While our study mainly followed SC infants, we also had the opportunity to assess a small sample of pregnancies that were conceived through ART, and observed a higher impact of air pollution — particularly with regard to ozone exposure. This is clearly a uniquely susceptible population that should be further explored."

Statistics link pollution to defects

For the study, funded by the Environmental Health Fund (EHF), the research team analyzed data on 216,730 born in Israel between 1997 and 2004. Air pollution data, including levels of sulfur dioxide (SO2), particulate matter (PM10), nitrogen oxides (NOx), and ozone (O3), were obtained from air monitoring stations for the study period. Using a geographic information system, exposure to air pollution during both the first trimester and the entire pregnancy was assessed for each woman according to her place of residence.

The researchers found that exposure to PM10 and NOX pollutants throughout full-term pregnancies were associated with an increased risk of congenital malformations, with specific defects evident in the circulatory system (from PM10 and NOX exposure) and genital organs (from NOX exposure). They also discovered that exposure to SO2 and O3 in ART pregnancies were associated, although not significantly, with a higher risk of congenital defects.

"Considering the worldwide decline in fertility, and the increasing number of children born through ART treatments, our findings about their increased risk of congenital malformations are very relevant," said Prof. Lerner-Geva. "It is essential we continue to evaluate this unique population."

According to Prof. Lerner-Geva, a national ART registry has been established in Israel to provide important data on all ART cycles. This database will serve as a basis for a future larger study to identify susceptible subpopulations at higher risk of adverse pregnancy outcomes. Prof. Lerner-Geva is currently engaged in a more detailed assessment of environmental exposure during pregnancy.

Genetic Mutation Found to Cause Ovarian Failure
12/17/2014

TAU researchers discover unique genetic disorder responsible for ovarian insufficiency in women under 40

Premature ovarian failure, also known as primary ovarian insufficiency (POI), affects 1% of all women worldwide. In most cases, the exact cause of the condition, which is often associated with infertility, is difficult to determine.

A new Tel Aviv University study throws a spotlight on a previously-unidentified cause of POI: a unique mutation in a gene called SYCE1 that has not been previously associated with POI in humans. The research, published in the Journal of Clinical Endocrinology and Metabolism, was led by Dr. Liat de Vries and Prof. Lina Basel-Vanagaite of TAU's Sackler Faculty of Medicine and Schneider Children's Medical Center and conducted by a team of researchers from both TAU and Schneider.

While the genes involved in chromosome duplication and division had been shown to cause POI in animal models, this is the first time a similar mutation has been identified in humans.

A new insight

"Researchers know that POI may be associated with Turner's syndrome, a condition in which a woman has only one X chromosome instead of two, or could be due to toxins like chemotherapy and radiation therapy," said Dr. de Vries. "However, in 90% of the cases, the exact cause remains a mystery."

The idea for the study surfaced when Dr. de Vries was asked to treat two POI patients, daughters of two sets of Israeli-Arab parents who were related to each other. The girls presented with typical POI symptoms: one had the appearance of puberty but had not gotten her period, and the other one had not started puberty at all. After ruling out the usual suspects (toxins, autoimmune disease, and known chromosomal and genetic diseases), the researchers set out to identify the genetic cause of POI in the two young women.

"One of my main topics of interest is puberty," said Dr. de Vries. "The clinical presentation of the two sisters, out of 11 children of first-degree cousins, was interesting. In each of the girls, POI was expressed differently. One had reached puberty and was almost fully developed but didn't have menses. The second, 16 years old, showed no signs of development whatsoever."

The researchers performed genotyping in the patients, their parents, and siblings. For this, DNA from the affected sisters was subjected to whole-exome sequencing. Genotyping was also performed in 90 ethnically matched control individuals.

Finding the culprit

The genotyping revealed a mutation that results in nonfunctional protein product in the SYCE1 gene in both affected sisters. The parents and three brothers were found to be carriers of the mutation, and an unaffected sister did not carry the mutation.

"By identifying the genetic mutation, we saved the family a lot of heartache by presenting evidence that any chance of inducing fertility in these two girls is slight," said Dr. de Vries. "As bad as the news is, at least they will not spend years on fertility treatments and will instead invest efforts in acquiring an egg donation, for example. Knowledge is half the battle — and now the entire family knows it should undergo genetic testing for this mutation."

The researchers are currently investigating evidence of the effects of this genetic mutation on male members of the family. "We are trying to get more family members tested, but it is not always easy in traditional societies. There is still a lot to be done on this subject," said Dr. de Vries.

A Better Biomonitor for Children with Asthma
12/10/2014

TAU takes groundbreaking new diagnostic technique from Ground Zero to the playground

For the firefighters and rescue workers conducting the rescue and cleanup operations at Ground Zero from September 2001 to May 2002, exposure to hazardous airborne particles led to a disturbing "WTC cough" — obstructed airways and inflammatory bronchial hyperactivity — and acute inflammation of the lungs. At the time, bronchoscopy, the insertion of a fiber optic bronchoscope into the lung, was the only way to obtain lung samples. But this method is highly invasive and impractical for screening large populations.

That motivated Prof. Elizabeth Fireman of Tel Aviv University's Sackler Faculty of Medicine and the Institute for Pulmonary and Allergic Diseases at TAU-affiliated Tel Aviv Sourasky Medical Center to experiment with a new technique: Induced Sputum (IS). Hypertonic saline is inhaled to produce a mucus expectorate which can be tested for hazardous particles. She flew to Ground Zero and tested 39 New York City firefighters using the IS biomonitoring method and then compared these results against a control group of Israeli firefighters. Her technique identified very dangerous metals such as mercury in the rescue workers' lungs.

Now, in a new study published in the International Archives of Occupational and Environmental Health, Prof. Fireman and a team of researchers at Tel Aviv Sourasky Medical Center examine the benefits of using the IS technique to assess the effect of pollution on urban asthmatic children, revealing that environmental sampling stations located in cities around the world are not sufficient to protect the health of these children.

A boon to children

"After our last study on occupational exposure, I decided to examine the most vulnerable sector in the field of asthma — children," said Prof. Fireman. "Environmental monitoring systems are only capable of measuring large particle matter, which is mostly expelled by the lungs. I wanted to know what happened to the small particle matter capable of evading the body's immunological mechanisms. And I wanted to know how they affected asthmatic kids."

For the purposes of the study, Prof. Fireman's team recruited 136 children from two to twelve years of age who had already been referred for asthmatic evaluations to Tel Aviv Sourasky Medical Center. Their parents completed a clinical and demographic International Study of Asthma and Allergy in Childhood (ISAAC)-based questionnaire that included passive smoking status, known present and past diseases, and respiratory symptoms. Afterward, all of the children underwent IS testing in order to detect and measure particulate matter in their lungs.

In the course of the IS testing, the children inhaled 3% nebulised material for up to twenty minutes through an ultrasonic nebulizer, which harnesses mist to administer medication.

A solution for larger populations?

"We compared our results with the indices published by rooftop pollution stations in Tel Aviv," said Prof. Fireman. "And while we do not discount the importance of maintaining such environmental stations, we found their measurements to be at odds with our own findings, suggesting they cannot be used as the sole measurement of pollution levels."

While further studies are necessary to investigate the practicality and feasibility of using IS to assess large populations, Prof. Fireman is confident her findings demonstrate the capability of IS to biologically monitor the accumulation of airborne particles in the lungs of children with asthma.

"Most important, perhaps, we have found that environmental monitoring is not enough. You need a biomonitoring technique, like IS, which is a more physiologically sensitive," said Prof. Fireman. "This study suggests that we are not well protected by environmental stations. To help parents determine whether they should continue to live with their children in polluted areas, we will need to combine our strategies."

Nanotubes May Restore Sight to Blind Retinas
12/2/2014

TAU researchers develop groundbreaking wireless material capable of sparking neuronal activity in response to light

The aging process affects everything from cardiovascular function to memory to sexuality. Most worrisome for many, however, is the potential loss of eyesight due to retinal degeneration.

New progress towards a prosthetic retina could help alleviate conditions that result from problems with this vital part of the eye. An encouraging new study published in Nano Letters describes a revolutionary novel device, tested on animal-derived retinal models, that has the potential to treat a number of eye diseases. The proof-of-concept artificial retina was developed by an international team led by Prof. Yael Hanein of Tel Aviv University's School of Electrical Engineering and head of TAU's Center for Nanoscience and Nanotechnology and including researchers from TAU, the Hebrew University of Jerusalem, and Newcastle University.

"Compared to the technologies tested in the past, this new device is more efficient, more flexible, and can stimulate neurons more effectively," said Prof. Hanein. "The new prosthetic is compact, unlike previous designs that used wires or metals while attempting to sense light. Additionally, the new material is capable of higher spatial resolution, whereas older designs struggled in this area."

A natural shape

The researchers combined semiconductor nanorods and carbon nanotubes to create a wireless, light-sensitive, flexible film that could potentially replace a damaged retina. The researchers tested the new device with chick retinas which were not yet light sensitive to prove that the artificial retina is able to induce neuronal activity in response to light.

Patients with age-related macular degeneration (AMD), which usually affects people age 60 or older who have damage to a specific part of the retina, will stand to benefit from the nanotube device if it is proved compatible in animals over the long term.

According to TAU doctoral student and research team member Dr. Lilach Bareket, there are already medical devices that attempt to treat visual impairment by sending sensory signals to the brain. While scientists are trying different approaches to develop an implant that can "see" light and send visual signals to a person's brain, to counter the effects of AMD and related vision disorders, many of these approaches require the use of metallic parts and cumbersome wiring or result in low resolution images. The researchers set out to make a more compact device.

Progress in the right direction

"In comparison with other technologies, our new material is more durable, flexible, and efficient, as well as better able to stimulate neurons," said Prof. Hanein. "We hope our carbon nanotube and semiconductor nanorod film will serve as a compact replacement for damaged retinas."

"We are still far away from actually replacing the damaged retina," said Dr. Bareket. "But we have now demonstrated that this new material stimulates neurons efficiently and wirelessly with light. If you compare this to other devices based on silicon technology, which require wiring to outside energy or light sources, this is a groundbreaking new direction."

The research team received funding for their study from the Israel Ministry of Science and Technology, the European Research Council, and the Biotechnology and Biological Sciences Research Council.

Enriched Environments Hold Promise for Brain Injury Patients
11/11/2014

TAU study finds improved living conditions led to rehabilitation of mice following traumatic brain injury

As football players are learning, a violent blow to the head has the potential to cause mild to severe traumatic brain injury — physical damage to the brain that can be debilitating, even fatal. The long-term effects run the gamut of human functioning, from trouble communicating to extensive cognitive and behavioral deterioration. To date, there is no effective medical or cognitive treatment for patients with traumatic brain injuries.

But a new study from Tel Aviv University researchers points to an "enriched environment" — specially enhanced surroundings — as a promising path for the rehabilitation of mild traumatic brain injury (mTBI) patients. The research, published in Behavioral Brain Research, was led by Prof. Chagi Pick of TAU's Sagol School of Neuroscience and Sackler Faculty of Medicine and conducted by a team of researchers from both TAU and TAU-affiliated Tel Aviv Sourasky Medical Center.

Mice move on up

The study, conducted on mice at a TAU laboratory, followed two groups of animals with minimal traumatic brain injury. The first group was kept in standard cages and maintained under routine conditions, while the second enjoyed "enriched environments," replete with sensory stimuli, open space, and plentiful opportunities to eat and exercise.

"A house may survive an earthquake, but up close you will see cracks in the walls. This is what may happen following traumatic brain injury," said Prof. Pick. "An MRI might determine that the brain looks normal, but fast forward two years and the patient, who was married and successful, is suddenly unemployed, divorced, and miserable — without any awareness or understanding that new and lasting cognitive and emotional difficulties (including various degrees of amnesia, difficulty concentrating, depression, apathy, anxiety, and even a prominent personality change) emerged due to a car accident two years earlier.

"Doctors in the emergency room harness the Glasgow Coma Scale to assess the extent of brain trauma in incoming patients — from a child who falls off the bed to a victim of a major accident," Prof. Pick continued. "In the majority of cases, doctors determine minimal damage according to the symptoms that appear over a very short period of monitoring — just 30 minutes. In 85% of cases, this is accurate, but in 15% of cases, a cascade of serious damage has just begun, and we don't really know why. But this is what we are trying to figure out."

An environment of riches

According to the study, an "enriched environment" may play a critical role in brain regulation, behavior, and physiology. Using a model of minimal TBI in mice, the team evaluated the effect of transition to an enriched environment on behavioral and cognitive parameters. Using the Novel Object Recognition task, in which mice exhibit different levels of curiosity about new objects placed in their cages, and run different mazes to establish navigation abilities, the researchers sought to determine the mice's level of functioning in standard cages versus enriched environments — cages with additional stimuli, running wheels, plenty of food, open space, and water. The mice exposed to an enriched environment showed a marked improvement in recovery from brain injuries.

"We have shown that just six weeks in an enriched environment can help animals recover from cognitive dysfunctions after traumatic brain injury," said Prof. Pick. "Possible clinical implications indicate the importance of adapting elements of enriched environments to humans, such as prolonged and intensive physical activity, possibly combined with intensive cognitive stimulation. Through proper exercise, stimuli, and diet, we can improve a patient's condition. No one is promising a cure, but now we have evidence that this can help."

Obesity Plays Major Role in Triggering Autoimmune Diseases
11/10/2014

TAU study says obesity is a primary environmental factor sparking disorders like Crohn's Disease and multiple sclerosis

Autoimmune diseases like Crohn's Disease and multiple sclerosis, in which the immune system attacks its own body rather than predatory invaders, affect 5-20% of the global community. A study published recently in Autoimmunity Reviews by Prof. Yehuda Shoenfeld, the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel Aviv University's Sackler Faculty of Medicine and Head of Zabludowicz Center for Autoimmune Diseases at Chaim Sheba Medical Center, Tel Hashomer, points to the major role obesity plays in triggering and prolonging these autoimmune diseases.

According to the research, obesity leads to a breakdown of the body's protective self-tolerance, creating the optimal environment for autoimmune diseases, and generates a pro-inflammatory environment likely to worsen the disease's progression and hinder its treatment.

"We've been aware of a long list of causes of autoimmune disorders — infections, smoking, pesticides, lack of vitamins, and so forth. But in last five years, a new factor has emerged that cannot be ignored: obesity," said Prof. Shoenfeld. "According to the World Health Organization, approximately 35% of the global community is overweight or obese, and more than ten autoimmune diseases are known to be associated with increased weight. So it's critical to investigate obesity's involvement in the pathology of such diseases."

The culprit in fat: Adipokines

In addition to their own research, Prof. Shoenfeld and his team from Tel Hashomer hospital conducted a systematic review of 329 studies from around the world on the relationship between obesity, adipokines (compounds secreted by fat tissue and involved in numerous physiological functions, including the immune response), and immune-related conditions like rheumatoid arthritis, multiple sclerosis, type-1 diabetes, psoriasis, inflammatory bowel disease, psoriatic arthritis, and Hashimoto thyroiditis.

"According to our study and the clinical and experimental data reviewed, the involvement of adipokines in the pathogenesis of these autoimmune diseases is clear," said Prof. Shoenfeld. "We were able to detail the metabolic and immunological activities of the main adipokines featured in the development and prognosis of several immune-related conditions."

A dose of Vitamin D

Prof. Shoenfeld conducted a study on mouse populations with multiple sclerosis given a Mediterranean diet rich in unsaturated fats. He found that Vitamin D deficiency was also a result of obesity and, once corrected, alleviated paralysis and kidney deterioration associated with the disorder. It also improved the prognosis and survival of the mice.

"Modern life makes us all prone to Vitamin D deficiency," said Prof. Shoenfeld. "We live in labs, offices, and cars. When Vitamin D is secreted in fat tissue, it is not released into the body, which needs Vitamin D to function properly. Since Vitamin D supplements are very cheap and have no side effects, they are an ideal compound that should be prescribed to anyone at risk of a compromised immune system."

Prof. Shoenfeld welcomes the general trend toward personalized medicine, and believes his research can be a basis for specific therapies to treat autoimmune syndrome. "If a patient is at risk, he or she should be told to do everything in his or her power to maintain a healthy weight," he said.

TAU Professors Awarded Inaugural Prize for Groundbreaking Innovation in Cancer Treatment
11/7/2014

Profs. Dan Peer and Rimona Margalit selected among top Israeli inventors for Untold News Awards

Prof. Dan Peer
Prof. Dan Peer

Prof. Rimona Margalit
Prof. Rimona Margalit

Tel Aviv University's Prof. Dan Peer of the Department of Cell Research and Immunology and Prof. Rimona Margalit of the Department of Biochemistry and Molecular Biology will be awarded $10,000 for their groundbreaking development in cancer treatment at the inaugural Untold News Awards on Wednesday, November 12, 2014, from 6:00 to 8:00 p.m. at the Harmonie Club in New York City. Theirs is one of three Israeli inventions to be selected for the award out of a pool of candidates submitted by prestigious Israeli institutions including TAU, Weizmann Institute of Science, Technion Israel Institute of Technology, and Hebrew University, amongst others.

An American non-profit, Untold News is dedicated to promoting Israeli inventors and educating Americans on the positive news generated from the State of Israel.

Prof. Peer, who is also Head of Nanomedicine and the Scientific Director of the Center for Nanoscience and Nanotechnology at TAU, and Prof. Margalit will be honored for their development of the "cancer bullet." The treatment is an injectable form of patient-friendly chemotherapy that targets only diseased cells. According to Peer, this is the first time nanoparticles are used in clusters instead of individually and has shown little to now side effects in trials.

Winners were selected by a jury of American leaders including Mr. David Schizer, former Dean of Columbia Law School; Dr. Barry Coller, Chief Medical Officer, Rockefeller University; Tony Tether, former Director of DARPA; and Heidi Jacobus, Chariman and CEO of Cybernet Systems. This year's winners also include Israeli professor Shlomo Magdassi and engineer Idan Tobis.

Following their New York appearance, the winners will visit Philadelphia, Boston, and Washington DC.

A global hub of inventions

Untold News was founded by lifelong New Yorker and former advertising executive Marcella Rosen, who discovered that Israel is home to almost as many start-ups, inventions, and patents as the entirety of the European Union and has attracted twice as much venture capital per capita as the United States. "My mission," says Rosen, "is to help the world understand that Israel is more than a country at war. Our first ever Untold News Awards reception will showcase three amazing inventors and their inventions, whom the jury and I feel will unequivocally make a mark on the worldwide stage."

All Kidding Aside: Medical Clowns Calm Children During Uncomfortable Allergy Test
11/6/2014

For the first time, TAU study empirically confirms effectiveness of "medical clowns" in puncture tests

The dreaded scratch or puncture test is the most common way of assessing allergic reactions to as many as 40 different substances at once. But because the test involves needles that prick multiple points along the skin's surface, it's a particularly high-stress examination for children — and their understandably anxious parents.

A new study by Tel Aviv University researchers provides the first quantitative analysis of the role of "medical clowns" in assuaging the anxiety and pain felt by children undergoing allergy tests. The research, published in Allergy, was conducted by a team led by Prof. Arnon Goldberg and Dr. Ronit Confino-Cohen of TAU's Sackler Faculty of Medicine and Meir Medical Center.

The study found that not only do medical clowns significantly decrease the level of anxiety expressed by children undergoing these tests, but they also assuage the pain the children experience.

Caring for the kids

"Our research group is comprised of experienced allergists," said Prof. Goldberg, "so we all knew that children, and occasionally their parents, express deep anxiety and fear of the skin tests. We wanted to see what could be done to improve the situation."

The study involved 91 children, aged two to 17 years, who underwent skin-prick testing at the Allergy and Clinical Immunology Unit of Meir Medical Center in Israel. A clown from Dream Doctors, an organization that provides Israeli medical centers with medical clowns, accompanied 45 of the children, while 46 kids underwent testing without clowns. Children with coulrophobia, a fear of clowns, were excluded. Children aged eight and older and all the children's parents rated their anxiety in questionnaires administered before and after testing.

Both older and younger children accompanied by clowns were far less anxious during testing than the control group. Their parents were also less anxious preceding the testing than parents in the control group, and their anxiety was further reduced after testing. No change in either anxiety level was recorded in control parents.

"The intervention of medical clowns during various medical procedures performed on children has been used to relieve anxiety and pain, but their role in allergy skin testing has never been evaluated," said Prof. Goldberg. "Our work offers a better method for easing the pain and anxiety induced in children by these tests. Children and parents will definitely benefit from the contribution of medical clowns to stressful medical tests like the skin prick test."

Frozen "Poop Pills" May Help Treat Life-Threatening Infection
11/3/2014

Joint study by TAU, Harvard, and other researchers finds feces capsules effective and more accessible than other treatments

The stubborn bacterium Clostridium difficile (C. difficile) is severe enough to send its victims to the hospital with life-threatening diarrhea. Americans spend an estimated $3.2 billion battling this bacterium, involved in some 14,000 deaths in the U.S. each year.

A study published recently in the Journal of the American Medical Association suggests an unconventional way of treating the C. difficile infections — capsules that contain frozen feces. The research, conducted by a team from Tel Aviv University, Harvard University, Massachusetts General Hospital, and Boston Children's Hospital, suggests the solution may be found in frozen fecal samples of healthy people, whose gastrointestinal tracts contain just the right mix of bacteria. By transplanting fecal samples from healthy patients into guts infected by C. difficile, the researchers were able to resuscitate the ailing gastrointestinal tracts.

For their study, the scientists collected samples from four healthy donors who hadn't taken antibiotics for at least six months. The donated stool was screened for diseases and harmful bacteria, placed in a blender and mixed with saline, then strained. The remaining "slurry" was concentrated and packed into capsules, which were then frozen.

Overall, the researchers found, the frozen "poop pills" led to a clinical resolution of diarrhea in 90% of the patients. On average, it took four days for the pills to work. Though the researchers described the results as preliminary, they said they could help make fecal transplants "accessible to a wider population of patients, in addition to potentially making the procedure safer."

For more, read the story in the Los Angeles Times: "Study: Frozen poop pills may make fecal transplants simpler and safer"

Geneticist and Humanitarian: Prof. Mary-Claire King Receives Lasker Award
10/29/2014

TAU honorary doctor recognized with "American Nobel" for cancer research and genetic identification of human rights victims

Prof. Karen Avraham and Prof. Mary-Claire King
TAU's Prof. Karen Avraham (left) with Prof. Mary-Claire King at the Lasker Award ceremony in New York

At a ceremony held in New York City on September 19, 2014, leading geneticist and humanitarian Prof. Mary-Claire King, the American Cancer Society Professor of Genome Sciences and Medicine at the University of Washington in Seattle and 2008 Honorary Doctor of Philosophy of Tel Aviv University, was awarded the 2014 Lasker-Koshland Special Achievement Award in Medical Science.

In addition to her honorary degree from TAU, Prof. King was the 2012-2013 Sackler Lecturer at the TAU School of Medicine, and for the past 18 years she has been the research partner of Prof. Karen Avraham, Professor of Human Molecular Genetics and Vice Dean at the Sackler Faculty of Medicine.

The prize, awarded annually since 1946 by the Albert and Mary Lasker Foundation, is considered by many the "American Nobel."

"Prof. Mary-Claire King has employed her intellect, dedication, and ethical sensibilities to generate knowledge that has catalyzed profound changes in health care, and she has applied her expertise to promote justice where nefarious governments have terrorized their citizens," the foundation stated.

Prof. King is one of the world's leading scientists in the field of human molecular genetics. She was the first to demonstrate that a genetic predisposition for breast cancer exists as the result of inherited mutations in the gene she named BRCA1. More recently, she devised a plan to screen for all genes that predispose to breast and ovarian cancers.

Prof. King also pioneered the use of genetic identification to identify victims of human rights violations. Beginning in the 1980s, Prof. King helped find children in Argentina taken from their families during the "Dirty War" of the late 1970s and early 1980s, using a novel approach based on mitochondrial DNA sequencing. She used the same method to identify victims of the bombing of the Jewish community center in Buenos Aires in 1994, and victims of other human rights abuses, natural disasters and man-made tragedies.

For more, visit the Lasker Foundation Web site at http://www.laskerfoundation.org/awards/2014_s_description.htm

Breathe Easier: Get Your D
10/28/2014

TAU study finds asthmatics with Vitamin D deficiency are 25 percent more likely to experience acute attacks

Asthma, which inflames and narrows the airways, has become more common in recent years. While there is no known cure, asthma can be managed with medication and by avoiding allergens and other triggers. A new study by a Tel Aviv University researcher points to a convenient, free way to manage acute asthmatic episodes — catching some rays outside.

According to a paper recently published in the journal Allergy, measuring and, if need be, boosting Vitamin D levels could help manage asthma attacks. The research, conducted by Dr. Ronit Confino-Cohen of TAU's Sackler Faculty of Medicine, Meir Medical Center, and the Clalit Research Institute, and Dr. Becca Feldman of the Clalit Research Institute drew on the records of millions of patients and used physician diagnoses, rather than self-reports, for evidence of asthma episodes.

"Vitamin D has significant immunomodulatory effects and, as such, was believed to have an effect on asthma — an immunologically mediated disease," said Dr. Confino-Cohen. "But most of the existing data regarding Vitamin D and asthma came from the pediatric population and was inconsistent. Our present study is unique because the study population of young adults is very large and 'uncontaminated' by other diseases."

A broad study

Dr. Confino-Cohen and her team of researchers analyzed the medical records of nearly four million members of Clalit Health Services, Israel's largest health care provider. The Vitamin D levels of 307,900 people were measured between 2008 and 2012. Researchers also took into account key predictors of asthma, such as obesity, smoking, and other chronic diseases. Of some 21,000 asthma patients in Israel studied, those with a Vitamin D deficiency were 25 percent more likely than other asthmatics to have had at least one flare-up in the recent past.

The researchers found that Vitamin D-deficient asthmatics were at a higher risk of an asthma attack. "Uncontrolled asthma" was defined as being prescribed at least five rescue inhalers, one prescription of oral corticosteroids, or visiting the doctor for asthma at least four times in a single year.

"Our results add more evidence to the link between Vitamin D and asthma, suggesting beneficial effects of Vitamin D on asthma exacerbations," said Dr. Confino-Cohen. "We expect that further prospective studies will support our results. In the meantime, our results support a recommendation for screening of Vitamin D levels in the subgroup of asthma patients who experience recurrent exacerbations. In those with Vitamin D deficiency, supplementation may be necessary."

Sunny side up?

While most of the Vitamin D in people's bodies comes from exposure to the sun, dermatologists recommend obtaining the ingredient from other sources — fish, eggs, cod liver oil, fortified milk, or a dietary supplement — due to the dangers of overexposure to the sun.

"We know a lot about this disease and many therapeutic options are available. So it's quite frustrating that the prevalence of asthma is not decreasing and many patients suffer exacerbations and significant impairment in their quality of life," Dr. Confino-Cohen, an allergy and clinical immunology specialist, said. "Increasing Vitamin D levels is something we can easily do to improve patients' quality of life."

Based on the findings, the researchers recommend that people whose asthma cannot be controlled with existing treatments have their Vitamin D levels tested. For those with a vitamin D deficiency, supplements may make sense.

"This study provided an exceptional opportunity to research asthma. I received a research grant from Clalit Health Services, which provided us with the opportunity to use their very large database and to conduct the study with the professional staff of Clalit Research Institute," said Dr. Confino-Cohen. "We anticipate further prospective research that will support our findings and open a new treatment modality to the population of uncontrolled asthmatics."

Slowing the Biological Clock
10/27/2014

TAU study finds neutralizing an immune system gene could improve the success of fertility treatments in women

Difficulty in conceiving a child is a major challenge for one in seven heterosexual couples in America, especially for those over the age of 35. Now a new discovery by researchers at Tel Aviv University and Chaim Sheba Medical Center at Tel Hashomer could boost the chances of conception in women undergoing in vitro fertilization (IVF) treatments.

Their new research reveals a linkage between the genes of the innate immune system — immunity with which human beings are born, rather than immunity they acquire during their lives — and ovarian longevity. The study, published recently in the Proceedings of the National Academy of Sciences, constituted the doctoral work of Dr. Shiri Uri-Belapolsky of TAU's Sackler School of Medicine. The research was led by Prof. Ruth Shalgi, of the Department of Cell and Developmental Biology at TAU's Sackler School of Medicine, Dr. Yehuda Kamari and Prof. Dror Harats of TAU's Sackler Faculty of Medicine and Sheba Medical Center, and Dr. Aviv Shaish of Sheba Medical Center.

According to research conducted on laboratory mice, the genetic deletion of the protein Interleukin-1 (IL-1), a key player in the innate immune system, could improve the number of eggs available for fertilization as well as improve the ovarian response to hormonal stimulation involved in IVF procedures. This could prove especially effective in women who initially respond poorly to hormonal treatment.

Neutralizing the risks

"We revealed a clear linkage between the genes of the innate immune system and female reproduction," said Dr. Uri-Belapolsky. "The results of our study, which point to neutralizing the effects of the IL-1 protein to slow down the natural processes that destroy the eggs, may set the basis for the development of new treatments, such as an IL-1 blockade that would raise the number of eggs recovered during an IVF cycle and reduce the amount of hormones injected into women undergoing the treatment."

The connection between IL-1 and fertility was discovered by accident in the course of research performed by the scientists on the role of IL-1 in atherosclerosis, the hardening of the arteries. In a surprise result of the research, the fertility lifespan of IL-1-deficient mice was found to be 20% longer than that of control wild-type mice.

Keeping the clock ticking

Female mammals, including humans, are born with a finite number of eggs and are subject to a biological clock that dictates the end of the reproductive lifespan at around 50 years of age. Over the past decade, a trend of postponing childbearing into advanced age has led to a corresponding upward trend in the number of IVF treatments. Inflammation has been reported to affect both IVF outcomes and the ovarian reserve adversely. "Identifying a possible culprit, such as Interleukin-1, may offer new insight into the mechanisms responsible for egg loss as well as practical interventions," the study reports.

"Our revelation is secured with a patent application, and naturally, further study in mice and in humans is required to examine this therapeutic opportunity," said Prof. Shalgi. "I believe we will take this research forward into human clinical trials. However, there is still research to be done before we can start these trials."

The "Cyberwar" Against Cancer Gets a Boost from Intelligent Nanocarriers
10/7/2014

TAU researcher advances novel strategy to fight cancer by shoring up the immune system

Two years ago, Prof. Eshel Ben-Jacob of Tel Aviv University's School of Physics and Astronomy and Rice University's Center for Theoretical Biological Physics made the startling discovery that cancer, like an enemy hacker in cyberspace, targets the body's communication network to inflict widespread damage on the entire system. Cancer, he found, possessed special traits for cooperative behavior and used intricate communication to distribute tasks, share resources, and make decisions.

In research published in the Early Edition of the Proceedings of the National Academy of Sciences, Prof. Ben-Jacob and researchers from Rice University and the University of Texas M.D. Anderson Cancer Center, the leading cancer treatment center in the U.S., offer new insight into the lethal interaction between cancer cells and the immune system's communications network. Prof. Ben-Jacob and the study co-authors developed a computer program that models a specific channel of cell-to-cell communication involving exosomes (nanocarriers with crucial cellular "intelligence") that both cancer and immune cells harness to communicate with other cells.

"Recent research has found that cancer is already adept at using a kind of 'cyberwarfare' against the immune system. We studied the interplay between cancer and the immune system to see how we might be able to shift the balance against cancer," said Prof. Ben-Jacob, noting a difference between the innate and the adaptive qualities of the immune system. "In the beginning, cancer is inhibited by the body's innate immunity. But once cancer escapes the immunity, there is a race between the progression of cancer and the ability of the adaptive immune system to recognize and act against it."

Cyberwarfare of the body

"What we are dealing with is cyberwarfare, pure and simple. Cancer uses the immune systems' own communications network to attack not the soldiers but the generals that are coordinating the body's defense," said Prof. Ben-Jacob.

To better understand the role of exosome-mediated cell-to-cell communication in the battle between cancer and the immune system, the researchers created a computer model that captured the exosomal exchange between cancer cells, dendritic cells, and the other cells in the immune system.

The new model is based on earlier research, which showed that dendritic cells, mediators between the body's innate and adaptive immune systems (the former protects against all threats at all times and the latter guards more efficiently against specific, established dangers), employed exosomes to fulfil their task. The researchers discovered that, overtaken by cancer, these nanocarriers, which contain such vital components as signaling proteins, RNA snippets, and microRNAs, can command cells to change their tasks, placing the entire system at risk.

Finding a better balance between the strong and the weak

According to the new research, three possible cancer states can exist: strong, intermediary, and weak. The intermediary state — in which cancer is neither strong nor weak and in which the immune system is on high alert — could be the key to a new therapeutic approach with reduced side effects. Prof. Ben-Jacob believes it is possible to force cancer from a strong to moderate state, and then from a moderate to weak state, by alternating cycles of radiation or chemotherapy with immune-boosting treatments.

"Our first important discovery is that this situation is due to the exosome-based cyberwar between cancer and the immune system," said Prof. Ben-Jacob. "Without exosomes, the two possible states are only strong-weak and weak-strong. With exosomes, an intermediary state opens a new way to treat cancer using very a different approach."

Prof. Ben-Jacob likened the exchange to a tug-of-war between cancer and the immune system. "The challenge is to be familiar with the battlefield so that we can manipulate cancer therapies to change the balance in favor of the immune system. When cancer is detected, it is almost always in the context of a cancer-immunity competition," said Prof. Ben-Jacob. "We showed that the way to stop and reverse tumor progression without causing strong side effects is an individualized approach of mixed treatments — i.e., four days of radiation followed by a few days of immune system boosting, followed again by four days of radiation, and so on. If provided in the right order, the treatments could indeed shift the balance toward the immune system's 'victory' in reducing the cancer to the moderate-strong state."

The study was supported by the Cancer Prevention and Research Institute of Texas, the National Science Foundation, and the Tauber Family Funds.

How Rabies "Hijacks" Neurons to Attack the Brain
10/6/2014

Groundbreaking TAU study tracks precise path of deadly virus to the central nervous system

Rabies causes acute inflammation of the brain, producing psychosis and violent aggression. The virus, which paralyzes the body's internal organs, is always deadly for those unable to obtain vaccines in time. Some 55,000 people die from rabies every year.

For the first time, Tel Aviv University scientists have discovered the exact mechanism this killer virus uses to efficiently enter the central nervous system, where it erupts in a toxic explosion of symptoms. The study, published in PLOS Pathogens, was conducted by Dr. Eran Perlson and Shani Gluska of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, in collaboration with the Friedrich Loeffler Institute in Germany.

"Rabies not only hijacks the nervous system’s machinery, it also manipulates that machinery to move faster," said Dr. Perlson. "We have shown that rabies enters a neuron in the peripheral nervous system by binding to a nerve growth factor receptor, responsible for the health of neurons, called p75. The difference is that its transport is very fast, even faster than that of its endogenous ligand, the small molecules that travel regularly along the neuron and keep the neuron healthy."

Faster than a speeding train

To track the rabies virus in the nervous system, the researchers grew mouse sensory neurons in an observation chamber and used live cell imaging to track the path taken by the virus particles. The researchers "saw" the virus hijack the "train" transporting cell components along a neuron and drove it straight into the spinal cord. Once in the spinal cord, the virus caught the first available train to the brain, where it wrought havoc before speeding through the rest of the body, shutting it down organ by organ.

Nerve cells, or neurons, outside the central nervous system are highly asymmetric. A long protrusion called an axon extends from the cell body to another nerve cell or organ along a specific transmission route. In addition to rapid transmission of electric impulses, axons also transport molecular materials over these distances.

"Axonal transport is a delicate and crucial process for neuronal survival, and when disrupted it can lead to neurodegenerative diseases," said Dr. Perlson. "Understanding how an organism such as rabies manipulates this machinery may help us in the future to either restore the process or even to manipulate it to our own therapeutic needs."

Hijacking the hijacker

"A tempting premise is to use this same machinery to introduce drugs or genes into the nervous system," Dr. Perlson added. By shedding light on how the virus hijacks the transport system in nerve cells to reach its target organ with maximal speed and efficiency, the researchers hope their findings will allow scientists to control the neuronal transport machinery to treat rabies and other neurodegenerative diseases.

Disruptions of the neuron train system also contribute to neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). According to Dr. Perlson, "An improved understanding of how the neuron train works could lead to new treatments for these disorders as well."

Viral Infection May Trigger Childhood Diabetes in Utero
10/3/2014

TAU research says prenatal exposure to viruses may cause type 1 diabetes and other autoimmune diseases in children

The incidence of type 1 childhood diabetes has been increasing rapidly worldwide. If blood sugar levels aren't well-controlled, juvenile diabetes can affect nearly every organ of a child's body. And while long-term complications of the disease develop gradually, they may become disabling and even life-threatening. The exact cause of juvenile diabetes has eluded scientists, but a new study from Tel Aviv University suggests a likely trigger before birth.

In a recent paper published in Diabetic Medicine, Prof. Zvi Laron, Professor Emeritus of Pediatric Endocrinology at TAU's Sackler Faculty of Medicine, Director of the Endocrinology and Diabetes Research Unit at Schneider Children's Medical Center of Israel, and Head of the WHO Collaborating Center for the Study of Diabetes in Youth, puts forth evidence that the autoimmune disease is initiated in utero. According to the research, conducted in collaboration with an international team of researchers, women who contract a viral infection during pregnancy transmit viruses to their genetically susceptible fetuses, sparking the development of type 1 diabetes.

Prof. Laron is internationally known for the discovery of the Laron Syndrome, also known as Laron-type Dwarfism, an autosomal recessive disorder characterized by an insensitivity to growth hormone.

The "right season" for diabetes

"We knew that type 1 diabetes was associated with other autoimmune diseases like Hashimoto Thyroiditis, celiac disease, and multiple sclerosis, so we investigated the seasonality of birth months for these respective diseases in Israel and other countries," said Prof. Laron. "We found that the seasonality of the birth of children who went on to develop these diseases did indeed differ from that of the general public.

"In further studies, we found evidence that viral infections of the mother during pregnancy induced damage to the pancreas of the mother and/or the fetus, evidenced by specific antibodies including those affecting the pancreatic cells producing insulin," Dr. Laron said.

For the study, Prof. Laron and his team of researchers from Israel, the University of Washington, and Lund University, Sweden, conducted blood tests of 107 healthy pregnant women, testing for islet cell autoantibodies — evidence of diabetes that appears years before initial symptoms do. They also tested for anti-rotavirus and anti-CoxB3 antibodies.

The researchers found a striking difference between women tested in different seasons, suggesting a link to winter epidemics. The concurrent presence of GAD65 antibodies in cord blood and their mothers indicated autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. In other words, during viral epidemics of winter months, ten percent of the healthy pregnant women who had no family background of autoimmune diseases tested positive for damaging antibodies.

Vaccination before conception

In addition, the cord blood antibody concentrations that exceeded those of the corresponding maternal sample, or antibody-positive cord blood samples with antibody-negative maternal samples, implied an in utero immune response by the fetus.

"If our hypothesis can be verified, then preventive vaccine before conception would be useful in stopping the increasing incidence of type 1 diabetes and other autoimmune diseases," said Prof. Laron. "There is no cure for this diabetes, so true intervention would be important not only medically but also psychologically and financially, as the costs of the lifelong treatment of this chronic disease and other autoimmune diseases are great."

Prof. Laron and his international collaborators are currently raising funds to expand their research to include nearly 1,000 women and newborns.

A Heartbeat Away? Hybrid "Patch" Could Replace Transplants
9/30/2014

TAU researcher harnesses gold nanoparticles to engineer novel biocompatible cardiac patch

Because heart cells cannot multiply and cardiac muscles contain few stem cells, heart tissue is unable to repair itself after a heart attack. Now Tel Aviv University researchers are literally setting a new gold standard in cardiac tissue engineering.

Dr. Tal Dvir and his graduate student Michal Shevach of TAU's Department of Biotechnology, Department of Materials Science and Engineering, and Center for Nanoscience and Nanotechnology, have been developing sophisticated micro- and nanotechnological tools — ranging in size from one millionth to one billionth of a meter — to develop functional substitutes for damaged heart tissues. Searching for innovative methods to restore heart function, especially cardiac "patches" that could be transplanted into the body to replace damaged heart tissue, Dr. Dvir literally struck gold. He and his team discovered that gold particles are able to increase the conductivity of biomaterials.

In a study published by Nano Letters, Dr. Dvir's team presented their model for a superior hybrid cardiac patch, which incorporates biomaterial harvested from patients and gold nanoparticles. "Our goal was twofold," said Dr. Dvir. "To engineer tissue that would not trigger an immune response in the patient, and to fabricate a functional patch not beset by signalling or conductivity problems."

A scaffold for heart cells

Cardiac tissue is engineered by allowing cells, taken from the patient or other sources, to grow on a three-dimensional scaffold, similar to the collagen grid that naturally supports the cells in the heart. Over time, the cells come together to form a tissue that generates its own electrical impulses and expands and contracts spontaneously. The tissue can then be surgically implanted as a patch to replace damaged tissue and improve heart function in patients.

According to Dr. Dvir, recent efforts in the scientific world focus on the use of scaffolds from pig hearts to supply the collagen grid, called the extracellular matrix, with the goal of implanting them in human patients. However, due to residual remnants of antigens such as sugar or other molecules, the human patients' immune cells are likely to attack the animal matrix.

In order to address this immunogenic response, Dr. Dvir's group suggested a new approach. Fatty tissue from a patient's own stomach could be easily and quickly harvested, its cells efficiently removed, and the remaining matrix preserved. This scaffold does not provoke an immune response.

Using gold to create a cardiac network

The second dilemma, to establish functional network signals, was complicated by the use of the human extracellular matrix. "Engineered patches do not establish connections immediately," said Dr. Dvir. "Biomaterial harvested for a matrix tends to be insulating and thus disruptive to network signals."

At his Laboratory for Tissue Engineering and Regenerative Medicine, Dr. Dvir explored the integration of gold nanoparticles into cardiac tissue to optimize electrical signaling between cells. "To address our electrical signalling problem, we deposited gold nanoparticles on the surface of our patient-harvested matrix, 'decorating' the biomaterial with conductors," said Dr. Dvir. "The result was that the nonimmunogenic hybrid patch contracted nicely due to the nanoparticles, transferring electrical signals much faster and more efficiently than non-modified scaffolds."

Preliminary test results of the hybrid patch in animals have been positive. "We now have to prove that these autologous hybrid cardiac patches improve heart function after heart attacks with minimal immune response," said Dr. Dvir. "Then we plan to move it to large animals and after that, to clinical trials."

Dr. Dvir has been awarded a fellowship from the American Heart Association, the Marie Curie Award for Young Investigators, the Alon Fellowship for Young Investigators from the Israeli Ministry of Education, and the Slezak Super Center Award for Cardiac Research.

Single-Neuron “Hub” Orchestrates Activity of an Entire Brain Circuit
9/29/2014

TAU maps precise triggers that activate and neutralize brain cell networks

The idea of mapping the brain is not new. Researchers have known for years that the key to treating, curing, and even preventing brain disorders such as Alzheimer's disease, epilepsy, and traumatic brain injury, is to understand how the brain records, processes, stores, and retrieves information.

New Tel Aviv University research published in PLOS Computational Biology makes a major contribution to efforts to navigate the brain. The study, by Prof. Eshel Ben-Jacob and Dr. Paolo Bonifazi of TAU's School of Physics and Astronomy and Sagol School of Neuroscience, and Prof. Alessandro Torcini and Dr. Stefano Luccioli of the Instituto dei Sistemi Complessi, under the auspices of TAU's Joint Italian-Israeli Laboratory on Integrative Network Neuroscience, offers a precise model of the organization of developing neuronal circuits.

In an earlier study of the hippocampi of newborn mice, Dr. Bonifazi discovered that a few "hub neurons" orchestrated the behavior of entire circuits. In the new study, the researchers harnessed cutting-edge technology to reproduce these findings in a computer-simulated model of neuronal circuits. "If we are able to identify the cellular type of hub neurons, we could try to reproduce them in vitro out of stem cells and transplant these into aged or damaged brain circuitries in order to recover functionality," said Dr. Bonifazi.

Flight dynamics and brain neurons

"Imagine that only a few airports in the world are responsible for all flight dynamics on the planet," said Dr. Bonifazi. "We found this to be true of hub neurons in their orchestration of circuits' synchronizations during development. We have reproduced these findings in a new computer model."

According to this model, one stimulated hub neuron impacts an entire circuit dynamic; similarly, just one muted neuron suppresses all coordinated activity of the circuit. "We are contributing to efforts to identify which neurons are more important to specific neuronal circuits," said Dr. Bonifazi. "If we can identify which cells play a major role in controlling circuit dynamics, we know how to communicate with an entire circuit, as in the case of the communication between the brain and prosthetic devices."

Conducting the orchestra of the brain

In the course of their research, the team found that the timely activation of cells is fundamental for the proper operation of hub neurons, which, in turn, orchestrate the entire network dynamic. In other words, a clique of hubs works in a kind of temporally-organized fashion, according to which "everyone has to be active at the right time," according to Dr. Bonifazi.

Coordinated activation impacts the entire network. Just by alternating the timing of the activity of one neuron, researchers were able to affect the operation of a small clique of neurons, and finally that of the entire network.

"Our study fits within framework of the 'complex network theory,' an emerging discipline that explores similar trends and properties among all kinds of networks — i.e., social networks, biological networks, even power plants," said Dr. Bonifazi. "This theoretical approach offers key insights into many systems, including the neuronal circuit network in our brains."

Parallel to their theoretical study, the researchers are conducting experiments on in vitro cultured systems to better identify electrophysiological and chemical properties of hub neurons. The joint Italy-Israel laboratory is also involved in a European project aimed at linking biological and artificial neuronal circuitries to restore lost brain functions.

Life, Liberty, and the Pursuit of Healthcare?
9/23/2014

TAU study finds wealthiest older Americans worse off than poorest counterparts in other countries

The Affordable Care Act — "Obamacare" — was signed into law in 2010 and promised the largest overhaul of the U.S. healthcare system since the 1960s. Designed to provide medical care to uninsured Americans, it has been widely decried as an unwarranted intrusion into the affairs of private businesses and individuals.

However, an independent comparative study of healthcare systems in six Western countries, published last month in Social Science and Medicine, supports a move away from privatized medicine toward state-sponsored healthcare systems. In her research, Dina Maskileyson of Tel Aviv University's Gershon H. Gordon Faculty of Social Sciences found that privatized medical care in the U.S. has contributed to greater wealth-health inequality than state-sponsored healthcare systems in Sweden, the U.K., Israel, Germany, and the Czech Republic. According to her new study, the wealthiest older people in the U.S. surprisingly suffered from worse health than the poorest older people in the other countries reviewed. Moreover, household wealth has a far more powerful effect on the state of an older person's health in the U.S. than in any of the other countries.

"The positive association between household wealth and health is about twice as strong in the U.S. than in the other countries examined," said Ms. Maskileyson. "In the U.S., every additional percentage point in household wealth increased physical health by about twice as much as it did in the other countries. Among the six countries, household wealth was the most important factor in predicting health outcomes of older Americans."

A survey of surveys

Using a statistical model estimating individual-level data for 41,533 individuals aged 50 and older, Ms. Maskileyson drew her information from the Survey on Health, Ageing and Retirement in Europe (SHARE), the U.S. Health and Retirement Study (HRS), and the English Longitudinal Study of Ageing (ELSA). She decided to focus on total household wealth instead of income because household wealth reflects the cumulative and dynamic nature of economic well-being that is especially relevant for older citizens and retirees who do not receive a monthly salary but rely on medical care substantially more than younger sectors of society.

According to the study, the U.S.'s private-based healthcare system not only produced poorer health outcomes and increased the wealth-health inequality gap, it also left the wealthiest Americans, with access to the "best money can offer," still worse off than the poorest citizens in the U.K., Germany, Sweden, and the Czech Republic.

Trends to privatization in Israel

"The fact that Israel in recent decades has shifted from public to private healthcare — the opposite direction of other developed countries — reinforced my motivation to examine how differently funded healthcare systems may influence population health and health inequality," said Ms. Maskileyson. "Dangerous trends of privatization in the Israeli healthcare system may lead to an increase in total national expenditure on health by promoting expensive health services, like those in the U.S. that only wealthy people can access."

"I hope policy makers in the United States and Israel look to the experiences of other countries for guidance," said Ms. Maskileyson.

Ms. Maskileyson is currently researching health disparities among immigrants in the U.S.

Lack of Thyroid Hormone Blocks Hearing Development
9/22/2014

TAU researchers discover that a genetic form of deafness is due to absence of thyroid hormone


Scanning electron microscopy of inner hair cells from cochleas of wild type (top) and mutant (bottom) mice. Image courtesy Dr. Karen Avraham and Dr. Amiel Dror.

Fatigue, weight gain, chills, hair loss, anxiety, excessive perspiration — these symptoms are a few of the signs that the thyroid gland, which regulates the body's heart rate and plays a crucial role in its metabolism, has gone haywire. Now, new research from Tel Aviv University points to an additional complication caused by thyroid imbalance: congenital deafness.

The study, published in Mammalian Genome, was conducted by Prof. Karen B. Avraham and Dr. Amiel Dror of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler School of Medicine. Using state-of-the-art imaging, the researchers found that congenital deafness can be caused by an absence of a thyroid hormone during development.

"Since our laboratory mainly focuses on the system of the inner ear, the study of a system such as the thyroid gland was new to us and therefore challenging," said Dr. Dror. "My curiosity as to how these two systems interact together to develop normal hearing led to this multidisciplinary study."

A colorful approach

Prof. Karen Avraham and Dr. Amiel Dror
Dr. Karen Avraham and Dr. Amiel Dror.

The researchers used mouse populations to study a form of congenital deafness that affects humans. Harnessing electron microscopy at the Sackler Cellular & Molecular Imaging Center, researchers tracked the inner hair cells of the cochlea (the auditory portion of the inner ear) in two groups — control (wild) mice and mutant (congenitally deaf) mice. Inner-ear hair bundles in the affected mice were labelled with bright colors to highlight the disorganization of the ear's hair cells.

Examination of the inner ear showed a spectrum of structural and molecular defects consistent with hypothyroidism or disrupted thyroid hormone action. The researchers' analysis of the images revealed defective formation of the mice's thyroid glands: labelled thyroid follicles did not grow or grew incompletely.

"Our work demonstrated that normal hearing fails to develop when thyroid hormone availability is insufficient as a result of a genetic mutation," said Dr. Dror. "Our model provides a platform to test therapeutic approaches in order to prevent hearing loss before it occurs. There is still long way ahead before we get to the point of practical treatments with our research, but we believe we are moving in the right direction."

A lifelong commitment

"My attraction to sound began very early as a child," said Dr. Dror. "I play string instruments and pay great attention to sound quality and perception. As a graduate student in the Avraham laboratory, I was exposed to the fascinating world of genetics and the opportunity to combine two fields of research that I am interested in: genetics and hearing. Now that I have continued this research as a medical student, the direct interaction with patients with hearing impairments encouraged me to explore the clinical significance of my research."

As a physician, Dr. Dror believes it is important to pursue research with clinical consequences for his patients. "The basis of all advanced medicine relies on both basic science and clinical research. I hope that our study will contribute a modest part to global efforts for improved medical care and treatment of hearing impairments," Dr. Dror said.

The study was supported by the National Institutes of Health and I-CORE Gene Regulation in Complex Human Disease.

Study Finds Drop in Death Rates from Strokes Over Last Two Decades
9/15/2014

But positive trend is inconsistent among different age groups, warns TAU researcher

Despite the significant reduction in the overall incidence and death rates from strokes in the United States over the past twenty years, more attention needs to be paid to specific age groups, a recent study found.

The new research, conducted by Dr. Silvia Koton of Tel Aviv University's Sackler Faculty of Medicine and the Bloomberg School of Public Health at Johns Hopkins University, Prof. Josef Coresh of the Bloomberg School of Public Health, and a team of experts at Hopkins, the University of North Carolina, Chapel Hill and the University of Arizona, found a 24 percent decline per decade in first‐time strokes and a 20 percent drop per decade in deaths after strokes in the last 24 years.

Published in the Journal of the American Medical Association, the study provides empirical evidence of a decline in stroke incidence and subsequent mortality across racial and gender groups. However, it also indicates a disparity of stroke incidence across different age groups.

An ounce of prevention

According to the study, the decline in stroke risk was concentrated mainly in the over‐65 set, with little progress in reducing the risk of strokes among young people. In contrast, the drop in stroke‐related deaths was primarily found among those under age 65, with mortality rates holding firm in older people.

If the obesity epidemic in the U.S. and other countries progresses as expected, the incidence of high blood pressure, diabetes, and high cholesterol levels will rise, and millions will face an increased risk of stroke, says Dr. Koton. "Stroke is not only the number four cause of death in the U.S., but the leading cause of long-term disability in adults. As a result, the prevention of strokes is crucial," said Dr. Koton.

"Since strokes mainly affect older populations, and our population is aging, it is important to learn about changes in stroke incidence and mortality. Our findings are encouraging, but they also suggest that there are specific groups that require more attention. Adopting a healthy life style and controlling cardiovascular risk factors is important for everybody, but apparently there is a need to focus stroke prevention efforts on particular population subgroups."

Extensive study population

The study based its findings on data presented by Atherosclerosis Risk in Communities (ARIC) research, which monitored 15,792 residents between the ages of 45 and 64 in four U.S. communities starting in the late 1980s. In the new study, researchers followed the progress of 14,357 participants who were free of stroke in 1987, with an eye to stroke hospitalizations and deaths between 1987-2011.

Extensive information was collected through interviews and physical exams at baseline (1987-1989) and in three follow-up visits (1990-92, 1993-95, and 1996-98). In addition to the check-ups, annual phone interviews were conducted as well as active surveillance of discharges from local hospitals until December 31, 2011.

"Decreases in stroke incidence and mortality have previously been demonstrated, but empirical data on validated stroke incidence are scarce," said Dr. Koton. "In the ARIC study, each stroke was confirmed by expert review of medical charts using uniform criteria. In addition, previous reports on long-term trends in stroke incidence by race have not been consistent, with some studies in the U.S. showing decreases in stroke incidence over time only among whites — but not African-Americans. Our study shows that stroke incidence and mortality are decreasing also among African-Americans."

The researchers hope their findings will provide a basis for future studies that focus on the reasons for age disparities in stroke incidence and subsequent mortality.

Back to School? Bring Your Inhaler
9/10/2014

TAU research says September is the cruellest month for kids with asthma

A Tel Aviv University study suggests that the riskiest time for children with asthma is September — just as they head back to school.

In a study published in the journal Pediatrics, Dr. Herman Avner Cohen of TAU's Sackler Faculty of Medicine, found that the incidence of asthma attacks is twice as high in September as in August. Not surprisingly, the research points to more than double the prescriptions for asthma rescue inhalers issued in September compared to those issued in August.

To study the phenomenon, researchers reviewed five years of health data from more than 900,000 Israeli children between the ages of 2 and 15. From that group, nearly 9 percent (or more than 82,000) had been diagnosed with asthma.

"Returning to school after summer is strongly associated with an increased risk for asthma exacerbation and unscheduled visits to the primary care physician," said Dr. Cohen. By identifying trends in asthma incidence, parents and physicians can be better prepared to treat their children's asthma flare-ups, he says.

The researchers suggest that the use of asthma-controlling medications is likely at its lowest level of the year just before children return to school. Factors that may cause a rise in September are additional exposures to fall allergens and greater exposure to infections as children congregate at school.

For more, read the story in U.S. News and World Report:

September Peak Month for Kids' Asthma Flares: Study

New Molecular Target is Key to Enhanced Brain Plasticity
9/9/2014

TAU researcher says discovery may lead to improved memory, cognitive function in Alzheimer's patients

As Alzheimer's disease progresses, it kills brain cells mainly in the hippocampus and cortex, leading to impairments in "neuroplasticity," the mechanism that affects learning, memory, and thinking. Targeting these areas of the brain, scientists hope to stop or slow the decline in brain plasticity, providing a novel way to treat Alzheimer's. Groundbreaking new research has discovered a new way to preserve the flexibility and resilience of the brain.

The study, led by Tel Aviv University's Prof. Illana Gozes and published in Molecular Psychiatry, reveals a nerve cell protective molecular target that is essential for brain plasticity. According to Prof. Gozes, "This discovery offers the world a new target for drug design and an understanding of mechanisms of cognitive enhancement."

Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of TAU's Sagol School of Neuroscience. Also contributing to the study were Dr. Saar Oz, Oxana Kapitansky, Yanina Ivashco-Pachima, Anna Malishkevich, Dr. Joel Hirsch, Dr. Rina Rosin-Arbersfeld, and their students, all from TAU. TAU staff scientists Dr. Eliezer Gildai and Dr. Leonid Mittelman provided the state-of-the-art molecular cloning and cellular protein imaging necessary for the study.

Building on past breakthroughs

The new finding is based on Prof. Gozes' discovery of NAP, a snippet of a protein essential for brain formation (activity-dependent neuroprotective protein [ADNP]). As a result of this discovery, a drug candidate that showed efficacy in mild cognitive impairment patients, a precursor to Alzheimer's disease, is being developed. NAP protects the brain by stabilizing microtubules — tiny cellular cylinders that provide "railways and scaffolding systems" to move biological material within cells and provide a cellular skeleton. Microtubules are of particular importance to nerve cells, which have long processes and would otherwise collapse. In neurodegenerative diseases like Alzheimer's, the microtubule network falls apart, hindering cellular communication and cognitive function.

"Clinical studies have shown that Davunetide (NAP) protects memory in patients suffering from mild cognitive impairment preceding Alzheimer's disease," said Prof. Gozes. "While the mechanism was understood in broad terms, the precise molecular target remained a mystery for years. Now, in light of our new research, we know why and we know how to proceed."

Stabilizing microtubules

The breakthrough was the discovery of the mechanism promoting microtubule growth at the tips of the tubes ("rails"). The researchers found that the NAP structure allows it to bind to the tip of the growing microtubule, the emerging "railway," through specific microtubule end-binding proteins, which adhere to microtubules a bit like locomotors to provide for growth and forward movement, while the other end of the microtubule may to be disintegrating. These growing tips enlist regulatory proteins that are essential for providing plasticity at the nerve cell connection points, the synapses.

"We have now revealed that ADNP through its NAP motif binds the microtubule end binding proteins and enhances nerve cell plasticity, providing for brain resilience. We then discovered that NAP further enhances ADNP microtubule binding," said Prof. Gozes.

Researchers hope their discovery will help move Davunetide (NAP) and related compounds into further clinical trials, increasing the potential of future clinical use. Prof. Gozes is continuing to investigate microtubule end-binding proteins to better understand their protective properties in the brain.

Innovative Algorithm Spots Interactions Lethal to Cancer
9/3/2014

TAU research identifying cancer-busting "genetic partners" can personalize cancer treatment

Despite the revolutionary biotechnological advancements of the last few decades, an ideal anti-cancer treatment — one that's immediately lethal to cancer cells, harmless to healthy cells, and resistant to cancer's relapse — is still a dream.

But a concept called "synthetic lethality" holds great promise for researchers. Two genes are considered synthetically lethal when their combined inactivation is lethal to cells, while inhibiting just one of them is not. Synthetic lethality promises to deliver personalized, more effective, and less toxic therapy. If a particular gene is found to be inactive in a tumor, then inhibiting its synthetic lethal partner with a drug is likely to kill only the cancer cells, causing little damage to healthy cells.

While this promising approach has been widely anticipated for almost two decades, its potential could not be realized due to the difficulty experimentally identifying synthetic lethal pairs in cancer. Now new research published last week in the highly prestigious journal Cell overcomes this fundamental hurdle and presents a novel strategy for identifying synthetic lethal pairs in cancer with the potential to bust cancer cells.

Tel Aviv University researchers have developed a computational data-driven algorithm, which identifies synthetic lethal interactions. In their comprehensive, multidisciplinary study, Dr. Eytan Ruppin of TAU's Blavatnik School of Computer Science and the Sackler School of Medicine and Ms. Livnat Jerby-Arnon of TAU's Blavatnik School of Computer Science worked together with other researchers from TAU, The Beatson Institute for Cancer Research (Cancer Research UK), and the Broad Institute of Harvard and MIT.

Taking cancer personally

Analyzing large sets of genetic and molecular data from clinical cancer samples, the scientists were able to identify a comprehensive set of synthetic lethal pairs that form the core synthetic lethality network of cancer. They have demonstrated for the first time that such a network can be used to successfully predict the response of cancer cells to various treatments and predict a patient's prognosis based on personal genomic information.

"We started this research from a very simple observation: If two genes are synthetically lethal, they are highly unlikely to be inactive together in the same cell," said Dr. Ruppin. "As cancer cells undergo genetic alterations that result in gene inactivation, we were able to identify synthetic lethal interactions by analyzing large sets of cancer genetic profiles. Genes that were found to be inactive in some cancer samples, but were almost never found to be inactive together in the same sample, were identified as synthetically lethal."

The crux of the study, according to Ms. Jerby-Arnon, is the synergy between the computational research and the ensuing experiments, conducted at the Beatson Institute and the Broad Institute, to verify the predictive power of the new algorithm.

A road to new therapies

In addition to their promising role in tailoring personalized cancer treatment, the synthetic lethal pairs discovered may also be used to repurpose drugs, which are currently used to treat other non-cancer disorders, to target specific cancer types. "We applied our pipeline to search for drugs that may be used to treat certain forms of renal cancer. We identified two such drugs, currently used to treat hypertension and cardiac dysrhythmia, that may be quite effective," said Dr. Ruppin. "Experiments in cell lines performed by the Gottlieb lab at the Beatson Institute support these findings, and we are now working on additional validations in mice."

The researchers are hopeful that their study will help boost the experimental detection of synthetic lethality in cancer cells and offer further insight into the unique susceptibilities of these pathological cells. "In this study, we have demonstrated the clinical utility of our framework, showing that it successfully predicts the response of cancer cells to various treatments as well as patient survival," said Ms. Jerby-Arnon. "In the long-run, we hope this research will help improve cancer treatment by tailoring the most effective treatment for a given patient."

The researchers are in the process of forming experimental and clinical international collaborations to test key emerging leads for novel drug targets and drug repurposing.

"Junk" Blood Tests May Offer Life-Saving Information
8/27/2014

TAU says contaminated blood cultures can serve as diagnostic predictor for more targeted antibiotics

Some 30 percent of all positive hospital blood culture samples are discarded every day because they're "contaminated" — they reflect the presence of skin germs instead of specific disease-causing bacteria.

Rather than toss these compromised samples into the trash, clinicians may be able to use the resistance profiles of skin bacteria identified by these tests to treat patients with antibiotics appropriate to their ailment, Tel Aviv University researchers say. Dr. Gidi Stein and Dr. Danny Alon of TAU's Sackler Faculty of Medicine and the Department of Internal Medicine B. at Beilinson Hospital, Rabin Medical Center, and Prof. Lilach Hadany and Uri Obolski of the Department of Molecular Biology and Ecology of Plants at TAU's Faculty of Life Sciences conducted a retrospective study on more than 2,500 patients. Their test results demonstrate the unique diagnostic value of "erroneous" cultures.

The study showed the immediate effects on both public health questions and the treatment of individuals whose blood has been contaminated. The results were published in the Journal of Antimicrobial Chemotherapy.

Think before you toss

The more resistant the skin germs, the higher the risk of the infecting bacteria to be resistant, the researchers found. "These results can certainly be used for on-site clinical decisions. Once a contaminated sample has been found to be highly resistant, it is likely that the blood-borne pathogens will have a similar resistance pattern. Thus antibiotic treatment may be better targeted for the actual pathogens," says Prof. Hadany.

In the study, the researchers processed the demographic information, hospital records, blood culture results, and date of death of all patients at the Rabin Medical Center with positive blood cultures from 2009-12. They found that out of 2,518 patients, 1,664 blood cultures drawn from 1,124 patients reflected the presence of a common skin contaminant, coagulase-negative staphylococci (CoNS). High overall CoNS resistance predicted high overall resistance of the bacteria causing disease or infection. Most importantly perhaps, highly resistant CoNS isolates were found to be associated with higher short-term mortality.

The researchers hope their conclusions will cause clinicians to pause before discarding contaminated blood test results.

"Because we have found a direct correlation between resistance profiles of CoNS contaminants and those of the actual infecting bacteria isolated from the same patient, the results of these 'junk' samples can be used to predict patient mortality and correct empirical antibiotic therapy," said Dr. Stein. "This should serve as an additional, non-invasive, diagnostic tool."

Public welfare

According to the researchers, most hospital patients are treated at the outset with broad spectrum antibiotics. Days later, after initial test results are known, clinicians replace broad spectrum antibiotics with more precise narrow-spectrum antibiotics, which treat the specific bacteria identified by the blood sample.

It is well known that narrow spectrum antibiotics are better for the body because they target specific bacteria as opposed to an entire microenvironment. Moreover, broad spectrum antibiotics might result in altered bacterial environments of the skin and gastro-intestinal tract, promoting inflammation and the emergence of resistant pathogens.

"The high rate of inappropriate antibiotic use puts patients and the general public at risk," said Prof. Hadany. "Improved matching of the treatment to the needs of the patient might reduce antibiotic load and the emergence of resistance."

Novel Nanovehicle Transports Drug Cocktail to Target Cancer
8/14/2014

TAU researcher demonstrates clear advantages of polymer carrier that combines several therapeutic drugs

Combination therapies, or "drug cocktails," are part and parcel of modern anti-cancer treatments today. The more researchers learn about cancer and its surreptitiously lethal impact on the body, the more urgent the need to diversify the arsenal at clinicians' disposal.

To that end, Prof. Ronit Satchi-Fainaro, and doctoral students Hemda Baabur-Cohen and Ela Markovsky of Tel Aviv University's Department of Physiology and Pharmacology, Sackler School of Medicine, have developed a novel nanomedical technique to more effectively attack and dismantle tumor cells, while staying "beneath the radar" of the body's immune system as the drugs travel through the body. The new research, to be published in the Journal of Controlled Release, demonstrates that this "synergistic" treatment is far more effective and less toxic than traditional chemotherapies or current combination therapies.

"For the first time, we conducted a systematic study to determine the requirements for a combination of biological materials and drugs: their different mechanisms of action, different toxicity profiles, and distinct defense mechanisms — acquired resistance — of tumor cells in response to them," said Prof. Satchi-Fainaro. "With these three criteria in hand, we were able to set the precise ratio of drugs required to be synergistically effective but not harmful to the body."

Working in combination

Prof. Satchi-Fainaro and her team leveraged the performance and toxicity of two common chemotherapy drugs — doxorubicin (DOX) and paclitaxel (PTX) — to produce the best combined ratio. Once an effective, safe level was established on mice afflicted with human breast cancer, the researchers sought the perfect carrier to safely transport these therapies to their ultimate destination: human cancer cells.

"When combination therapy is used, the drugs do not reach the tumor at the same time," said Prof. Satchi-Fainaro. "Each drug has a different pharmacokinetic profile — that is, a specific interaction between the drug and the body. So we looked for a unique nanocarrier that would bind the drugs and ensure they reach the tumor and release the drugs at the same time."

The researchers chose polyglutamic acid (PGA) as the nanovehicle to transport the two chemotherapies. The PGA-PTX-DOX combination demonstrated a major advantage over a combination of traditional therapies. Furthermore, it was the first time scientists were able to systematically demonstrate a model of combined nanomedicine that also exhibited superior anti-tumor efficacy.

"Stealth" carriers

"By putting several passengers in one 'taxi' made of a polymer, all of them can arrive at the same site at the same time," said Prof. Satchi-Fainaro. "This forces the drugs to share the same pharmacokinetic profile. The nanomedicine we designed is a pro-drug, activated by an enzyme produced in many types of cancers. Once the polymer 'taxi' is degraded, the drugs are released at the tumor site, facilitating a truly synergistic cooperation.

"We have developed a system that can be used for different chemotherapies and combined with drugs targeting the tumor microenvironment, such as anti-angiogenic and anti-inflammatory drugs. The applications are truly endless. This system can be exploited for personalized therapy in which we analyze each patient's tumor cells to tailor the right drug combination on the polymer for the cancer," Prof. Satchi-Fainaro continued.

"Our aim is to expand our arsenal of anti-cancer weapons while decreasing the toxicity of the chemotherapy drugs used. Our 'stealth' carriers travel under the radar of the immune system, straight to the tumor and its supporting microenvironment."

The researchers' innovative platform is patent pending.

Involuntary Eye Movement a Foolproof Indication for ADHD Diagnosis
8/13/2014

TAU researchers develop diagnostic tool for the most commonly misdiagnosed disorder

Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed — and misdiagnosed — behavioral disorder in children in America, according to the Centers for Disease Control and Prevention. Unfortunately, there are currently no reliable physiological markers to diagnose ADHD. Doctors generally diagnose the disorder by recording a medical and social history of the patient and the family, discussing possible symptoms and observing the patient's behavior. But an incorrect evaluation can lead to overmedication with Ritalin (methylphenidate), which has parents everywhere concerned.

Now a new study from Tel Aviv University researchers may provide the objective tool medical professionals need to accurately diagnose ADHD. According to the research, published in Vision Research, involuntary eye movements accurately reflect the presence of ADHD, as well as the benefits of medical stimulants that are used to treat the disorder.

Keeping an eye on the eyes

Dr. Moshe Fried, Dr. Anna Sterkin, and Prof. Uri Polat of TAU's Sackler Faculty of Medicine, Dr. Tamara Wygnanski-Jaffe, Dr. Eteri Tsitsiashvili, Dr. Tamir Epstein of the Goldschleger Eye Research Institute at Sheba Medical Center, Tel Hashomer, and Dr. Yoram S. Bonneh of the University of Haifa used an eye-tracking system to monitor the involuntary eye movements of two groups of 22 adults taking an ADHD diagnostic computer test called the Test of Variables of Attention (TOVA). The exercise, which lasted 22 minutes, was repeated twice by each participant. The first group of participants, diagnosed with ADHD, initially took the test un-medicated and then took it again under the influence of methylphenidate. A second group, not diagnosed with ADHD, constituted the control group.

"We had two objectives going into this research," said Dr. Fried, who as an adult was himself diagnosed with ADHD. "The first was to provide a new diagnostic tool for ADHD, and the second was to test whether ADHD medication really works — and we found that it does. There was a significant difference between the two groups, and between the two sets of tests taken by ADHD participants un-medicated and later medicated."

Foolproof, affordable, and accessible diagnosis

The researchers found a direct correlation between ADHD and the inability to suppress eye movement in the anticipation of visual stimuli. The research also reflected improved performance by participants taking methylphenidate, which normalized the suppression of involuntary eye movements to the average level of the control group.

"This test is affordable and accessible, rendering it a practical and foolproof tool for medical professionals," said Dr. Fried. "With other tests, you can slip up, make 'mistakes' — intentionally or not. But our test cannot be fooled. Eye movements tracked in this test are involuntary, so they constitute a sound physiological marker of ADHD.

"Our study also reflected that methylphenidate does work. It is certainly not a placebo, as some have suggested."

The researchers are currently conducting more extensive trials on larger control groups to further explore applications of the test.

A "Magnetic" Solution to Identify and Kill Tumors
8/13/2014

Though a valuable weapon against cancerous tumors, radiation therapy often harms healthy tissue as it tries to kill malignant cells. Now, Prof. Israel Gannot of Tel Aviv University's Department of Biomedical Engineering is developing a new way to destroy tumors with fewer side effects and minimal damage to surrounding tissue.

His innovative method, soon to be published in the journal Nanomedicine, uses heat to kill the tumor cells but leaves surrounding healthy tissue intact. Using specific biomarkers attached to individual tumors, Prof. Gannot's special mixture of nano-particles and antibodies locates and binds to the tumor itself.

"Once the nano-particles bind to the tumor, we excite them with an external magnetic field, and they begin to heat very specifically and locally," says Prof. Gannot. The magnetic field is manipulated to create a targeted rise in temperature, and it is this directed heat elevation which kills the tumors, he says.

The treatment has been proven effective against epithelial cancers, which can develop in almost any area of the body, such as the breast or lung. By using a special feedback process, also developed in his laboratory, the process can be optimized for individual treatment.

A cure without casualty

The specialized cocktail of nano-particles and antibodies is administered safely and simply, through topical local injection or injection into the blood stream. As an added benefit, the mixture washes out of the body without leaving a trace, minimizing side effects.

If clinical trials are successful, the technique may become a mainstay of patient care. The nano-particles themselves are already FDA-approved, and according to Prof. Gannot, the method is effective almost any type of tumor, as long as its specific markers and its antibodies can be identified.

The countdown to demolition

In addition to being minimally invasive, this treatment boasts sheer speed. It can be applied during an out-patient procedure — the entire technique lasts only six hours — which allows patients to recuperate in the comfort of their own homes.

Prof. Gannot is currently applying his technique to cell lines and to ex vivo tissues and tissue-like substitutes in his lab, and plans to start in vivo experiments by next year.


"Junk DNA" Can Sense Viral Infection
8/6/2014

Promising tool in the battle between pathogen and host, TAU research confirms

Once considered unimportant "junk DNA," scientists have learned that non-coding RNA (ncRNA) — RNA molecules that do not translate into proteins — play a crucial role in cellular function. Mutations in ncRNA are associated with a number of conditions, such as cancer, autism, and Alzheimer's disease.

Now, through the use of "deep sequencing," a technology used to sequence the genetic materials of the human genome, Dr. Noam Shomron of Tel Aviv University's Sackler Faculty of Medicine has discovered that when infected with a virus, ncRNA gives off biological signals that indicate the presence of an infectious agent, known as a pathogen. Not only does this finding give researchers a more complete picture of the interactions between pathogens and the body, but it provides scientists with a new avenue for fighting off infections.

His findings have been published in the journal Nucleic Acid Research.

Another battleground between pathogen and host

"If we see that the number of particular RNA molecules increases during a specific viral infection, we can develop treatments to stop or slow their proliferation," explains Dr. Shomron.

In the lab, the researchers conducted a blind study in which some cells were infected with the HIV virus and others were left uninfected. Using the deep sequencer, which can read tens of millions of sequences per experiment, they analyzed the ncRNA to discover if the infection could be detected in non-coding DNA materials. The researchers were able to identify with 100% accuracy both infected and non-infected cells — all because the ncRNA was giving off significant signals, explains Dr. Shomron.

These signals, which can include either the increase or decrease of specific ncRNA molecules within a cell, most likely have biological significance, he says. "With the introduction of a pathogen, there is a reaction in both the coding and non-coding genes. By adding a new layer of information about pathogen and host interactions, we better understand the entire picture. And understanding the reactions of the ncRNA following infection by different viruses can open up the battle against all pathogens."

Finding an “Achilles heel” of infections

The researchers believe that if an ncRNA molecule significantly manifests itself during infection by a particular pathogen, the pathogen has co-opted this ncRNA to help the pathogen devastate the host — such as the human body. To help the body fight off the infection, drugs that stop or slow the molecules' proliferation could be a novel and effective strategy.

This new finding allows researchers to develop treatments that attack a virus from two different directions at once, targeting both the coding and non-coding genetic materials, says Dr. Shomron. He suggests that ncRNA could prove to be the "Achilles heel" of pathogens.

Dr. Shomron and his team of researchers developed new software, called RandA, which stands for "ncRNA Read-and-Analyze," that performs ncRNA profiling and analysis on data generated through deep sequencing technology. It's this software that has helped them to uncover the features that characterize virus-infected cells.


A New “Whey” to Control Diabetes
8/5/2014

A whey protein drink before breakfast can control erratic glucose levels associated with type 2 diabetes, say Tel Aviv University researchers

Blood sugar surges — after-meal glucose "spikes" — can be life threatening for the 29 million Americans with diabetes. Diabetic blood sugar spikes have been linked to cardiovascular disease, cancer, Alzheimer’s disease, kidney failure, and retinal damage. Now a new Tel Aviv University study, published in Diabetologia, suggests a novel way to suppress these deadly post-meal glucose surges: the consumption of whey protein concentrate, found in the watery portion of milk separated from cheese curds, before breakfast.

According to TAU's Prof. Daniela Jakubowicz and Dr. Julio Wainstein of the Wolfson Medical Center's Diabetes Unit, Prof. Oren Froy of the Hebrew University of Jerusalem, and Prof. Bo Ahrén of Lund University in Sweden, the consumption of whey protein before meals may even keep diabetics' need for insulin treatment at bay.

"What's remarkable is that consuming whey protein before meals reduces the blood sugar spikes seen after meals. It also improves the body's insulin response, putting it in the same range or even higher than that produced by novel anti-diabetic drugs," said Prof. Jakubowicz. "High milk intake has long been associated with lower risk for type 2 diabetes and cardiovascular disease, and milk whey protein increases the production of a gut hormone called glucagon-like peptide-1 (GLP-1) that stimulates insulin secretion. This, in turn, reduces the blood glucose rise after meals."

A whey cocktail before breakfast

"We hypothesized that stimulating GLP-1 production by consuming whey protein before a meal would enhance insulin secretion and have beneficial glucose-lowering effects in type 2 diabetes," Prof. Jakubowicz said.

The study was conducted on 15 individuals with well-controlled type 2 diabetes at Wolfson Medical Center. The participants were randomized to receive either 50 grams of whey in 250 ml water or a placebo, followed by a standardized high-glycemic index breakfast of three slices of white bread and sugary jelly — a meal designed to produce the maximum post-meal glucose spike.

Blood samples were taken 30 minutes before the meal, when the whey protein or placebo drinks were consumed. Further blood samples, assessing plasma concentration of glucose, intact GLP-1, and insulin concentrations, were taken when the breakfast was served and at 15, 30, 60, 90, 120, 150, and 180 minute intervals after the meal.

The most important meal of the day?

The researchers found that glucose levels were reduced by 28 percent after the whey pre-load over the 180-minute post-meal period, with a uniform reduction during early and late phases. With whey pre-load, insulin and GLP-1 responses also were significantly higher (105 and 141 percent, respectively), producing a 96 percent increase in early insulin response.

"The early insulin response that usually is deficient in type-2 diabetes was significantly higher after whey protein than with placebo, and the whey protein preload significantly reduced the elevation of blood glucose after breakfast," said Prof. Jakubowicz. "Whey protein could therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes."

Based on the findings of this study, the authors are considering a long-term clinical trial to test the enduring benefits of whey protein consumption for diabetics.


Heat, Not Heart, Poses Biggest Risk to Athletes
8/4/2014

TAU study says heatstroke is more threatening to marathon runners than cardiac arrest

The sudden cardiac arrest of a young and healthy runner in the middle of a race is a shocking event that can draw media attention. But according to a new Tel Aviv University study published in the Journal of the American College of Cardiology, endurance athletes are actually ten times more likely to develop severe and life-threatening heatstroke — with a fever above 104 degrees that can cause the kidneys, brain, and other organs to fail.

According to lead author Dr. Sami Viskin of TAU's Sackler Faculty of Medicine and Tel Aviv Medical Center, "This research shows that heatstroke is a real threat to marathon and long-distance runners; however, there are no clinical studies of potential strategies to prevent heat stroke during these types of events."

Races longer than 6.2 miles have become increasingly popular among endurance athletes. To assess the greatest health risks associated with these types of events, the researchers analyzed information compiled on all deaths and hospitalizations that occurred in the course of 14 long-distance races in Tel Aviv between March 2007 and November 2013.

Out of nearly 140,000 runners, only two serious heart-related events were reported during the study period, and neither of these were life-threatening. The researchers also found, however, that 21 people developed heatstroke. Of these cases, two were fatal and 12 were considered life-threatening.

"It's important that clinicians educate runners on the ways to minimize their risk of heatstroke, including allowing 10 to 14 days to adjust to a warm climate, discouraging running if a person is ill or was recently ill. ... A pre-existing fever impairs the body's ability to dissipate additional heat stress," Viskin said. He added that better methods of monitoring body core temperature during physical activity need to be developed.

For more, read the story in Forbes:
http://www.forbes.com/sites/larryhusten/2014/07/28/death-by-running-its-the-heat-and-not-the-heart-2/

From the Cockpit to the Operating Table
7/28/2014

TAU researcher says doctors, like pilots, should use simulators to prepare for high-stakes scenarios

As a young combat pilot in the Israeli Air Force, Dr. Amitai Ziv of Tel Aviv University's Sackler School of Medicine practiced on a simulator for every possible nightmare scenario. But when he started medical school, he was surprised to find that medical trainees honed their skills not on simulators, but on real patients.

"We expect both health care and aviation to have very low tolerance for errors. But in health care, we are very much behind aviation in that respect," Dr. Ziv told the recent 2014 Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) meeting. "Our health care training, despite the simulation movement, is still by and large the old model: See one, teach one, do one, kill one. ... The patients are the ones who pay the price."

Dr. Ziv, a pediatrician, has spent the past 20 years trying to adapt the lessons of flight simulation training to the field of medical training. In 2001, Dr. Ziv founded the Israel Center for Medical Simulation (MSR) at the Sheba Medical Center, home to more than 100 different kinds of simulators and employing more than 150 professional actors for its courses. MSR trains health care workers for run-of-the-mill scenarios but also for the catastrophic "unimaginable" ones. Israel is known for its extensive mass casualty preparedness; much of that training is conducted at MSR.

The center is founded on the principle that simulation-based medical training and assessment can revolutionize the culture of safety in medicine.

For more, read the story in General Surgery News:
http://www.generalsurgerynews.com/ViewArticle.aspx?d=In%2bthe%2bNews&d_id=69&i=July+2014&i_id=1079&a_id=27707


In the area of training dental professionals, Tel Aviv University has been a pioneer for decades. Dr. Ben Williamowsky, a member of the Amercan Friends of Tel Aviv University Board and namesake of TAU's new Rothstein-Williamowsky Post-Graduate Clinics, notes:

It may be of interest to note that the Dental School at TAU was the first in the world to introduce the "Simadent," a simulator for teaching dental procedures and later developed to allow one instructor to view the simulated work of students from a single screen in his examining office.

It was developed by young (typically young) Israeli computer-savvy technicians in a facility located on a chicken farm near Jerusalem. Ralph Rothstein and I were taken there to see the "pilot" in use before it made its debut at TAU's School of Dental Medicine, perhaps in the 1980's. I believe the first dental school in the States to adopt it was at the University of Alabama.

Today, every dental school employs a type of teaching simulator ... often, one at every dental chair used by a student! I still remember the name of the young "scientist" who demonstrated the instrument. Her name was Imbal (age 30) and when I asked her where she studied Dentistry ... in great surprise ... informed us that she was not a dentist ... but a computer scientist! Of course she studied at TAU.

Proof: Parkinson's Enhances Creativity
7/14/2014

New TAU study confirms creative energy in Parkinson's sufferers is greater than in healthy individuals

Prof. Rivka Inzelberg of Tel Aviv University's Sackler Faculty of Medicine and the Sagol Neuroscience Center at Sheba Medical Center, Tel Hashomer, documented the exceptional creativity of Parkinson's patients two years ago in a review for Behavioral Neuroscience. Since then, she has conducted the first empirical study to verify a link between Parkinson's disease and artistic inclination.

That empirical study, now published in the Annals of Neurology, definitively demonstrates that Parkinson's patients are more creative than their healthy peers, and that those patients taking higher doses of medication are more artistic than their less-medicated counterparts.

"It began with my observation that Parkinson's patients have a special interest in art and have creative hobbies incompatible with their physical limitations," said Prof. Inzelberg. "In my last paper, I reviewed case studies from around the world and found them to be consistent. In my present research, we conducted the first comprehensive study to measure the creative thinking of Parkinson's patients. This was not a simple task, because how does one measure, or quantify, creativity? We had to think creatively ourselves."

Measuring artistic creativity

Prof. Inzelberg and a team of researchers from TAU, the Sheba Medical Center, and Bar-Ilan University conducted a full battery of tests on 27 Parkinson's patients treated with anti-Parkinson's drugs and 27 age- and education-matched healthy controls. Some of the tests were well-known and others newly adapted for the purpose of the study. The tests included the Verbal Fluency exam, in which a person is asked to mention as many different words beginning with a certain letter and in a certain category (fruit, for example) as possible.

The participants were then asked to undergo a more challenging Remote Association Test, in which they had to name a fourth word (following three given words) within a fixed context. The groups also took the Tel Aviv University Creativity Test, which tested their interpretation of abstract images and assessed the imagination inherent in answers to questions like "What can you do with sandals?" The final exam was a version of the Test for a Novel Metaphor, adapted specifically for the study.

Throughout the testing, Parkinson's patients offered more original answers and more thoughtful interpretations than their healthy counterparts.

In order to rule out the possibility that the creative process evident in the hobbies of patients was linked to obsessive compulsions like gambling and hoarding, to which many Parkinson's patients fall prey, participants were also asked to fill out an extensive questionnaire. An analysis indicated no correlation between compulsive behavior and elevated creativity.

Express yourself

The conclusions from the second round of testing — in which the Parkinson's participants were split into higher- and lower-medicated groups — also demonstrated a clear link between medication and creativity. Parkinson's patients suffer from a lack of dopamine, which is associated with tremors and poor coordination. As such, they are usually treated with either synthetic precursors of dopamine or dopamine receptor agonists.

According to Prof. Inzelberg, the results are hardly surprising, because dopamine and artistry have long been connected. "We know that Van Gogh had psychotic spells, in which high levels of dopamine are secreted in the brain, and he was able to paint masterpieces during these spells — so we know there is a strong relationship between creativity and dopamine," said Prof. Inzelberg.

Prof. Inzelberg hopes her research will be instrumental in spreading awareness. Parkinson's patients often feel isolated by their physical limitations, so artistic work could provide a welcome outlet of expression. "After my first paper, I helped organize exhibits of patients' paintings in Herzliya and Raanana and received feedback about similar exhibits in Canada and France," said Prof. Inzelberg. "These exhibits were useful in raising funds for Parkinson's research, providing occupational therapy for patients — and, most importantly, offering an opportunity for patients to fully express themselves."

Prof. Inzelberg is currently researching additional forms of creativity in Parkinson's patients.

New TAU Research Links Alzheimer's Disease to Brain Hyperactivity
6/30/2014

Study identifies molecular mechanism that triggers hyperactivity of brain circuits in early stages of the disease

Patients with Alzheimer's disease run a high risk of seizures. While the amyloid-beta protein involved in the development and progression of Alzheimer's seems the most likely cause for this neuronal hyperactivity, how and why this elevated activity takes place hasn't yet been explained — until now.

A new study by Tel Aviv University researchers, published in Cell Reports, pinpoints the precise molecular mechanism that may trigger an enhancement of neuronal activity in Alzheimer's patients, which subsequently damages memory and learning functions. The research team, led by Dr. Inna Slutsky of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, discovered that the amyloid precursor protein (APP), in addition to its well-known role in producing amyloid-beta, also constitutes the receptor for amyloid-beta. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a signalling cascade, which causes elevated neuronal activity.

Elevated activity in the hippocampus — the area of the brain that controls learning and memory — has been observed in patients with mild cognitive impairment and early stages of Alzheimer's disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer's disease. "These are truly exciting results," said Dr. Slutsky. "Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons."

With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.

Building on earlier research

The research project was launched five years ago, following the researchers' discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected "normal" neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta. "This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity," said Dr. Slutsky.

The researchers, collaborating with Prof. Joel Hirsch of TAU's Faculty of Life Sciences, Prof. Dominic Walsh of Harvard University, and Prof. Ehud Isacoff of University of California Berkeley, harnessed a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signalling in neural cultures, brain slices, and mouse models. Using highly sensitive biophysical techniques based on fluorescence resonance energy transfer (FRET) between fluorescent proteins in close proximity, they discovered that APP exists as a dimer at presynaptic contacts, and that the binding of amyloid-beta triggers a change in the APP-APP interactions, leading to an increase in calcium flux and higher glutamate release — in other words, brain hyperactivity.

A new approach to protecting the brain

"We have now identified the molecular players in hyperactivity," said Dr. Slutsky. "TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain."

Previous studies by Prof. Lennart Mucke's laboratory strongly suggest that a reduction in the expression level of "tau" (microtubule-associated protein), another key player in Alzheimer's pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models. "It will be crucial to understand the missing link between APP and 'tau'-mediated signalling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signalling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer's disease," said Dr. Slutsky.

The study was supported by European Research Council, Israel Science Foundation, and Alzheimer's Association grants.

By Any Stretch
6/20/2014

TAU researchers devise a kinder, gentler way to measure newborns

After their hectic experience of delivery, newborns are almost immediately stretched out on a measuring board to assess their length. Medical staff, reluctant to cause infants discomfort, are tasked with measuring their length, because it serves as an indispensable marker of growth, health and development. But the inaccuracy and unreliability of current measurement methods restrict their use, so routine measurements are often not performed.

Now Tel Aviv University researchers have taken a 21st century approach to the problem, using new software that harnesses computer vision to more accurately measure infant length. The technique, which is much easier on infants and at least as accurate as conventional measuring methods, was developed by a research team led by Prof. Lea Sirota, of TAU's Sackler Faculty of Medicine and head of the Neonatal Intensive Care Unit at Schneider Children's Medical Center, and Prof. Moshe Philip, a vice dean at TAU's Sackler Faculty of Medicine and head of the Institute for Endocrinology and Diabetes at Schneider Children's Medical Center, together with Dr. Nir Sokolover of TAU's Sackler Faculty of Medicine and Schneider Children's Medical Center, and Prof. Nahum Kiryati and Ms. Amalia Potruch of TAU's School of Engineering.

Results of a clinical trial of the new stereoscopic measurement system were published in Archives of Disease in Childhood.

Don't force it!

"The need to forcibly extend the infants against their will leads to unreliability and inaccuracy of the measurement, and staff members are understandably reluctant to do it," said Dr. Sokolover. "We wanted to develop an accurate, reliable, and practical tool for infant length measurement to facilitate evaluation and follow-up of growth without exposing newborns to a cold environment, infection, or discomfort."

In the study, 54 newborns, roughly half male and half female, were measured using the stereoscopic vision system. Two digital cameras connected and operated by a computer took photographs of each infant. Technology developed by the research team later calculated the infants' length by summing up four body segments from the heel to the crown. Most importantly perhaps, infants could be photographed while lying naturally on their backs, with no need to physically restrict them in a certain position.

In terms of accuracy, the study recorded negligibly different results than those of meticulously performed standard measurements, with a mean average difference of only 0.2 millimeters. According to Dr. Sokolover, the stereoscopic system does not reflect light or radiation on the measured infants, and is therefore considered safe.

A safe alternative

"I am a neonatologist who works daily in a neonatal intensive care unit, so I have experienced first-hand the difficulties of the standard measuring practice," said Dr. Sokolover. "The new system has the potential to improve compliance with routine health and development surveillance measurements, and thereby improve public health."

The team is currently observing the impact of the new system on neonatal intensive care units, where premature and sick infants unable to leave their incubators cannot be measured with the standard stretching practice.

"We are now testing a new and improved prototype of our system and clinically validating its ability to measure through incubators," said Dr. Sokolover. "We are encouraged by the results so far and by positive feedback from both local and international colleagues."

Breathalyzer Test May Detect Deadliest Cancer
6/18/2014

Researchers from TAU and partner institutions develop groundbreaking device that spots lung cancer – to stop it in its tracks

Lung cancer causes more deaths in the U.S. than the next three most common cancers combined (colon, breast, and pancreatic). The reason for the striking mortality rate is simple: poor detection. Lung cancer attacks without leaving any fingerprints, quietly afflicting its victims and metastasizing uncontrollably — to the point of no return.

Now a new device developed by a team of Israeli, American, and British cancer researchers may turn the tide by both accurately detecting lung cancer and identifying its stage of progression. The breathalyzer test, embedded with a "NaNose" nanotech chip to literally "sniff out" cancer tumors, was developed by Prof. Nir Peled of Tel Aviv University's Sackler Faculty of Medicine, Prof. Hossam Haick (inventor) of the Technion — Israel Institute of Technology, and Prof. Fred Hirsch of the University of Colorado School of Medicine in Denver.

The study, presented at a recent American Society of Clinical Oncology conference in Chicago, was conducted on 358 patients who were either diagnosed with or at risk for lung cancer. The participants enrolled at UC Denver, Tel Aviv University, University of Liverpool, and a Jacksonville, Florida, radiation center. Other researchers included Prof. Paul Bunn of UC Denver; Prof. Douglas Johnson, Dr. Stuart Milestone, and Dr. John Wells in Jacksonville; Prof. John Field of the University of Liverpool; and Dr. Maya Ilouze and Tali Feinberg of TAU.

The smell of cancer

"Lung cancer is a devastating disease, responsible for almost 2,000 deaths in Israel annually — a third of all cancer-related deaths," said Dr. Peled. "Lung cancer diagnoses require invasive procedures such as bronchoscopies, computer-guided biopsies, or surgery. Our new device combines several novel technologies with a new concept — using exhaled breath as a medium of diagnosing cancer.

"Our NaNose was able to detect lung cancer with 90 percent accuracy even when the lung nodule was tiny and hard to sample. It was even able to discriminate between subtypes of cancer, which was unexpected," said Dr. Peled.

Lung cancer tumors produce chemicals called volatile organic compounds (VOCs), which easily evaporate into the air and produce a discernible scent profile. Prof. Haick harnessed nanotechnology to develop the highly sensitive NaNose chip, which detects the unique "signature" of VOCs in exhaled breath. In four out of five cases, the device differentiated between benign and malignant lung lesions and even different cancer subtypes.

The bigger the tumor ...

"Cancer cells not only have a different and unique smell or signature, you can even discriminate between subtypes and advancement of the disease," said Dr. Peled. "The bigger the tumor, the more robust the signature."

The device and subsequent analysis accurately sorted healthy people from people with early-stage lung cancer 85 percent of the time, and healthy people from those with advanced lung cancer 82 percent of the time. The test also accurately distinguished between early and advanced lung cancer 79 percent of the time.

"The device could prove valuable in helping determine patients who need more intensive screening for lung cancer," said Dr. Peled. "We're hoping to have a device that would be able to give you a go/no-go result — something's wrong, go get an X-ray."

The Boston-based company Alpha Szenszor has licensed the technology and hopes to introduce it to the market within the next few years. Meanwhile, a new, smaller version of the device has since been developed that can plug into a computer's USB port.

The study was supported by the European Union LCAOS grant, an EU-funded collaborative whose aim is to enable the earliest possible detection of lung cancer, and the International Association for the Study of Lung Cancer (IASLC).

Regenerating Our Kidneys
6/13/2014

TAU research uses new technique to uncover the building blocks of kidney regeneration

Doctors and scientists have for years been astonished to observe patients with kidney disease experiencing renal regeneration. The kidney, unlike its neighbor the liver, was universally understood to be a static organ once it had fully developed.

Now a new study conducted by researchers at Sheba Medical Center, Tel Aviv University, and Stanford University turns that theory on its head by pinpointing the precise cellular signalling responsible for renal regeneration and exposing the multi-layered nature of kidney growth. The research, in Cell Reports, was conducted by principal investigators Dr. Benjamin Dekel of TAU's Sackler School of Medicine and Sheba Medical Center and Dr. Irving L. Weissman of Stanford University's School of Medicine, working with teams of researchers from both universities.

"We wanted to change the way people thought about kidneys — about internal organs altogether," said Dr. Dekel, who specializes in stem-cell research, genetics, and nephrology. "Very little is known even now about the way our internal organs function at the single cell level. This study flips the paradigm that kidney cells are static — in fact, kidney cells are continuously growing, all the time."

Dr. Dekel began researching the subject three years ago while on sabbatical at Stanford University. While the laboratory experiments and stem cell research were conducted at Stanford, the results were analyzed by researchers at TAU and Stanford.

According to Dr. Dekel, scientists knew kidney cells could reproduce outside the body, but the physiological process taking place inside the body at the single cell level was never explored. Uncovering that process became the focus of his efforts.

Dr. Dekel and his research team conducted a study using a "rainbow mouse" model developed at Stanford's Weissman lab, a mouse genetically altered to express one of four alternative fluorescent markers called "reporters" in each cell. The markers allowed researchers to trace cell growth in vivo — growth, they were surprised to find, that was sectional and multi-directional.

"We were amazed to find that renal growth does not depend on a single stem cell, but is rather compartmentalized," said Dr. Dekel. "Each part of the nephron is responsible for its own growth, each segment responsible for its own development, like a tree trunk and branches — each branch grows at a different pace and in a different direction."

Using the rainbow mouse, the researchers were able to pinpoint a specific molecule responsible for renal cellular growth called the "WNT signal." Once activated in specific precursor cells in each kidney segment, the WNT signal results in robust renal cellular growth and generation of long branches of cells.

"Our aim was to use a new technique to analyze an old problem," said Dr. Dekel. "No one had ever used a rainbow mouse model to monitor development of kidney cells. It was exciting to use these genetic tricks to discover that cellular growth was occurring all the time in the kidney — that, in fact, the kidney was constantly remodelling itself in a very specific mode."

Dr. Dekel and the research team are paving the way for novel cellular and molecular therapeutics to achieve human kidney regeneration and alleviate the shortage of kidney organs for transplantation. "This study teaches us that in order to regenerate the entire kidney segments different precursor cells grown outside of our bodies will have to be employed,” he said. "In addition, If we were able to further activate the WNT pathway, then in cases of disease or trauma we could activate the phenomena for growth and really boost kidney regeneration to help patients. This is a platform for the development of new therapeutics, allowing us to follow the growth and expansion of cells following treatment."

A Vibrating “Pill” to Replace Laxatives?
6/10/2014

Research from TAU-affiliated Tel Aviv Sourasky Medical Center provides promising basis for treatment of constipation

Constipation, the most common digestive health disorder, affects up to 42 million Americans. Symptoms of chronic constipation include pain, bloating, infrequent bowel movements, and painful and hard stools.

Now a new treatment in the form of a vibrating pill-size capsule may serve to alleviate chronic constipation, as demonstrated by a new pilot study from researchers led by Dr. Yishai Ron of the Department of Gastroenterology and Hepatology at Tel Aviv University-affiliated Tel Aviv Sourasky Medical Center. The team presented its findings last month at the Digestive Disease Week convention in Chicago.

The capsule houses a small engine which is programmed to begin vibrating six to eight hours after ingestion. The mechanical stimulation caused by the pill produces contractions in the intestines, facilitating the movement of stool through the digestive tract.

According to the study, the vibrating capsule was found to nearly double the weekly bowel movements of patients suffering from chronic idiopathic constipation (CIC) and constipation predominant irritable bowel syndrome (C-IBS). The innovative non-drug therapy may offer a solution for anyone who suffers from chronic constipation but finds laxatives, fiber drinks, enemas, and other standard treatments unhelpful or uncomfortable.

When medicine isn't enough

"Despite the widespread use of medication to treat constipation, nearly 50 percent of patients are unsatisfied with the treatment either because of side effects, safety concerns about long-term use, or the fact that it simply doesn't work," Dr. Ron told Science Daily.

In the study, 26 patients took the vibrating capsule twice each week and responded to a questionnaire about their daily bowel movements and laxative use. Study participants reported an increase in spontaneous bowel movements from two to four times per week, as well as a decrease in constipation symptoms, including reduced difficulty in passing stools and incomplete evacuation. The study also found minimal side effects from the capsule use.

"Sometimes, drug therapies bring more issues than relief for these patients," Dr. Ron said. "The results of this study point to the potential for an alternative treatment that avoids the typical drug side effects, such as bloating and electrolyte imbalance, by imitating the body's natural physiology."

Dr. Ron and his team plan to initiate a controlled, double-blind study to expand on these findings and further explore the capsule's potential.

For more, read this USA Today story about the research:
http://www.usatoday.com/story/news/nation/2014/05/04/constipation-vibrating-capsule/8513473/

How Breast Cancer "Expresses Itself"
5/29/2014

A new study finds that gene patterns responsible for normal breast tissue may also play a role in the development of cancer

About one in eight women in the United States will contract breast cancer in her lifetime. Now new research from Tel Aviv University-affiliated researchers, in collaboration with Johns Hopkins University, has provided another tool to help women, clinicians, and scientists searching for a cure to the one of the most widespread yet incurable diseases on the planet.

Dr. Ella Evron and Dr. Ayelet Avraham of the TAU-affiliated Assaf Harofeh Medical Center, together with Prof. Saraswati Sukumar of Johns Hopkins, have found that "gene regulation," the process that shuts off certain parts of a cell's DNA code or blueprint in healthy breast tissue cells, may also play a critical role in the development of breast cancer. Their research, published in PLOS ONE, focused on one particular gene — TRIM29 — selected from a pool of 100 genes with regulatory patterns specific to normal breast tissue, to prove the link between breast-specific genes and the pathology of cancer.

"We found that normal tissue affects the cancer that grows in that organ — in other words, the specific pattern of gene regulation in the normal breast affects breast cancer, the characteristics of the disease, and its clinical behavior," said Dr. Avraham, a biologist and a researcher in the lab. "We hope that this study will lead to a better understanding of the cancer predisposition of mammary tissues and point to new targets for cancer intervention."

Searching for the right gene

In the study, normal tissue samples taken from conventional breast reduction surgeries were examined in a laboratory. The researchers isolated the milk ducts and purified the breast-tissue cells to create a cell culture, which was then tested for different gene regulation profiles.

While all cell types share the same genetic code (DNA), certain genes are specifically "expressed" or "silenced" in each cell type. Consequently, the unique gene expression patterns in every tissue dictate its structure and function. Various "gatekeeper" mechanisms either allow or block gene expression in our cells. One such mechanism is "DNA methylation," which shuts off or silences parts of the genetic code to form a specific pattern that identifies each tissue type.

The researchers compared the DNA methylation profiles of thousands of genes in breast, colon, lung, and endometrial tissues, selecting one gene, TRIM29, for further analysis. They found that the TRIM29 gene bore a unique DNA regulation in normal and cancerous breast tissues as opposed to other organ tissues.

"In breast tissue we found that this gene was expressed in normal cells and silenced in the cancer cells," said Dr. Avraham. "In contrast, in other bodily tissues, the gene was silenced in normal cells and over-expressed in tumors. This emphasizes the link between tissue-specific gene regulation and the development of cancer."

Silencing the cancer

"Tissue-specific genes often take part in carcinogenesis. A well known example is estrogen, which is involved in the normal differentiation of the breast and also in breast cancer development," said Dr. Evron, a senior oncologist and a researcher in the lab. "Thus, the estrogen receptor over-expresses in nearly 70% of breast cancers. It's the target of very effective anti breast cancer therapy. In this study we identify more genes that have specific regulation in normal breast tissue as compared with other organ tissues."

"Another example is women who carry a mutation in the BRCA1/2 genes and develop cancers almost exclusively in the breast and ovary," said Dr. Evron. "This led to the hypothesis that these tissues are 'marked' for cancer predisposition during differentiation. Searching for these marks may throw light on this process.

"Certainly the concept of looking for genes that are involved in both in differentiation and in carcinogenesis is promising, and the novel list of breast-specific regulated genes we found may encourage further study in this direction. But we can't stop here. If we know which genes are responsible for breast cancer, then we can tailor therapies to target those genes specifically."

Novel Protein Fragments May Protect Against Alzheimer's
5/13/2014

TAU researcher's discovery can lead to new drug candidates to treat the neurodegenerative disease

The devastating loss of memory and consciousness in Alzheimer's disease is caused by plaque accumulations and tangles in neurons, which kill brain cells. Alzheimer's research has centered on trying to understand the pathology as well as the potential protective or regenerative properties of brain cells as an avenue for treating the widespread disease.

Now Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University's Sagol School of Neuroscience, has discovered novel protein fragments that have proven protective properties for cognitive functioning.

In a study published in the Journal of Alzheimer's Disease, Prof. Gozes examined the protective effects of two newly discovered protein fragments in mice afflicted with Alzheimer's disease-like symptoms. Her findings have the potential to serve as a pipeline for new drug candidates to treat the disease.

NAP time for Alzheimer's

"Several years ago we discovered that NAP, a snippet of a p

rotein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s," said Prof. Gozes. "Now, we're investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery."

Prof. Gozes' research focused on the microtubule network, a crucial part of cells in our bodies. Microtubules act as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer's, ALS, and Parkinson's, this network breaks down, hindering motor abilities and cognitive function.

"NAP operates through the stabilization of microtubules — tubes within the cell which maintain cellular shape. They serve as 'train tracks' for movement of biological material," said Prof. Gozes. "This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer's disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."

Down the tubes

In her new study, Prof. Gozes and her team looked at the subunit of the microtubule — the tubulin — and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer's; increased tangle accumulation is indicative of cognitive deterioration. Prof. Gozes decided to test both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, she tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients' brains.

"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline," said Prof. Gozes. "We tested one compound — a tubulin fragment — and saw that it protected against cognitive deficits. When we looked at the 'dementia'-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."

Prof. Gozes and her team also measured the brain-to-body mass ratio, an indicator of brain degeneration, and saw a significant decrease in the mouse model compared to normal mice. Following the introduction of the tubulin fragments, however, the mouse's brain to body ratio returned to normal. "We clearly see here the protective effect of the treatment," said Prof. Gozes. "We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models."

Unlocking a mystery of thalidomide
5/1/2014

TAU research pinpoints mechanism causing rare and severe congenital syndrome

In the 1950s and 1960s, pregnant women with morning sickness were often prescribed the new drug thalidomide. Shortly after the medicine was released on the market, a reported 10,000 infants were born with an extreme form of the rare congenital phocomelia syndrome, which caused death in 50 percent of cases and severe physical and mental disabilities in others. Although various factors are now known to cause phocomelia, the prominent roots of the disease can be found in the use of the drug thalidomide.

Now, half a century later, new research by Dr. Noam Shomron, Prof Arkady Torchinsky, and doctoral student Eyal Mor at Tel Aviv University's Sackler Faculty of Medicine, published in Archives of Toxicology, identifies a regulator responsible for the malformation of limbs in phocomelia, pinpointing a specific target for possible future intervention.

"We were reading old textbooks from the 1950s and '60s, trying to understand th

e studies carried out then on this intriguing topic, and we saw that we could undertake an in-depth examination of the disorder's processes using careful planning and execution of experiments on mouse and rat models," said Dr. Shomron. "We hoped to gain a much better understanding of embryo malformation."

In the genes

Prof. Torchinsky worked together with Mor to carry out an experiment on animal models in the laboratory. They injected mice and rats with an embryo malformation factor or "teratogen" (called 5-aza-2'-deoxycytidin) with effects similar to thalidomide. The chemical is also used in chemotherapeutics. With the factor, the researchers induced phocomelia in either the forelimbs or hind limbs of the animals.

Afterward, by analyzing the entire gene and tiny regulatory RNA molecules called microRNAs in all the mouse limbs (both healthy and afflicted), the researchers were able to pinpoint the genetic regulator — the precise "switch" turned on or off during genetic processes — responsible for the malformation, p53, and its downstream target gene, MicroRNA34.

"We have added another perspective to the overall picture by investigating the genetic mechanisms involved — in other words, the gene expression rather than the genetic code affected during pathology," said Dr. Shomron. "I expect that further understanding of the mechanisms involved in teratogens and how they induce phocomelia will help reveal the dangers associated with toxins and will also reveal the underlying functional role of genes and microRNAs modulating genetic expression in the process."

Dr. Shomron said the work carried out by the team addresses a long-standing paradigm of limb malformation in mammals and reflects the role that epigenetic regulation, as opposed to genetic regulation, plays in the development of disease. In other words, embryonic development can be caused by a genetic mutation (a "mis-print" in the book of life) or, in this case, by turning the genes on or off without any change in the genetic code itself. Dr. Shomron and his team are currently studying the effects of other toxins on the mal-development of mammalian embryos.

On the Defensive
4/23/2014

TAU discovers that protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells

People diagnosed with Huntington's disease, most in their mid-thirties and forties, face a devastating prognosis: complete mental, physical, and behavioral decline within two decades. "Mutant" protein clusters, long blamed for the progression of the genetic disease, have been the primary focus of therapies in development by pharmaceutical companies. But according to new research from Prof. Gerardo Lederkremer and Dr. Julia Leitman of Tel Aviv University's Department of Cell Research and Immunology, in collaboration with Prof. Ulrich Hartl of the Max Planck Institute for Biochemistry, these drugs may not only be ineffective — they may pose a serious threat to patients.

In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington's disease. On the contrary, these aggregates actually serve as a defense mechanism for "stressed" brain cells. Conducted on tissue cultures using cutting-edge microscopic technology, their studies identified a different causative agent — the "stress response" of affected brain cells.

"The upsetting implication for therapy of this di

sease is that drugs being developed to interfere with the formation of protein aggregates may in fact be detrimental," said Prof. Lederkremer. "The identification of the new cause will hopefully lead to the development of new therapeutic approaches. This may hold true for other neurodegenerative diseases as well."

Starting from genetic scratch

Prof. Lederkremer and his team chose to examine the effect of protein aggregates in the pathology of Huntington's disease because its genetic cause is well-known, unlike those of other neurodegenerative diseases, such as Parkinson's, whose origins remain less clear.

"What we found in this study — a surprise, although we suspected it — was that damage to the cells, the cell 'stress' that leads to death of cells, appeared well before the protein aggregates did," said Prof. Lederkremer. "And even more surprising, when the aggregates finally appeared, the stress was reduced, in some cases even stopping. The actual process of forming an aggregate was protective, isolating and segregating the problematic proteins. This explains why in autopsies of people who died of Huntington's and other diseases like Alzheimer's or old age, the protein aggregates in the brains were all quite similar, reflecting no specific disease link."

By interfering with the stress response of brain cells, rather than the formation of protein clusters, scientists may be able to slow, or even halt, the progression of neurodegenerative diseases. According to Prof. Lederkremer, this research paves the way for a revolutionary new direction for pharmaceutical research to treat Huntington's, Alzheimer's, Parkinson's, and other neurodegenerative diseases.

Response to stress

"The practical consequences are that several companies are already in advanced stages of development of drugs inhibiting this form of protein aggregate, interfering with the body's natural process to protect the brain," said Prof. Lederkremer. "But the drugs should be focused on another area altogether, and the protein aggregates, a protective resource for the brain, should be left intact."

Samples of brain cells from mouse models afflicted with Huntington's disease were examined using "live cell imaging," the study of live cells through time-lapse microscopy. Prof. Lederkremer and his team were thus able to identify a compound that modified brain cells' response to stress, promoting their survival.

"Our approach was to interfere with the stress response instead of the formation of the protein aggregates, and the lab succeeded in identifying a compound that altered the response, rescuing affected cells from death," said Prof. Lederkremer. "Our findings are most encouraging for the development of a therapy for this devastating disease, which is presently incurable."

From Mouse Ears to Man's?
3/24/2014

TAU researcher uses DNA therapy in lab mice to improve cochlear implant functionality

 One in a thousand children in the United States is deaf, and one in three adults will experience significant hearing loss after the age of 65. Whether the result of genetic or environmental factors, hearing loss costs billions of dollars in healthcare expenses every year, making the search for a cure critical.

Now a team of researchers led by Karen B. Avraham of the Department of Human Molecular Genetics and Biochemistry at Tel Aviv University's Sackler Faculty of Medicine and Yehoash Raphael of the Department of Otolaryngology–Head and Neck Surgery at University of Michigan's Kresge Hearing Research Institute have discovered that using DNA as a drug — commonly called gene therapy — in laboratory mice may protect the inner ear nerve cells of humans suffering from certain types of progressive hearing loss.

In the study, doctoral student Shaked Shivatzki created a mouse population possessing the gene that produces the most prevalent form of hearing loss in humans: the mutated connexin 26 gene. Some 30 percent of American children born deaf have this form of the gene. Because of its prevalence and the inexp

ensive tests available to identify it, there is a great desire to find a cure or therapy to treat it.

"Regenerating" neurons

Prof. Avraham's team set out to prove that gene therapy could be used to preserve the inner ear nerve cells of the mice. Mice with the mutated connexin 26 gene exhibit deterioration of the nerve cells that send a sound signal to the brain. The researchers found that a protein growth factor used to protect and maintain neurons, otherwise known as brain-derived neurotrophic factor (BDNF), could be used to block this degeneration. They then engineered a virus that could be tolerated by the body without causing disease, and inserted the growth factor into the virus. Finally, they surgically injected the virus into the ears of the mice. This factor was able to "rescue" the neurons in the inner ear by blocking their degeneration.

"A wide spectrum of people are affected by hearing loss, and the way each person deals with it is highly variable," said Prof. Avraham. "That said, there is an almost unanimous interest in finding the genes responsible for hearing loss. We tried to figure out why the mouse was losing cells that enable it to hear. Why did it lose its hearing? The collaborative work allowed us to provide gene therapy to reverse the loss of nerve cells in the ears of these deaf mice."

Although this approach is short of improving hearing in these mice, it has important implications for the enhancement of sound perception with a cochlear implant, used by many people whose connexin 26 mutation has led to impaired hearing.

Embryonic hearing?

Inner ear nerve cells facilitate the optimal functioning of cochlear implants. Prof. Avraham's research suggests a possible new strategy for improving implant function, particularly in people whose hearing loss gets progressively worse with time, such as those with profound hearing loss as well as those with the connexin gene mutation. Combining gene therapy with the implant could help to protect vital nerve cells, thus preserving and improving the performance of the implant.

More research remains. "Safety is the main question. And what about timing? Although over 80 percent of human and mouse genes are similar, which makes mice the perfect lab model for human hearing, there's still a big difference. Humans start hearing as embryos, but mice don't start to hear until two weeks after birth. So we wondered, do we need to start the corrective process in utero, in infants, or later in life?" said Prof. Avraham.

"Practically speaking, we are a long way off from treating hearing loss during embryogenesis. But we proved what we set out to do: that we can help preserve nerve cells in the inner ears of the mouse," Prof. Avraham continued. "This already looks very promising."

The research team is currently working on finding better "vehicles" for the corrected gene, such as finding more suitable viruses to transport the injected gene to the appropriate place in the inner ear. The study was supported by grants from the NIDCD of the National Institutes of Health and I-CORE Gene Regulation in Complex Human Disease.

Not Just What You Eat
3/20/2014

TAU research shows fat mass in cells expands with disuse

Over 35 percent of American adults and 17 percent of American children are considered obese, according to the latest survey conducted by the Centers for Disease Control and Prevention. Associated with diabetes, heart disease, stroke, and even certain types of cancer, obesity places a major burden on the health care system and economy. It's usually treated through a combination of diet, nutrition, exercise, and other techniques.

To understand how obesity develops, Prof. Amit Gefen, Dr. Natan Shaked and Ms. Naama Shoham of Tel Aviv University's Department of Biomedical Engineering, together with Prof. Dafna Benayahu of TAU's Department of Cell and Developmental Biology, used state-of-the-art technology to analyze the accumulation of fat in the body at the cellular level. According to their findings, nutrition is not the only factor driving obesity. The mechanics of "cellular expansion" plays a primary role in fat production, they discovered.

By exposing the mechanics of fat production at a cellular level, the researchers offer insight into the development of obesity. And with a better understanding of the process, the team is now creating a platform to develop new therapies and technologies to prevent or even reverse fat gain. The research was published this week in the Biophysical Journal.

Getting to the bottom of obesity

"Two years ago, Dafna and I were awarded a grant from the Israel Science Foundation to investigate how mechanical forces increase the fat content within fat cells. We wanted to find out why a sedentary lifestyle results in obesity, other than making time to eat more hamburgers," said Prof. Gefen. "We found that fat cells exposed to sustained, chronic pressure — such as what happens to the buttocks when you're sitting down — experienced accelerated growth of lipid droplets, which are molecules that carry fats.

"Contrary to muscle and bone tissue, which get mechanically weaker with disuse, fat depots in fat cells expanded when they experienced sustained loading by as much as 50%. This was a substantial discovery."

The researchers discovered that, once it accumulated lipid droplets, the structure of a cell and its mechanics changed dramatically. Using a cutting-edge atomic force microscope and other microscopy technologies, they were able to observe the material composition of the transforming fat cell, which became stiffer as it expanded. This stiffness alters the environment of surrounding cells by physically deforming them, pushing them to change their own shape and composition.

"When they gain mass and change their composition, expanding cells deform neighboring cells, forcing them to differentiate and expand," said Prof. Gefen. "This proves that you're not just what you eat. You're also what you feel — and what you're feeling is the pressure of increased weight and the sustained loading in the tissues of the buttocks of the couch potato."

The more you know ...

"If we understand the etiology of getting fatter, of how cells in fat tissues synthesize nutritional components under a given mechanical loading environment, then we can think about different practical solutions to obesity," Prof. Gefen says. "If you can learn to control the mechanical environment of cells, you can then determine how to modulate the fat cells to produce less fat."

The team hopes that its observations can serve as a point of departure for further research into the changing cellular environment and different stimulations that lead to increased fat production.

Restoring Order in the Brain
3/11/2014

TAU finds that brain cell regeneration may alleviate symptoms of Alzheimer's disease

Alzheimer's disease is the most widespread degenerative neurological disorder in the world. Over five million Americans live with it, and one in three senior citizens will die with the disease or a similar form of dementia. While memory loss is a common symptom of Alzheimer's, other behavioral manifestations — depression, loss of inhibition, delusions, agitation, anxiety, and aggression — can be even more challenging for victims and their families to live with.

Now Prof. Daniel Offen and Dr. Adi Shruster of Tel Aviv University's Sackler School of Medicine have discovered that by reestablishing a population of new cells in the part of the brain associated with behavior, some symptoms of Alzheimer's disease significantly decreased or were reversed altogether.

The research, published in the journal Behavioural Brain Research, was conducted on mouse models; it provides a promising target for Alzheimer's symptoms in human beings as well.

"Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you aged or as the result of injury or disease," said Prof. Offen, who also serves as Chief Scientific Officer at BrainStorm, a biotech company at the forefront of innovative stem cell research. "We now know that stem cells can be used to regenerate areas of the brain."

Speeding up recovery

After introducing stem cells in brain tissue in the laboratory and seeing promising results, Prof. Offen leveraged the study to mice with Alzheimer's disease-like symptoms. The gene (Wnt3a) was introduced in the part of the mouse brain that controls behavior, specifically fear and anxiety, in the hope that it would contribute to the formation of genes that produce new brain cells.

According to Prof. Offen, untreated Alzheimer's mice would run heedlessly into an unfamiliar and dangerous area of their habitats instead of assessing potential threats, as healthy mice do. Once treated with the gene that increased new neuron population, however, the mice reverted to assessing their new surroundings first, as usual.

"Normal mice will recognize the danger and avoid it. Mice with the disease, just like human patients, lose their sense of space and reality," said Prof. Offen. "We first succeeded in showing that new neuronal cells were produced in the areas injected with the gene. Then we succeeded in showing diminished symptoms as a result of this neuron repopulation."

"The loss of inhibition is a cause of great embarrassment for most patients and relatives of patients with Alzheimer's," said Prof. Offen. "Often, patients take off their pants in public, having no sense of their surroundings. We saw parallel behavior in animal models with Alzheimer's."

Next: Memory

After concluding that increased stem cell production in a certain area of the brain had a positive effect on behavioral deficits of Alzheimer's, Prof. Offen has moved to research into the area of the brain that controls memory. He and his team are currently exploring it in the laboratory and are confident that the results of the new study will be similar.

"Although there are many questions to answer before this research produces practical therapies, we are very optimistic about the results and feel this is a promising direction for Alzheimer's research," said Prof. Offen.

Off with Your Glasses
3/4/2014

TAU researchers discover a link between sharp vision and the brain's processing speed

Middle-aged adults who suddenly need reading glasses, patients with traumatic brain injuries, and people with visual disorders such as "lazy eye" may have one thing in common — "visual crowding," an inability to recognize individual items surrounded by multiple objects. Visual crowding makes it impossible to read, as single letters within words are rendered illegible. And basic cognitive functions such as facial recognition can also be significantly hampered. Scientists and clinicians currently attribute crowding to a disorder in peripheral vision.

Now Prof. Uri Polat, Maria Lev, and Dr. Oren Yehezkel of Tel Aviv University's Goldschleger Eye Research Institute at the Sackler Faculty of Medicine have discovered new evidence that correlates crowding in the fovea — a small part of the retina responsible for sharp vision — and the brain's processing speed. These findings, published in Nature's Scientific Reports, could greatly alter earlier models of visual crowding, which emphasized peripheral impairment exclusively. And for many adults lost without their reading glasses, this could improve their vision significantly.

"Current theories strongly stress that visual crowding does not exist in the fovea, that it's a phenomenon that exists only in peripheral visual fields," said Prof. Polat. "But our study points to another part of the eye altogether — the fovea — and contributes to a unified model for how the brain integrates v

isual information."

A trained eye

According to Prof. Polat, vision is dynamic and changes rapidly, but it takes time for the brain to process this visual information. Rapidly moving tickers on TV, or traffic signs seen as the driver speeds past, are difficult for anyone to read. However, given enough time, someone with excellent vision can fully recognize the words. Those with slower processing speeds — usually the result of poor perceptive development or age — may not be able to decipher the tickers or the traffic signs. In the study, Prof. Polat employed his expertise in improving vision by retraining the brain and the foveal part of the eye, using exercises in which speed is a key element.

"Training adults to reduce foveal crowding leads to improved vision. A similar training we conducted two years ago allowed adults to eliminate their use of reading glasses altogether, using a technology provided by the GlassesOff company. Other patients who had lost sharp vision for whatever reason were also able to benefit from the same training and improve their processing speed and visual capabilities," said Prof. Polat.

Maria Lev, who performed the study as a part of her doctoral thesis, said one young subject had experienced significant limitations in school for years and had been unable to obtain a driver's license due to severe visual impairment from foveal crowding. After undergoing training that emphasized a foveal rather than a peripheral focus, he was able to overcome the handicap.

"He finally managed to learn to read properly and found his way forward," said Lev. "I'm proud to say that today he is not only eligible for a driver's license, he's also been able to earn his master's degree."

Prof. Polat and his team are currently exploring how visual integration and foveal crowding develop in various clinical cases.

Researchers Devise a Fast and Effective Mechanism to Combat One of the Most Aggressive Cancers
2/24/2014

TAU targets drug-resistant ovarian tumors with nanotechnology

Ovarian cancer accounts for more deaths of American women than any other cancer of the female reproductive system. According to the American Cancer Society, one in 72 American women will be diagnosed with ovarian cancer, and one in 100 will ultimately die of the condition.

Now Prof. Dan Peer of Tel Aviv University's Department of Cell Research and Immunology has proposed a new strategy to tackle an aggressive subtype of ovarian cancer using a new nanoscale drug-delivery system designed to target specific cancer cells. He and his team — Keren Cohen and Rafi Emmanuel from Peer's Laboratory of Nanomedicine and Einat Kisin-Finfer and Doron Shabbat, from TAU's Department of Chemistry — have devised a cluster of nanoparticles called gagomers, made of fats and coated with a kind of polysugar. When filled with chemotherapy drugs, these clusters accumulate in tumors, producing dramatically therapeutic benefits.

The objective of Peer's research is two-fold: to provide a specific target for anti-cancer drugs to increase their therapeutic benefits, and to reduce the toxic side effects of anti-cancer therapies. The study was published in February in the journal ACS Nano.

Why chemotherapy fails

According to Prof. Peer, traditional courses of chemotherapy are not an effective line of attack. Chemotherapy's failing lies in the inability of the medicine to be absorbed and maintained within the tumor cell long enough to destroy it. In most cases, the chemotherapy drug is almost immediately ejected by the cancer cell, severely damaging the healthy organs that surround it, leaving the tumor cell intact.

But with their new therapy, Peer and his colleagues saw a 25-fold increase in tumor-accumulated medication and a dramatic dip in toxic accumulation in healthy organs. Tested on laboratory mice, the gagomer mechanism effects a change in drug-resistant tumor cells. Receptors on tumor cells recognize the sugar that encases the gagomer, allowing the binding gagomer to slowly release tiny particles of chemotherapy into the cancerous cell. As more and more drugs accumulate within the tumor cell, the cancer cells begin to die off within 24-48 hours.

"Tumors become resistant very quickly. Following the first, second, and third courses of chemotherapy, the tumors start pumping drugs out of the cells as a survival mechanism," said Prof. Peer. "Most patients with tumor cells beyond the ovaries relapse and ultimately die due to the development of drug resistance. We wanted to create a safe drug-delivery system, which wouldn't harm the body's immune system or organs."

A personal perspective

Prof. Peer chose to tackle ovarian cancer in his research because his mother-in-law passed away at the age of 54 from the disease. "She received all the courses of chemotherapy and survived only a year and a half," he said. "She died from the drug-resistant aggressive tumors.

"At the end of the day, you want to do something natural, simple, and smart. We are committed to try to combine both laboratory and therapeutic arms to create a less toxic, focused drug that combats aggressive drug-resistant cancerous cells," said Prof. Peer. "We hope the concept will be harnessed in the next few years in clinical trials on aggressive tumors," said Prof. Peer.


Nipping Diabetes in the Bud
1/27/2014

TAU researchers find a simple blood test can predict diabetes risk much earlier

An estimated 25.8 million Americans have diabetes. Another 79 million are thought to have "prediabetes," meaning they are at risk of developing type-2 diabetes.

Now Dr. Nataly Lerner of Tel Aviv University's Sackler Faculty of Medicine and her colleagues have discovered that a simple blood test reveals an individual's risk of developing type-2 diabetes before they develop either condition — far earlier than previously believed. The findings, published in the European Journal of General Practice, could help doctors provide earlier diagnosis and treatment. Dr. Michal Shani and Prof. Shlomo Vinker of the Sackler Faculty of Medicine and Clalit Health Services collaborated on the study.

"Our study supports the idea that the A1c test, used to diagnose type-2 diabetes, can also be used at a much earlier stage to screen for the disease in the high risk population, like overweight patients," said Dr. Lerner.

Testing the test

In healthy people, glucose is absorbed from the blood for use by various tissues. But the cells of people with type-2 diabetes are resistant to insulin, which is produced by the pancreas and is central to regulating carbohydrate and fat metabolism in the body. These individuals have higher-than-normal blood glucose levels. People with prediabetes have blood glucose levels somewhere between normal and diabetic.

Blood glucose can be directly tested in several ways, but these tests only provide a snapshot. To get a picture of blood glucose levels over time, doctors test for levels of glycated hemoglobin, or A1c, in the blood. When blood glucose levels are high, more A1c is formed. So A1c serves as a biomarker, indicating average blood glucose levels over a two- to three-month period.

The A1c test has long been used to monitor type-2 diabetes. And in the past few years, the American Diabetes Association and World Health Organization have added the test to their guidelines as a criterion for diagnosing type-2 diabetes. According to the ADA, having an A1c level of 6.5 percent or more is an indicator of the disease and an A1c level of between 5.7 and 6.4 percent is an indicator of prediabetes. As a bonus, the test is simpler to administer than the most common blood glucose tests, requiring neither fasting nor consuming anything.

To evaluate the A1c test's ability to screen for diabetes in high-risk patients, the researchers analyzed the medical history of 10,201 patients who were given the test in central Israel between 2002 and 2005. They found that overall, 22.5 percent of the patients developed diabetes within five to eight years. Patients with A1c levels as low as 5.5 percent — below the official threshold for diagnosing diabetes were significantly more likely to develop diabetes than patients with A1c levels below 5.5 percent. Every 0.5 percent increase in A1c levels up to 7 percent doubled the patients' risk of developing diabetes. Obesity also doubled patients' risk of developing diabetes, the researchers found.

Risk management

"We were actually able to quantify how risk increases with A1c levels," said Dr. Lerner. "This could allow doctors to make more informed decisions regarding diabetes prevention."

The study, one of the most comprehensive of its kind, provides compelling new evidence that the A1c test can accurately gauge risk at an earlier stage than is currently recognized. In combination with blood glucose tests and the identification of risk factors — like family history, poor diet, lack of exercise, and obesity — the test could help doctors provide earlier treatment. In some cases, lifestyle changes or medication could head off the disease, which is difficult or impossible to cure once developed.


The Unexpected Power of Baby Math
1/22/2014

TAU researcher finds that adults still think about numbers like kids

Children understand numbers differently than adults. For kids, one and two seem much further apart then 101 and 102, because two is twice as big as one, and 102 is just a little bigger than 101. It's only after years of schooling that we’re persuaded to see the numbers in both sets as only one integer apart on a number line.

Now Dror Dotan, a doctoral student at Tel Aviv University's School of Education and Sagol School of Neuroscience and Prof. Stanislas Dehaene of the Collège de France, a leader in the field of numerical cognition, have found new evidence that educated adults retain traces of their childhood, or innate, number sense — and that it's more powerful than many scientists think.

"We were surprised when we saw that people never completely stop thinking about numbers as they did when they were children," said Dotan. "The innate human number sense has an impact, even on thinking about double-digit numbers." The findings, a significant step forward in understanding how people process numbers, could contribute to the development of methods to more effectively educate or treat children with learning disabilities and people with brain injuries.

Digital proof of a primal sense

Educated adults understand numbers "linearly," based on the familiar number line from 0 to infinity. But children and uneducated adults, like tribespeople in the Amazon, understand numbers "logarithmically" — in terms of what percentage one number is of another. To analyze how educated adults process numbers in real time, Dotan and Dehaene asked the participants in their study to place numbers on a number line displayed on an iPad using a finger.

Previous studies showed that people who understand numbers linearly perform the task differently than people who understand numbers logarithmically. For example, linear thinkers place the number 20 in the middle of a number line marked from 0 to 40. But logarithmic thinkers like children may place the number 6 in the middle of the number line, because 1 is about the same percentage of 6 as 6 is of 40.

On the iPad used in the study, the participants were shown a number line marked only with "0" on one end and "40" on the other. Numbers popped up one at a time at the top of the iPad screen, and the participants dragged a finger from the middle of the screen down to the place on the number line where they thought each number belonged. Software tracked the path the finger took.

Changing course

Statistical analysis of the results showed that the participants placed the numbers on the number line in a linear way, as expected. But surprisingly — for only a few hundred milliseconds — they appeared to be influenced by their innate number sense. In the case of 20, for example, the participants drifted slightly rightward with their finger — toward where 20 would belong in a ratio-based number line — and then quickly corrected course. The results provide some of the most direct evidence to date that the innate number sense remains active, even if largely dormant, in educated adults.

"It really looks like the two systems in the brain compete with each other," said Dotan.

Significantly, the drift effect was found with two-digit as well as one-digit numbers. Many researchers believe that people can only convert two-digit numbers into quantities using the learned linear numerical system, which processes the quantity of each digit separately — for example, 34 is processed as 3 tens plus 4 ones. But Dotan and Dehaene's research showed that the innate number sense is, in fact, capable of handling the complexity of two-digit numbers as well.


Heart Attacks Hit Poor the Hardest
1/8/2014

TAU researchers show that socioeconomic status is predictor of higher risk of disease and death after an attack

As people get older, their bodies wear down and become less resilient. In old age, it's common for people to become "clinically frail," and this "frailty syndrome" is emerging in the field of public health as a powerful predictor of healthcare use and death.

Now researchers Vicki Myers and Prof. Yariv Gerber of the Department of Epidemiology and Preventive Medicine at the School of Public Health at Tel Aviv University's Sackler Faculty of Medicine and colleagues have found that poor people are more than twice as likely as the wealthy to become frail after a heart attack. The findings, published in the International Journal of Cardiology, could help doctors and policymakers improve post-heart-attack care for the poor.

"By defining frailty, which combines many areas of medicine, we can predict which people are at the highest risk after a heart attack," said Ms. Myers. "And we found a strong connection between frailty and socioeconomic status."

Prof. Uri Goldbourt of the Department of Epidemiology and Preventive Medicine at the School of Public Health and Prof. Yaacov Drory of the Department of Rehabilitation at TAU's Sackler Faculty of Medicine collaborated on the study. Prof. Drory, the founder of the Israel Study of First Acute Myocardial Infarction, passed away last month. His colleagues remember him as a dedicated cardiologist and researcher, who published numerous papers and books and made a great contribution to the field of heart attack and cardiac rehabilitation.

The weakest among us

Because the definition of frailty covers physical, psychological, and functional aspects, it can be effectively diagnosed by looking at the accumulation of health problems in any given individual. Ms. Myers and her colleagues created an index of 40 health-related variables, which in a previous study were shown to be effective in diagnosing frailty in heart attack patients.

Using medical records and interviews, the researchers applied the index to 1,151 patients who had suffered heart attacks in central Israel from 10 to 13 years prior to the study. The most frequent health problems were type-2 diabetes, physical inactivity, lack of energy, work limitations, limitation climbing stairs, and self-rated health deterioration. The index also assessed the presence of a range of diseases, significant weight loss, limitations to activities of daily living, anxiety, depression, and pain.

The researchers found that 35 percent of the patients in the study had become frail in the decade following their heart attack. The frail patients were more likely to have suffered a severe heart attack and to have been older and obese when they were first evaluated in 1992 to 1993, just after their heart attacks. They were also more likely to have had a lower socioeconomic status (with fewer years of education and lower family income), to have been unemployed, and to have lived a neighborhood in one of Israel's lowest socioeconomic categories.

Surprisingly, despite being sicker in general, frail patients were less likely to have been admitted to intensive care, to have undergone surgery, or to have been prescribed certain medications commonly prescribed after a heart attack. These findings, the researchers say, may reflect poorer access to healthcare among the poor. "Not only was low income associated with twice the risk of becoming frail, living in a deprived neighborhood was linked to a 60 percent increased risk of frailty compared to living in a wealthy neighborhood, irrespective of personal circumstances," Myers said.

A holistic view of the heart

Low socioeconomic status has been shown to contribute to poor health in various ways. In general, poor people have less access to healthcare, lower health literacy, and a higher prevalence of risk factors, like smoking, inactivity, and unhealthy diet. But despite an abundance of theories, it remains uncertain exactly how socioeconomic status affects health after a heart attack in particular.

By providing some of the first compelling evidence linking socioeconomic status to frailty after a heart attack, Ms. Myers and her colleagues hope to provide doctors and decision-makers a solid basis on which to make healthcare decisions. They recommend initiatives to prevent frailty after a heart attack among high-risk groups, and additional healthcare services in disadvantaged areas to address socioeconomic inequalities, with a particular emphasis on cardiac rehabilitation. They also say doctors should take a more holistic view of patients after a heart attack to help prevent frailty and its associated risks.


Turning Off the "Aging Genes"
1/2/2014

Computer algorithm developed by TAU researchers identifies genes that could be transformed to stop the aging process

Restricting calorie consumption is one of the few proven ways to combat aging. Though the underlying mechanism is unknown, calorie restriction has been shown to prolong lifespan in yeast, worms, flies, monkeys, and, in some studies, humans.

Now Keren Yizhak, a doctoral student in Prof. Eytan Ruppin's laboratory at Tel Aviv University's Blavatnik School of Computer Science, and her colleagues have developed a computer algorithm that predicts which genes can be "turned off" to create the same anti-aging effect as calorie restriction. The findings, reported in Nature Communications, could lead to the development of new drugs to treat aging. Researchers from Bar-Ilan University collaborated on the research.

"Most algorithms try to find drug targets that kill cells to treat cancer or bacterial infections," says Yizhak. "Our algorithm is the first in our field to look for drug targets not to kill cells, but to transform them from a diseased state into a healthy one."

A digital laboratory

Prof. Ruppin's lab is a leader in the growing field of genome-scale metabolic modeling or GSMMs. Using mathematical equations and computers, GSMMs describe the metabolism, or life-sustaining, processes of living cells. Once built, the individual models serve as digital laboratories, allowing formerly labor-intensive tests to be conducted with the click of a mouse. Yizhak's algorithm, which she calls a "metabolic transformation algorithm," or MTA, can take information about any two metabolic states and predict the environmental or genetic changes required to go from one state to the other.

"Gene expression" is the measurement of the expression level of individual genes in a cell, and genes can be "turned off" in various ways to prevent them from being expressed in the cell. In the study, Yizhak applied MTA to the genetics of aging. After using her custom-designed MTA to confirm previous laboratory findings, she used it to predict genes that can be turned off to make the gene expression of old yeast look like that of young yeast. Yeast is the most widely used genetic model because much of its DNA is preserved in humans.

Some of the genes that the MTA identified were already known to extend the lifespan of yeast when turned off. Of the other genes she found, Yizhak sent seven to be tested at a Bar-Ilan University laboratory. Researchers there found that turning off two of the genes, GRE3 and ADH2, in actual, non-digital yeast significantly extends the yeast's lifespan.

"You would expect about three percent of yeast's genes to be lifespan-extending," said Yizhak. "So achieving a 10-fold increase over this expected frequency, as we did, is very encouraging."

Hope for humans

Since MTA provides a systemic view of cell metabolism, it can also shed light on how the genes it identifies contribute to changes in genetic expression. In the case of GRE3 and ADH2, MTA showed that turning off the genes increased oxidative stress levels in yeast, thus possibly inducing a mild stress similar to that produced by calorie restriction.

As a final test, Yizhak applied MTA to human metabolic information. MTA was able to identify a set of genes that can transform 40-to-70 percent of the differences between the old and young information from four different studies. While currently there is no way to verify the results in humans, many of these genes are known to extend lifespan in yeast, worms, and mice.

Next, Yizhak will study whether turning off the genes predicted by MTA prolongs the lifespan of genetically engineered mice. One day, drugs could be developed to target genes in humans, potentially allowing us to live longer. MTA could also be applied to finding drug targets for disorders where metabolism plays a role, including obesity, diabetes, neurodegenerative disorders, and cancer.


Crowdsourcing Medicine
12/24/2013

TAU medical faculty offers course on improving entries for the online encyclopedia Wikipedia

Tel Aviv University's Sackler Faculty of Medicine is this year offering a course on producing entries for Wikipedia, the crowd-edited online encyclopedia — the first Israeli university to do so.

"I'm convinced that the students who take the course will vastly improve the level of online medical information available to the public," the medical school's dean, Prof. Yosef Makori, told the Israeli newspaper Haaretz.

TAU designed the one-credit elective — called "Wiki-medicine: The Wonderful World of Wiki and Free Medical Information in Hebrew Wikipedia" — with the help of Wikipedia Israel. Participants will meet with regular contributors to Wikipedia in both Hebrew and English to learn how to write and edit reliable entries and to understand intellectual property rights.

Wikipedia has previously worked with educational institutions in Israel and around the world to offer instruction in writing for the web site. But TAU is the first academic institution in Israel to offer a course dedicated entirely to writing Wikipedia entries.

For more, see the Haaretz story at:
http://www.aftau.org/site/DocServer/Digital_age_doctors.pdf?docID=20241


Chewing Gum is Often the Culprit for Migraine Headaches in Teens
12/19/2013

TAU study finds that 87 percent of teens who quit chewing experience significant relief

Teenagers are notorious for chewing a lot of gum. The lip smacking, bubble popping, discarded gum stuck to the sole give teachers and parents a headache.

Now, Dr. Nathan Watemberg of Tel Aviv University-affiliated Meir Medical Center has found that gum-chewing teenagers, and younger children as well, are giving themselves headaches too. His findings, published in Pediatric Neurology, could help treat countless cases of migraine and tension headaches in adolescents without the need for additional testing or medication.

"Out of our 30 patients, 26 reported significant improvement, and 19 had complete headache resolution," said Dr. Watemberg. "Twenty of the improved patients later agreed to go back to chewing gum, and all of them reported an immediate relapse of symptoms."

Right under our noses

Headaches are common in childhood and become more common and frequent during adolescence, particularly among girls. Typical triggers are stress, tiredness, lack of sleep, heat, video games, noise, sunlight, smoking, missed meals, and menstruation. But until now there has been little medical research on the relationship between gum chewing and headaches.

At Meir Medical Center's Child Neurology Unit and Child Development Center and community clinics, Dr. Watemberg noticed that many patients who reported headaches were daily gum chewers. Teenage girl patients were particularly avid chewers — a finding supported by previous dental studies. Dr. Watemberg found that in many cases, when patients stopped chewing gum at his suggestion, they got substantially better.

Taking a more statistical approach, Dr. Watemberg asked 30 patients between six and 19 years old who had chronic migraine or tension headaches and chewed gum daily to quit chewing gum for one month. They had chewed gum for at least an hour up to more than six hours per day. After a month without gum, 19 of the 30 patients reported that their headaches went away entirely and seven reported a decrease in the frequency and intensity of headaches. To test the results, 26 of them agreed to resume gum chewing for two weeks. All of them reported a return of their symptoms within days.

Two previous studies linked gum chewing to headaches, but offered different explanations. One study suggested that gum chewing causes stress to the temporomandibular joint, or TMJ, the place where the jaw meets the skull. The other study blamed aspartame, the artificial sweetener used in most popular chewing gums. TMJ dysfunction has been shown to cause headaches, while the evidence is mixed on aspartame.

Gumming up the works

Dr. Watemberg favors the TMJ explanation. Gum is only flavorful for a short period of time, suggesting it does not contain much aspartame, he says. If aspartame caused headaches, he reasons, there would be a lot more headaches from diet drinks and artificially sweetened products. On the other hand, people chew gum well after the taste is gone, putting a significant burden on the TMJ, which is already the most used joint in the body, he says.

"Every doctor knows that overuse of the TMJ will cause headaches," said Dr. Watemberg. "I believe this is what's happening when children and teenagers chew gum excessively."

Dr. Watemberg says his findings can be put to use immediately. By advising teenagers with chronic headaches to simply stop chewing gum, doctors can provide many of them with quick and effective treatment, without the need for expensive diagnostic tests or medications.


Do Patients in a Vegetative State Recognize Loved Ones?
12/16/2013

TAU researchers find unresponsive patients' brains may recognize photographs of their family and friends

Patients in a vegetative state are awake, breathe on their own, and seem to go in and out of sleep. But they do not respond to what is happening around them and exhibit no signs of conscious awareness. With communication impossible, friends and family are left wondering if the patients even know they are there.

Now, using functional magnetic resonance imaging (fMRI), Dr. Haggai Sharon and Dr. Yotam Pasternak of Tel Aviv University's Functional Brain Center and Sackler Faculty of Medicine and the Tel Aviv Sourasky Medical Center have shown that the brains of patients in a vegetative state emotionally react to photographs of people they know personally as though they recognize them.

"We showed that patients in a vegetative state can react differently to different stimuli in the environment depending on their emotional value," said Dr. Sharon. "It's not a generic thing; it's personal and autobiographical. We engaged the person, the individual, inside the patient."

The findings, published in PLOS ONE, deepen our understanding of the vegetative state and may offer hope for better care and the development of novel treatments. Researchers from TAU's School of Psychological Sciences, Department of Neurology, and Sagol School of Neuroscience and the Loewenstein Hospital in Ranaana contributed to the research.

Talking to the brain

For many years, patients in a vegetative state were believed to have no awareness of self or environment. But in recent years, doctors have made use of fMRI to examine brain activity in such patients. They have found that some patients in a vegetative state can perform complex cognitive tasks on command, like imagining a physical activity such as playing tennis, or, in one case, even answering yes-or-no questions. But these cases are rare and don’t provide any indication as to whether patients are having personal emotional experiences in such a state.

To gain insight into "what it feels like to be in a vegetative state," the researchers worked with four patients in a persistent (defined as "month-long") or permanent (persisting for more than three months) vegetative state. They showed them photographs of people they did and did not personally know, then gauged the patients' reactions using fMRI, which measures blood flow in the brain to detect areas of neurological activity in real time. In response to all the photographs, a region specific to facial recognition was activated in the patients' brains, indicating that their brains had correctly identified that they were looking at faces.

But in response to the photographs of close family members and friends, brain regions involved in emotional significance and autobiographical information were also activated in the patients' brains. In other words, the patients reacted with activations of brain centers involved in processing emotion, as though they knew the people in the photographs. The results suggest patients in a vegetative state can register and categorize complex visual information and connect it to memories – a groundbreaking finding.

The ghost in the machine

However, the researchers could not be sure if the patients were conscious of their emotions or just reacting spontaneously. So they then verbally asked the patients to imagine their parents' faces. Surprisingly, one patient, a 60-year-old kindergarten teacher who was hit by a car while crossing the street, exhibited complex brain activity in the face- and emotion-specific brain regions, identical to brain activity seen in healthy people. The researchers say her response is the strongest evidence yet that vegetative-state patients can be "emotionally aware." A second patient, a 23-year-old woman, exhibited activity just in the emotion-specific brain regions. (Significantly, both patients woke up within two months of the tests. They did not remember being in a vegetative state.)

"This experiment, a first of its kind, demonstrates that some vegetative patients may not only possess emotional awareness of the environment but also experience emotional awareness driven by internal processes, such as images," said Dr. Sharon.

Research focused on the "emotional awareness" of patients in a vegetative state is only a few years old. The researchers hope their work will eventually contribute to improved care and treatment. They have also begun working with patients in a minimally conscious state to better understand how regions of the brain interact in response to familiar cues. Emotions, they say, could help unlock the secrets of consciousness.


Coffee or Beer? The Choice Could Affect Your Genome
12/5/2013

TAU says caffeine and alcohol can change a part of DNA linked to aging and cancer

Coffee and beer are polar opposites in the beverage world. Coffee picks you up, and beer winds you down.

Now Prof. Martin Kupiec and his team at Tel Aviv University's Department of Molecular Microbiology and Biotechnology have discovered that the beverages may also have opposite effects on your genome. Working with a kind of yeast that shares many important genetic similarities with humans, the researchers found that caffeine shortens and alcohol lengthens telomeres — the end points of chromosomal DNA, implicated in aging and cancer.

"For the first time we've identified a few environmental factors that alter telomere length, and we've shown how they do it," said Prof. Kupiec. "What we learned may one day contribute to the prevention and treatment of human diseases."

Researchers from TAU's Blavatnik School of Computer Science and Columbia University's Department of Biological Sciences collaborated on the research, published in PLOS Genetics.

Between death and immortality

Telomeres, made of DNA and proteins, mark the ends of the strands of DNA in our chromosomes. They are essential to ensuring that the DNA strands are repaired and copied correctly. Every time a cell duplicates, the chromosomes are copied into the new cell with slightly shorter telomeres. Eventually, the telomeres become too short, and the cell dies. Only fetal and cancer cells have mechanisms to avoid this fate; they go on reproducing forever.

The researchers set out to expand on a 2004 study by Nobel Prize-winning molecular biologist Prof. Elizabeth Blackburn, which suggested that emotional stress causes the shortening of the telomeres characteristic of aging, presumably by generating free radicals in the cells. The researchers grew yeast cells in conditions that generate free radicals to test the effect on telomere length. They were surprised to find that the length did not change.

They went on to expose the yeast cells to 12 other environmental stressors. Most of the stressors — from temperature and pH changes to various drugs and chemicals — had no effect on telomere length. But a low concentration of caffeine, similar to the amount found in a shot of espresso, shortened telomeres, and exposure to a 5-to-7 percent ethanol solution lengthened telomeres.

From yeasts to you

To understand these changes, the TAU researchers scanned 6,000 strains of the yeast, each with a different gene deactivated. They then conducted genetic tests on the strains with the longest and shortest telomeres, revealing that two genes, Rap1 and Rif1, are the main players mediating environmental stressors and telomere length. In total, some 400 genes interact to maintain telomere length, the TAU researchers note, underscoring the importance of this gene network in maintaining the stability of the genome. Strikingly, most of these yeast genes are also present in the human genome.

"This is the first time anyone has analyzed a complex system in which all of the genes affecting it are known," said Prof. Kupiec. "It turns out that telomere length is something that's very exact, which suggests that precision is critical and should be protected from environmental effects."

More laboratory work is needed to prove a causal relationship, not a mere correlation, between telomere length and aging or cancer, the researchers say. Only then will they know whether human telomeres respond to the same signals as yeast, potentially leading to medical treatments and dietary guidelines. For now, Prof. Kupiec suggests, "Try to relax and drink a little coffee and a little beer."


A New Weapon in the War Against Superbugs
12/2/2013

TAU researchers find a protein that viruses use to kill bacteria

In the arms race between bacteria and modern medicine, bacteria have gained an edge. In recent decades, bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat. Scientists worry that a particularly virulent and deadly "superbug" could one day join the ranks of existing untreatable bacteria, causing a public health catastrophe comparable with the Black Death.

Now research led by Dr. Udi Qimron of Tel Aviv University's Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine has discovered a protein that kills bacteria. The isolation of this protein, produced by a virus that attacks bacteria, is a major step toward developing a substitute for conventional antibiotics. "To stay ahead of bacterial resistance, we have to keep developing new antibiotics," said Dr. Qimron. "What we found is a small protein that could serve as a powerful antibiotic in the future."

Dr. Ido Yosef, Ruth Kiro, and Shahar Molshanski-Mor of TAU's Sackler Faculty of Medicine and Dr. Sara Milam and Prof. Harold Erickson of Duke University contributed to the research, published in the Proceedings of the National Academy of Sciences.

Teaming up with a killer

Bacterial resistance is a natural process. But over the past sixty years or so, the misuse and overuse of antibiotics has pushed more and more bacteria to become more and more resistant, undermining one of the pillars of modern health care. Recently, the World Health Organization named growing antibiotic resistance one of the three greatest threats to public health.

Bacteriophages, often referred to as "phages," are viruses that infect and replicate in bacteria. Because they coevolved with bacteria, they are optimized to kill them. As proof of their endurance, phages are the most common life form on earth, outnumbering bacteria 10 to one. In places like the former Soviet Union, phages have been used to treat bacterial infections for the past hundred years. Harmless to humans, they inject their DNA into bacteria and rapidly replicate, killing their hosts.

"Ever since the discovery of bacteriophages in the early 20th century, scientists have understood that, on the principle of the 'enemy of my enemy is my friend,' medical use could be made of phages to fight viruses," said Dr. Qimron.

Breaking out the little guns

Dr. Qimron and his colleagues set out to understand how all 56 proteins found in T7, a particularly virulent phage that infects Escherichia coli bacteria, contribute to its functioning. They discovered that one of the proteins, called 0.4, impedes cell division in E. coli, causing the cells of the bacteria to elongate and then die. The protein is common to many bacteria and a similar process occurs in all bacteria, so the finding may have wide application.

No bacteriophage preparation has been approved in Western medicine for treating systemic bacterial infections. One reason is their inability to penetrate body tissues effectively. They are filtered effectively from the bloodstream by the spleen and liver, and occasionally neutralized by antibodies. But the 0.4 protein is much smaller than a whole phage, and so should be able to penetrate tissue better, getting to the bacteria to do its deadly work.

The major challenge for pharmaceutical companies will be figuring out how exactly to deliver the protein as a drug, said Dr. Qimron. In the meantime, he continues to hunt for other proteins that kill bacteria.


New Hope for Victims of Traumatic Brain Injury
11/18/2013

Researchers from TAU demonstrate hyperbaric oxygen therapy significantly revives brain functions and life quality

Every year, nearly two million people in the United States suffer traumatic brain injury (TBI), the leading cause of brain damage and permanent disabilities that include motor dysfunction, psychological disorders, and memory loss. Current rehabilitation programs help patients but often achieve limited success.

Now Dr. Shai Efrati and Prof. Eshel Ben-Jacob of Tel Aviv University's Sagol School of Neuroscience have proven that it is possible to repair brains and improve the quality of life for TBI victims, even years after the occurrence of the injury.

In an article published in PLoS ONE, Dr. Efrati, Prof. Ben Jacob, and their collaborators present evidence that hyperbaric oxygen therapy (HBOT) should repair chronically impaired brain functions and significantly improve the quality of life of mild TBI patients. The new findings challenge the often-dismissive stand of the US Food and Drug Administration, Centers for Disease Control and Prevention, and the medical community at large, and offer new hope where there was none.

The research trial

The trial included 56 participants who had suffered mild traumatic brain injury one to five years earlier and were still bothered by headaches, difficulty concentrating, irritability, and other cognitive impairments. The patients' symptoms were no longer improving prior to the trial.

The participants were randomly divided into two groups. One received two months of HBOT treatment while the other, the control group, was not treated at all. The latter group then received two months of treatment following the first control period. The treatments, administered at the Institute of Hyperbaric Medicine at Assaf Harofeh Medical Center, headed by Dr. Efrati, consisted of 40 one-hour sessions, administered five times a week over two months, in a high pressure chamber, breathing 100% oxygen and experiencing a pressure of 1.5 atmospheres, the pressure experienced when diving under water to a depth of 5 meters. The patients' brain functions and quality of life were then assessed by computerized evaluations and compared with single photon emission computed tomography (SPECT) scans.

Persuasive confirmation

In both groups, the hyperbaric oxygen therapy sessions led to significant improvements in tests of cognitive function and quality of life. No significant improvements occurred by the end of the period of non-treatment in the control group. Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to the control periods of non-treatment.

"What makes the results even more persuasive is the remarkable agreement between the cognitive function restoration and the changes in brain functionality as detected by the SPECT scans," explained Prof. Ben-Jacob. "The results demonstrate that neuroplasticity can be activated for months and years after acute brain injury."

"But most important, patients experienced improvements such as memory restoration and renewed use of language," Dr. Efrati said. "These changes can make a world of difference in daily life, helping patients regain their independence, go to work, and integrate back into society."

The regeneration process following brain injury involves complex processes, such as building new blood vessels and rebuilding connections between neurons, and requires much energy.

"This is where HBOT treatment can help," said Dr. Efrati. "The elevated oxygen levels during treatment supply the necessary energy for facilitating the healing process."

The findings offer new hope for millions of traumatic brain injury patients, including thousands of veterans wounded in action in Iraq and Afghanistan. The researchers call for additional larger scale, multi-center clinical studies to further confirm the findings and determine the most effective and personalized treatment protocols. But since the hyperbaric oxygen therapy is the only treatment proven to heal TBI patients, the researchers say that the medical community and the US Armed Forces should permit the victims of TBI benefit from the new hope right now, rather than waiting until additional studies are completed.


Putting the Brakes on Immunity
11/12/2013

TAU researchers discover a powerful mechanism that keeps white blood cells from going rogue

The immune system is a double-edged sword. While its primary role is to fight infections, it can also become overactive, leading to problems like allergies and autoimmune diseases.

For example, the part of the immune system responsible for resisting parasites acts by releasing white blood cells called eosinophil granulocytes into the blood. But elevated eosinophil levels are also responsible for allergic reactions, including most forms of asthma, gastrointestinal diseases, blood disorders, and cancers.

Now a study, led by Dr. Ariel Munitz of the Department of Clinical Microbiology and Immunology at the Sackler School of Medicine at Tel Aviv University, and conducted by graduate students Netali Baruch Morgenstern and Dana Shik, has found a mechanism that pushes eosinophils to die before they get into the blood and wreak havoc. The discovery is a breakthrough in science's understanding of the immune system and suggests powerful new treatments for eosinophilic diseases such as asthma.

"We've discovered an important and powerful pathway that works to kill eosinophils," says Dr. Munitz. "The fundamental knowledge we have gained may one day yield even bigger results and therapies."

Published online in Nature Immunology in November, the research was funded in part by the United States-Israel Binational Science Foundation, the Israel Science Foundation, the Israel Cancer Research Fund, and the Fritz Thyssen Stiftung. The Division of Allergy and Immunology at the Cincinnati Children's Hospital Medical Center collaborated on it.

The body's tug-of-war

The level of eosinophils in the blood is relatively low in healthy people, accounting for just 2 to 5 percent of white blood cells in circulation. But in eosinophilic disorders, a signalling protein called interleukin 5, or IL-5, triggers a rush of eosinophils from the bone marrow, where they are produced, and into the blood, where they are transported to various organs. IL-5 has lately been investigated as a new target for asthma medications, some of which have proven effective in clinical trials.

Analyzing the bone marrow of mice, the researchers found that the expansion of eosinophils caused by IL-5 is actually part of a broader mechanism that regulates the lifecycle of the cells. While IL-5 commands eosinophils to expand and enter the bloodstream, a cell receptor called paired immunoglobulin-like receptor A, or PIR-­A, commands eosinophils to die. So eosinophils are in a constant "tug-of-war" between survival signals delivered by IL-5 and death orders delivered by PIR-A.

Although the death order by PIR-A is dominant, it is never executed. Eosinophils express another receptor, called PIR-B, which closely resembles PIR-A and inhibits its actions. In order for PIR-A to carry out its death order to the cell, PIR-B must be shut down.

"PIR-A is always inhibited by PIR-B from the very early stages of eosinophil development," says Dr. Munitz. "We had to remove the expression of PIR-B from the cells to see PIR-A's powerful effects."

Two new approaches to nip disease in the bud

After identifying the mechanism in cell culture systems, the researchers verified that it also operates in mice. As expected, they found that asthmatic mice without PIR-B in their bodies had very little expansion of eosinophils into their blood and lungs and therefore less asthmatic inflammation in their lungs than normal mice. Unhindered by PIR-B, PIR-A appeared to keep eosinophils from reaching harmful levels in their bodies. Because human eosinophils also express PIR-like molecules, there is good reason to believe the same mechanism works in people.

In addition to advancing knowledge of eosinophils — a basic and important cell type — the researchers' work opens up two new avenues for treating eosinophilic disorders. Instead of lowering IL-5 levels to try to reduce eosinophil expansion, scientists can now target PIR-A to enhance its ability to kill eosinophils. Alternatively, they could weaken PIR-B so that it inhibits PIR-A less.

The researchers have preliminary evidence that PIR-B inhibits other mechanisms that drive cell death. Identifying them is the focus of their current research.


Torture Permanently Damages Normal Perception of Pain
11/5/2013

TAU researchers study the long-term effects of torture on the human pain system

Israeli soldiers captured during the 1973 Yom Kippur War were subjected to brutal torture in Egypt and Syria. Held alone in tiny, filthy spaces for weeks or months, sometimes handcuffed and blindfolded, they suffered severe beatings, burns, electric shocks, starvation, and worse. And rather than receiving treatment, additional torture was inflicted on existing wounds.

Forty years later, research by Prof. Ruth Defrin, of the Department of Physical Therapy, a part of the Stanley Steyer School of Health Professions in the Sackler Faculty of Medicine at Tel Aviv University, shows that the ex-prisoners of war (POWs), continue to suffer from dysfunctional pain perception and regulation, likely as a result of their torture. The study — conducted in collaboration with Prof. Zahava Solomon and Prof. Karni Ginzburg of TAU's Bob Shapell School of Social Work and Prof. Mario Mikulincer of the School of Psychology at the Interdisciplinary Center, Herzliya — was published in the European Journal of Pain.

"The human body's pain system can either inhibit or excite pain. It's two sides of the same coin," says Prof. Defrin. "Usually, when it does more of one, it does less of the other. But in Israeli ex-POWs, torture appears to have caused dysfunction in both directions. Our findings emphasize that tissue damage can have long-term systemic effects and needs to be treated immediately."

A painful legacy

The study focused on 104 combat veterans of the Yom Kippur War. Sixty of the men were taken prisoner during the war, and 44 of them were not. In the study, all were put through a battery of psychophysical pain tests — applying a heating device to one arm, submerging the other arm in a hot water bath, and pressing a nylon fiber into a middle finger. They also filled out psychological questionnaires.

The ex-POWs exhibited diminished pain inhibition (the degree to which the body eases one pain in response to another) and heightened pain excitation (the degree to which repeated exposure to the same sensation heightens the resulting pain). Based on these novel findings, the researchers conclude that the torture survivors' bodies now regulate pain in a dysfunctional way.

It is not entirely clear whether the dysfunction is the result of years of chronic pain or of the original torture itself. But the ex-POWs exhibited worse pain regulation than the non-POW chronic pain sufferers in the study. And a statistical analysis of the test data also suggested that being tortured had a direct effect on their ability to regulate pain.

Head games

The researchers say non-physical torture may have also contributed to the ex-POWs' chronic pain. Among other forms of oppression and humiliation, the ex-POWs were not allowed to use the toilet, cursed at and threatened, told demoralizing misinformation about their loved ones, and exposed to mock executions. In the later stages of captivity, most of the POWs were transferred to a group cell, where social isolation was replaced by intense friction, crowding, and loss of privacy.

"We think psychological torture also affects the physiological pain system," says Prof. Defrin. "We still have to fully analyze the data, but preliminary analysis suggests there is a connection."


Untangling Alzheimer's Disease
10/28/2013

TAU researchers identify specific molecules that could be targeted to treat the disorder

Plaques and tangles made of proteins are believed to contribute to the debilitating progression of Alzheimer's disease. But proteins also play a positive role in important brain functions, like cell-to-cell communication and immunological response. Molecules called microRNAs regulate both good and bad protein levels in the brain, binding to messenger RNAs to prevent them from developing into proteins.

Now, Dr. Boaz Barak and a team of researchers in the lab of Prof. Uri Ashery of Tel Aviv University's Department of Neurobiology at the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience have identified a specific set of microRNAs that detrimentally regulate protein levels in the brains of mice with Alzheimer's disease and beneficially regulate protein levels in the brains of other mice living in a stimulating environment.

"We were able to create two lists of microRNAs — those that contribute to brain performance and those that detract — depending on their levels in the brain," says Dr. Barak. "By targeting these molecules, we hope to move closer toward earlier detection and better treatment of Alzheimer's disease."

Prof. Daniel Michaelson of TAU's Department of Neurobiology in the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Dr. Noam Shomron of TAU's Department of Cell and Developmental Biology and Sagol School of Neuroscience, Dr. Eitan Okun of Bar-Ilan University, and Dr. Mark Mattson of the National Institute on Aging collaborated on the study, published in Translational Psychiatry .

A double-edged sword

Alzheimer's disease is the most common form of dementia. Currently incurable, it increasingly impairs brain function over time, ultimately leading to death. The TAU researchers became interested in the disease while studying the brains of mice living in an "enriched environment" — an enlarged cage with running wheels, bedding and nesting material, a house, and frequently changing toys. Such environments have been shown to improve and maintain brain function in animals much as intellectual activity and physical fitness do in people.

The researchers ran a series of tests on a part of the mice's brains called the hippocampus, which plays a major role in memory and spatial navigation and is one of the earliest targets of Alzheimer's disease in humans. They found that, compared to mice in normal cages, the mice from the enriched environment developed higher levels of good proteins and lower levels of bad proteins. Then, for the first time, they identified the microRNAs responsible for regulating the expression of both good and bad proteins.

Armed with this new information, the researchers analyzed changes in the levels of microRNAs in the hippocampi of young, middle-aged, and old mice with an Alzheimer's-disease-like condition. They found that some of the microRNAs were expressed in exactly inverse amounts in mice with Alzheimer's disease as they were in mice from the enriched environment. The results were higher levels of bad proteins and lower levels of good proteins in the hippocampi of old mice with Alzheimer's disease. The microRNAs the researchers identified had already been shown or predicted to regulate the expression of proteins in ways that contributed to Alzheimer's disease. Their finding that the microRNAs are inversely regulated in mice from the enriched environment is important, because it suggests the molecules can be targeted by activities or drugs to preserve brain function.

Brain-busting potential

Two findings appear to have particular potential for treating people with Alzheimer's disease. In the brains of old mice with the disease, microRNA-325 was diminished, leading to higher levels of tomosyn, a protein that is well known to inhibit cellular communication in the brain. The researchers hope that eventually microRNA-325 can be used to create a drug to help Alzheimer's patients maintain low levels of tomosyn and preserve brain function. Additionally, the researchers found several important microRNAs at low levels starting in the brains of young mice. If the same can be found in humans, these microRNAs could be used as biomarker to detect Alzheimer's disease at a much earlier age than is now possible — at 30 years of age, for example, instead of 60.

"Our biggest hope is to be able to one day use microRNAs to detect Alzheimer's disease in people at a young age and begin a tailor-made treatment based on our findings, right away," says Dr. Barak.


What Makes a Man?
10/10/2013

TAU doctors help an Israeli combat soldier with a testosterone disorder start a family

Dr. Karen Tordjman, a senior lecturer at Tel Aviv University's Sackler Faculty of Medicine didn't have an immediate diagnosis for the under-masculinized young man who walked into her office. A 25-year-old university student who had served in an elite commando unit in the Israeli navy, he was handsome in a fashion-model kind of way: rail thin, with a smooth face and delicate, feminine features. Closer inspection revealed no body hair other than sparse patches in his armpits and groin. His genitals were small and heavily scarred.

The young man had reluctantly agreed to visit the medical clinic at the insistence of his girlfriend, who wanted an explanation for his condition. He couldn't have known he was initiating a years-long medical journey that would lead Dr. Tordjman and a team of physicians to discover a new genetic mutation, bolster the case for a counterintuitive medical treatment, and push the limits of male fertility. "We offered treatment not for his future reproductive capabilities but for his appearance," says Dr. Tordjman. "We didn't guarantee him anything, but we said we'd try."

Her research, published in the journal Andrologia in June, will allow future genetic screening for the mutation.

Uncharted waters

Dr. Tordjman and her colleague Dr. Amnon Botchan, also a Sackler lecturer, began by obtaining the patient's medical records. The records showed that two of his uncles had been diagnosed with androgen receptor insensitivity — a rare condition that results in the body under-responding to the androgen hormones that drive male sexual development. Usually caused by a mutation in the androgen receptor gene, the condition impairs the development of male genitalia in the womb and of secondary male sexual characteristics during puberty.

In cases of complete androgen insensitivity, no male sexual development takes place. The result is men who look like women on the outside but have testes rather than female genitalia inside their bodies. Such cases are often diagnosed only during puberty, when the individuals develop breasts and other female sexual characteristics but do not start menstruating. In cases of partial androgen insensitivity, which range from mild to severe, the individuals are born with ambiguous genitalia. If doctors determine that surgically creating male genitalia is infeasible, they tend to assign the female gender.

Dr. Tordjman's patient, who reported a consistent heterosexual orientation, had not had sex reassignment surgery or been given androgen treatments to try to enhance his sexual development at birth. But he had been diagnosed with the same condition as his uncles and undergone operations to correct genital malformations at age three and to remove breast tissue during puberty. Genetic testing, performed with the help of French researchers Dr. Serge Lumbroso and Prof. Charles Sultan, confirmed that he had a mutation of his androgen receptor gene — one that had not previously been reported.

A family affair

Hoping to masculinize the patient per his wishes, Dr. Tordjman started him on high-dose testosterone therapy. Theoretically, this type of therapy makes little sense for patients with androgen receptor insensitivity, because their bodies create plenty of testosterone — it's just that they are unable to put it to use. But Tordjman had read about a case in which the therapy had worked and decided to give it a try.

After several months of weekly injections, the patient appeared dramatically more masculine. He gained 18 pounds — mostly of muscle — and grew hair on his face and body, leading him to shave for the first time in his life. His voice, which had always been high-pitched, did not change. (The voice, says Tordjman, is stubbornly resistant to hormone therapy.) The treatments continued for four years, during which the patient and his girlfriend got married and eventually began talking about having a baby.

Infertility in men with androgen receptor insensitivity is nearly universal, even in mild cases; and no one with a case as severe as the patient's was known to have successfully fathered a child. But having seen a significant improvement in his sperm count, Tordjman took another long shot and referred the couple for fertility treatment. When Tordjman next saw the patient several years later, he was pushing a baby girl into her office in a stroller.

Children have a 50-percent chance of inheriting a mutation for androgen receptor insensitivity from a parent. While fathers have typically been left out of the equation given the male sterility associated with the condition, this case will force a rethinking of that dogma and encourage the use of testosterone and fertility treatments in men with the condition, says Tordjman.

"My suggestion is in any case like this with partial androgen insensitivity, even if you don't know where in the androgen receptor gene the mutation lies, testosterone treatment is worth trying," she says.


TAU Smartphone App Brings Genetic Analysis to the Palm of Your Hand
10/8/2013

New software allows users to upload and then update the meaning of their genetic information

Until now, understanding and using genetic information has depended on the scientists and doctors who do the testing. No longer.

Now, software developed by researchers at Tel Aviv University is putting the power of genetic information in the hands of the people. GeneG, a smartphone app and associated web site created by Dr. Noam Shomron at TAU's Faculty of Medicine allows individuals to access and analyze their genome at any time. After undergoing whole genome sequencing, users can upload their data to the GeneG website for analysis. The results are available via the GeneG app on mobile devices.

"For the first time you can take your genome home and look at it whenever you want," says Shomron. "We are giving you eyes to peer into your genetics." And as new analytical tests are developed, you can apply them right away.

TAU graduate students Ofer Isakov and Gershon Celniker worked under Shomron to develop the software, which is to be released to physicians in October ahead of a public release. More information about the project can be found at http://www.geneg.org/.

Data-driven demand

The first map of the human genome, published in 2003, took eight years of work by thousands of researchers and cost $1 billion. Today, people can get their entire genome sequenced within a few weeks for around $1,000. Thousands have had it done, and the turnaround time and cost are fast decreasing as the technology advances. GeneG aims to meet the growing demand for ways to make sense of all this information.

At the moment, DNA sequencing focuses on specific areas, looking for quirks in sequences within individual genes, clusters of genes, or chromosomes. A downside of this targeted approach is that each genetic test requires donating new DNA and waiting for it to be processed. Shomron gives the example of a woman who wants to get tested before becoming pregnant. Currently, she has to take a day off work, travel to a lab to have her blood drawn, then wait for several weeks while a selection of her genes is amplified and sequenced. If she later decides to conceive again and wants the newest genetic tests, she has to start the whole process over again.

With GeneG, on the other hand, new tests are just a software update away. Users who have uploaded their genomes to the website can "query" them using digital genetic tests based on research from organizations like the National Institutes of Health, Stanford University, and the European Bioinformatics Institute. The software provides all the functions of more limited genetic testing, including diagnosing and predicting genetic diseases, checking potential parents for genetic traits that could cause disease in their future children, and screening unborn and newborn babies. And it can all be done without setting foot in a lab.

iGenome

But GeneG is not just a timesaver. By giving people instant access to their genomic information, Shomron hopes to help usher in an era of personalized medicine. He envisions people carrying their genomes with them on their mobile devices wherever they go, encouraging scientists to develop more tests and doctors to use the information in their treatment of patients.

"If we give this power to the general public, it will put pressure on the medical field to catch up with this information," said Shomron. But, he says, "It should be used with great caution and with sensible interpretation. Some people might not be ready to see all this information about themselves."

The software could be particularly effective, Shomron says, in advancing pharmacogenomics — the science of optimizing medications for each individual's unique genetic makeup. With the right tests, GeneG will tell patients and their doctors which medicines are likely to be the safest and most effective in treating whatever ails them. Specific applications could range from finding the right antidepressant to maximizing the effectiveness of cancer treatments.

Within a few iterations of the software, Shomron hopes the GeneG mobile app will be independent of the website. A bit further in the future, he says, you and your partner may be able to tap your smartphones together to see if you are as compatible genetically as you are personally.


Sending Multiple Sclerosis Up in Smoke
10/7/2013

TAU researchers find chemicals in marijuana could help treat MS

Multiple sclerosis is an inflammatory disease in which the immune system attacks the nervous system. The result can be a wide range of debilitating motor, physical, and mental problems. No one knows why people get the disease or how to treat it.

In a new study published in the Journal of Neuroimmune Pharmacology, Drs. Ewa Kozela, Ana Juknat, Neta Rimmerman and Zvi Vogel of Tel Aviv University's Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases and Sackler Faculty of Medicine demonstrate that some chemical compounds found in marijuana can help treat MS-like diseases in mice by preventing inflammation in the brain and spinal cord.

"Inflammation is part of the body's natural immune response, but in cases like MS it gets out of hand," says Kozela. "Our study looks at how compounds isolated from marijuana can be used to regulate inflammation to protect the nervous system and its functions." Researchers from the Weizmann Institute of Science co-authored the study.

Mind-altering findings

Israel has a strong tradition of marijuana research. Israeli scientists Raphael Mechoulam and Yechiel Gaoni discovered THC, or tetrahydrocannabinol, in 1964, kick-starting the scientific study of the plant and its chemical constituents around the world. Since then, scientists have identified about 70 compounds — called cannabinoids — that are unique to cannabis and have interesting biological effects. In the 1990s, Prof. Vogel was among the first researchers to describe endocannabinoids, molecules that act like THC in the body.

Besides THC, the most plentiful and potent cannabinoid in marijuana is cannabidiol, or CBD. The TAU researchers are particularly interested in CBD, because it offers medicinal benefits without the controversial mind-altering effects of THC.

In a 2011 study, they showed that CBD helps treat MS-like symptoms in mice by preventing immune cells in their bodies from transforming and attacking the insulating covers of nerve cells in the spinal cord. After inducing an MS-like condition in mice — partially paralyzing their limbs — the researchers injected them with CBD. The mice responded by regaining movement, first twitching their tails and then beginning to walk without a limp. The researchers noted that the mice treated with CBD had much less inflammation in the spinal cord than their untreated counterparts.

High hopes for humans

In the latest study, the researchers set out to see if the known anti-inflammatory properties of CBD and THC could also be applied to the treatment of inflammation associated with MS — and if so, how. This time they turned to the immune system.

The researchers took immune cells isolated from paralyzed mice that specifically target and harm the brain and spinal cord, and treated them with either CBD or THC. In both cases, the immune cells produced fewer inflammatory molecules, particularly one called interleukin 17, or IL-17, which is strongly associated with MS and very harmful to nerve cells and their insulating covers. The researchers concluded that the presence of CBD or THC restrains the immune cells from triggering the production of inflammatory molecules and limits the molecules' ability to reach and damage the brain and spinal cord.

Further research is needed to prove the effectiveness of cannabinoids in treating MS in humans, but there are reasons for hope, the researchers say. In many countries, CBD and THC are already prescribed for the treatment of MS symptoms, including pain and muscle stiffness.

"When used wisely, cannabis has huge potential," says Kozela, who previously studied opiates like morphine, derived from the poppy plant. "We're just beginning to understand how it works."


What Makes Triathletes So Tough?
10/3/2013

TAU researchers find triathletes feel less pain than the rest of us

Triathletes participate in a grueling endurance sport, swimming, bicycling, and running long distances without rest. In training and competitions, they regularly push their bodies beyond the limits most of us can endure. But while there is no doubt that triathletes are tough, very little is known about what gives them their exceptional abilities.

Now researchers at Tel Aviv University have discovered a possible explanation. Prof. Ruth Defrin and her doctoral student Nirit Geva of TAU's Department of Physical Therapy, part of the Stanley Steyer School of Health Professions at TAU's Sackler Faculty of Medicine, have found that triathletes feel less pain than casual exercisers. Their findings were published in the journal Pain in August.

"In our study, triathletes rated pain lower in intensity, tolerated it longer, and inhibited it better than individuals in a control group," says Prof. Defrin. "We think both physiological and psychological factors underlie these differences and help explain how triathletes are able to perform at such a high level."

Mind over matter

Nineteen triathletes and 17 non-athletes participated in the TAU researchers' study. The triathletes were people who trained for and competed in at least two triathlons per year — including in some cases the notoriously challenging Ironman Triathlon, which consists of a 2.4-mile swim, a 112-mile bicycle ride, and a 26.2-mile marathon run. The non-athletes were people who did non-competitive exercises, like jogging, swimming, or aerobics classes.

All the participants were put through a battery of psychophysical pain tests, involving the application of a heating device to one arm and the submersion of the other arm in a cold-water bath. They also filled out questionnaires about their attitudes toward pain.

In the tests, the triathletes identified pain just as well as non-athletes, but they perceived it as less intense and were able to withstand it longer. The researchers explain that detecting pain is a relatively straightforward sensory experience, whereas evaluating pain and being willing and able to endure it involves attitude, motivation, and life experience. The triathletes reported fearing and worrying less about pain, which may help explain their higher tolerance, the researchers say.

The triathletes also showed a better ability to inhibit pain than non-athletes, as measured by conditioned pain modulation — the degree to which the body eases one pain in response to another. The researchers say psychology may be a factor here too. The triathletes with less fear of pain tended to exhibit better pain regulation. Previous studies have similarly found that psychological manipulation can affect pain perception.

The chicken or the egg?

Another explanation for triathletes' lower pain ratings, higher pain tolerance, and better pain regulation is that they have taught their bodies to respond powerfully to painful stimuli through their intense training. The TAU researchers say their study — along with existing literature — suggests that psychology and physiology together enable triathletes to do what they do.

"It is very difficult to separate physiology and psychology," says Prof. Defrin. "But in general, experience is the sum of these factors."

The researchers plan to do further research to determine whether triathletes participate in their sport because they feel less pain or feel less pain because they participate in their sport. If it turns out that intense training in fact helps reduce and regulate pain, it could be used to treat people with chronic pain. Like triathletes, chronic pain patients suffer daily, but their pain is out of their control and has the opposite effect, weakening rather than strengthening pain inhibition.


Vaccination and the Gentle Art of Persuasion
10/1/2013

TAU research recommends that pediatricians respect parents' rights to make the case for immunization

Controversy about the risks of measles, mumps, and rubella vaccines has been rumbling in the United States for years — and now it's Israel's turn. After finding traces of the polio virus in sewage, Israel's Ministry of Health launched a national vaccination campaign that reached more than half a million children. Surprisingly, dissenting voices flooded social media and the mainstream news, calling for a halt to the campaign. Endorsements by public figures, like Israel's president Shimon Peres, did little to calm the storm.

Now a study led by researchers at Tel Aviv University demonstrates that nearly all pediatricians in Israel strongly support the vaccination of infants, but most do not believe that their role is to force treatment on parents. The study recommends that pediatricians use the art of persuasion, with the help of communication experts, as they discuss the risks and virtues of vaccination with parents.

"Our advice is that pediatricians find ways to communicate their views to parents in a respectful way that doesn't discourage them from seeking treatment for their children," says Dr. Ayala Maayan-Metzger of TAU's Sackler Faculty of Medicine. "This is something experts in modern communication could help with." The study was published in September in the journal Acta Paediatrica.

A clash of values

Every major medical body in the world — including Israel's Ministry of Health, the American Medical Association, and the World Health Organization — recommends a battery of infant vaccinations. But over the past decade, an increasing number of parents have chosen not to comply. Studies have identified various reasons for this trend, including a growing distrust of professional expertise, unproven theories about a causal effect for autism, and the parents' insistence on their own right to decide on medical care for their children.

Dr. Maayan-Metzger, who also works at the Department of Neonatology at The Edmond and Lili Safra Children's Hospital at Sheba Medical Center, and Dr. Peri Kedem-Friedrich of Bar-Ilan University's Psychology Department, set out with other TAU researchers to examine for the first time the issue of infant vaccination from the perspective of the working clinical physician. They hoped to understand pediatricians' attitudes and treatment intentions toward parents who refuse to vaccinate their infants.

To this end, they distributed an anonymous questionnaire to 376 pediatricians who work in hospitals and primary health care clinics in Israel. The pediatricians completed the questionnaire between May and November of 2010.

Ninety-two percent of the pediatricians agreed that vaccinations, which are widely available free of charge in Israel, are in infants' best interest. Seventy-one percent expressed negative feelings toward parents who refuse to vaccinate their infants. But 37 percent agreed that parents have a right to decide, and another 37 percent agreed that vaccinations should be officially enforced. Two percent said they would object to treating children who had not been vaccinated.

"The findings show how strongly doctors here support the vaccination program and stand behind the Ministry of Health," says Maayan-Metzger. "It's not a decision handed down from on high. We feel passionately that it’s the right thing to do."

A better bedside manner?

The study concludes that pediatricians are torn between two opposing values: the importance of immunizing infants and the parents' right to determine what is medically best for their children. Despite their strong — even angry — feelings, pediatricians do not feel it is their place to force the vaccinations on the parents and their children, favoring gentle persuasion or official enforcement over coercion, according to the study.

To build trust, the study suggests that pediatricians communicate to parents that they genuinely respect their rights. But the study also acknowledges pediatricians may simply not be equipped to change parents' minds on such a complex and personal issue. Communication experts may be necessary, it says, to help physicians combat anti-vaccination sentiment and communicate to parents the benefits of vaccinating their infants.


Putting the Spring Back in Broken Hearts
9/23/2013

TAU researchers develop spring-like fibers to help repair damaged heart tissue

The threat from a heart attack doesn't end with the event itself. Blockage of blood flow to the heart can cause irreversible cell death and scarring. With transplants scarce, half the people who live through a heart attack die within five years. Scientists are trying to address this problem by engineering cardiac tissue to patch up damaged areas.

Now doctoral students Sharon Fleischer and Ron Feiner — under the supervision of Dr. Tal Dvir of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Center for Nanoscience and Nanotechnology — have fabricated fibers shaped like springs that allow engineered cardiac tissue to pump more like the real thing. They reported their findings in the journal Biomaterials in August.

"Until now, when scientists have tried to engineer cardiac tissue, they've used straight fibers to support the contracting cells," says Dr. Dvir. "However, these fibers prevent the contraction of the engineered tissue. What we did was mimic the spring-like fibers that promote contraction and relaxation of the heart muscle. We found that by growing tissues on these fibers, we got more functional tissues.

Springing into action

Cardiac tissue is engineered by allowing cells taken from the hearts of patients or animals to grow on a three-dimensional scaffold, which replaces the extracellular matrix, a collagen grid that naturally supports the cells in the heart. Over time, the cells come together to form a tissue that generates its own electrical impulses and expands and contracts spontaneously. The tissue can then be surgically implanted to replace damaged tissue and improve heart function in patients.

Dr. Dvir's Laboratory for Tissue Engineering and Regenerative Medicine focuses on engineering complex tissues for medical use. When it comes to the heart, the researchers are always looking for ways to build a scaffold that better replicates the extracellular matrix and so yields more functional tissue. Earlier this year, they published research on integrating gold particles into cardiac tissue to optimize electrical signaling between cells.

More recently, the researchers identified spiral-shaped collagen fibers in the extracellular matrix of rat hearts. Seeing the potential for an advance, they set out to recreate them for the first time. After fabricating the spring-like fibers using advanced techniques, they subjected them to a variety of tests.

As the researchers predicted, the spring-like fibers showed better mechanical properties than straight fibers, with especially improved elasticity. And compared to tissue engineered with straight fibers, the tissue engineered with spring-like fibers contracted with greater force and less mechanical resistance.

"These properties are very important, because we want to transplant the tissue into the human heart, which expands and contracts constantly," says Fleischer.

Saving lives

Heart disease is responsible for a third of all deaths in the United States, according to a 2013 American Heart Association report. The researchers in Dr. Dvir's lab hope that tissue engineered with spring-like fibers will help fight this epidemic, improving and prolonging the lives of millions of people.

But additional research is needed first. The researchers say the processes for fabricating the fibers and assembling them into a scaffold need to be refined. Most importantly, they say, the ability of the tissue to improve heart function after a heart attack needs to be tested in humans — something they plan to do in pre-clinical and then clinical trials.


Why Kids Breathe Easier in Summer
9/17/2013

TAU researchers find winter viruses may be behind sleep-disordered breathing spike in children

A good night's sleep is important to our children's development. But with the first day of school just passed, many children are at increased risk for sleep breathing disorders that can impair their mental and physical development and hurt their academic performance.

A study conducted in North America in 2011 showed that the frequency of sleep-disordered breathing increases in the winter and spring. Until now, researchers believed asthma, allergies, and viral respiratory infections like the flu contributed to disorders that affect children's breathing during sleep.

Now, in a new study conducted at the Pediatric Sleep Center at the Tel Aviv Sourasky Medical Center and published in the journal Sleep Medicine, Dr. Riva Tauman and her fellow researchers of the Sackler Faculty of Medicine at Tel Aviv University have shown that asthma and allergies do not contribute to pediatric sleep-disordered breathing. Viruses alone, they say, may be responsible for the seasonal variation seen in children.

The researchers say the study has broad implications for the treatment of sleep-breathing disorders in children, bolstering the idea that the time of year is relevant when treating children for sleep-disordered breathing in borderline cases.

Blowing hot and cold

"We knew from research and clinical practice that sleep-disordered breathing in children gets worse during the colder months," Dr. Tauman says. "What we didn't expect is that the trend has nothing to do with asthma or allergies."

"Sleep-disordered breathing" is a blanket term for a group of disorders. One of the common disorders is obstructive sleep apnea, in which the upper airway becomes blocked, usually by enlarged tonsils or adenoids, causing snoring and, in more severe cases, breathing pauses that lead to poor-quality and fragmented sleep and decreased oxygen and elevated carbon dioxide levels in the bloodstream.

In the long term, sleep-disordered breathing in children can cause stunted growth, heart disease, and neurocognitive problems associated with diminished school performance, impaired language development, and behavioral issues.

In their study, Dr. Tauman and her Sackler Faculty of Medicine colleagues Michal Greenfeld and Yakov Sivan statistically analyzed the cases of more than 2,000 children and adolescents who were referred to the sleep center to be tested for suspected sleep-disordered breathing between 2008 and 2010. Confirming earlier results of a 2011 study of five- to nine-year-olds, the researchers found that pediatric sleep-disordered breathing is worse in the winter — which in Israel they defined as from November to March — than in the summer. The seasonal variability is most apparent in children less than five years old, they found.

The researchers also found that wheezing and asthma do not contribute to the trend.

Based on their findings, the researchers speculate that viral respiratory infections — which are more prevalent in younger children and during colder months — are the major contributor to the seasonal variability seen in pediatric sleep-disordered breathing.

Taking the long view

If the sleep clinic tests had all been conducted in the winter, the researchers estimate that seven percent more children would have been diagnosed with sleep-disordered breathing. Seven percent fewer would have been diagnosed if all the tests had been done in the summer, they estimate.

"Our study suggests that if a child comes into the sleep laboratory in the winter with a mild case, I may consider not treating him. I can assume he will be better in the summer," said Tauman. "But if he has only mild symptoms in the summer, I can assume they are more severe in the winter."


When Good Cells Go Bad
9/16/2013

TAU research could help prevent white blood cells from contributing to colon cancer and lung disease

Researchers at Tel Aviv University have gained new insight into the workings of white blood cells that contribute to several deadly diseases — an insight that offers hope for new and more successful treatments.

Dr. Ariel Munitz and doctoral student Danielle Karo-Atar of TAU's Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine found a receptor on the cells — called macrophages — involved in stopping the macrophages from becoming overactive and harmful.

Macrophages serve an essential role in the immune system, "eating" cellular debris and pathogens. But they also contribute to several diseases, including colon cancer and lung disease. In the laboratory, the researchers were able to determine how the receptor suppresses the macrophage behavior that contributes to colon cancer and idiopathic pulmonary fibrosis.

"We identified a cell-surface receptor on the macrophages, paired immunoglobulin-like receptor B, that regulates their response to suppress their wound-healing capacity," Dr. Munitz told the ISRAEL21c news website. He says the receptor could be a good candidate for drugs targeting diseases linked to macrophage activity.

Their preliminary findings were published in the American Journal of Respiratory Cell and Molecular Biology. For more, see the ISRAEL21c story:
http://israel21c.org/health/new-pathway-to-treat-colorectal-cancer-pulmonary-fibrosis/


Meal Timing Can Significantly Improve Fertility in Women with Polycystic Ovaries
8/13/2013

Managing insulin levels through meal timing boosts ovulation and decreases testosterone, says TAU researcher

Polycystic Ovarian Syndrome (PCOS), a common disorder that impairs fertility by impacting menstruation, ovulation, hormones, and more, is closely related to insulin levels. Women with the disorder are typically "insulin resistant" — their bodies produce an overabundance of insulin to deliver glucose from the blood into the muscles. The excess makes its way to the ovaries, where it stimulates the production of testosterone, thereby impairing fertility.

Now Prof. Daniela Jakubowicz of Tel Aviv University's Sackler Faculty of Medicine and the Diabetes Unit at Wolfson Medical Center has found a natural way to help women of normal weight who suffer from PCOS manage their glucose and insulin levels to improve overall fertility. And she says it's all in the timing.

The goal of her maintenance meal plan, based on the body's 24 hour metabolic cycle, is not weight loss but insulin management. Women with PCOS who increased their calorie intake at breakfast, including high protein and carbohydrate content, and reduced their calorie intake through the rest of the day, saw a reduction in insulin resistance. This led to lower levels of testosterone and dramatic increase in the ovulation frequency — measures that have a direct impact on fertility, notes Prof. Jakubowicz.

The research has been published in Clinical Science and was recently presented at the Endocrine Society's annual meeting in June. It was conducted in collaboration with Dr. Julio Wainstein of TAU and Wolfson Medical Center and Dr. Maayan Barnea and Prof. Oren Froy of the Hebrew University of Jerusalem.

Managing insulin to increase ovulation

Many of the treatment options for PCOS are exclusively for obese women, Prof. Jakubowicz explains. Doctors often suggest weight loss to manage insulin levels, or prescribe medications that are used to improve the insulin levels of overweight patients. But many women who suffer from PCOS maintain a normal weight — and they are looking for ways to improve their chances of conceiving and giving birth to a healthy baby.

In a recent study, Prof. Jakubowicz and her fellow researchers confirmed that a low-calorie weight-loss plan focusing on larger breakfasts and smaller dinners also lowers insulin, glucose, and triglycerides levels. This finding inspired them to test whether a similar meal plan could be an effective therapeutic option for women with PCOS.

Sixty women suffering from PCOS with a normal body mass index (BMI) were randomly assigned to one of two 1,800 calorie maintenance diets with identical foods. The first group ate a 983 calorie breakfast, a 645 calorie lunch, and a 190 calorie dinner. The second group had a 190 calorie breakfast, a 645 calorie lunch, and 983 calorie dinner. After 90 days, the researchers tested participants in each group for insulin, glucose, and testosterone levels as well as ovulation and menstruation.

As expected, neither group experienced a change in BMI, but other measures differed dramatically. While participants in the "big dinner" group maintained consistently high levels of insulin and testosterone throughout the study, those in the "big breakfast" group experienced a 56 percent decrease in insulin resistance and a 50 percent decrease in testosterone. This reduction of insulin and testosterone levels led to a 50 percent rise in ovulation rate, indicated by a rise in progesterone, by the end of the study.

A natural therapy

According to Prof. Jakubowicz, these results suggest that meal timing — specifically a meal plan that calls for the majority of daily calories to be consumed at breakfast and a reduction of calories throughout the day — could help women with PCOS manage their condition naturally, providing new hope for those who have found no solutions to their fertility issues, she says. PCOS not only inhibits natural fertilization, but impacts the effectiveness of in vitro fertilization treatments and increases the rate of miscarriage.

And beyond matters of fertility, this method could mitigate other symptoms associated with the disorder, including unwanted body hair, oily hair, hair loss, and acne. Moreover, it could protect against developing type-2 diabetes.


A "GPS System" in the Human Brain
8/8/2013

TAU neurosurgeon and two American colleagues discover the "grid cells" behind the body's navigational system

Neurosurgeon Prof. Itzhak Fried of Tel Aviv University's Sackler School of Medicine and the University of California, Los Angeles, is part of a team of scientists that recently located cells that act like GPS systems in the human brain. Fried discovered the so-called "grid cells" along with Drs. Joshua Jacobs of Drexel University and Michael J. Kahana of the University of Pennsylvania. They reported their findings in the journal Nature Neuroscience.

When scientists found in 2005 that rodents, bats, and nonhuman primates have grid cells that form navigation systems in their brains, it was one of the most important brain-research developments of the past few decades. Grid cells are neurons that emit pulses of electricity in a regular pattern that maps the animal's movement. Although scientists predicted they would find grid cells in humans, until now no one had previously been able to prove they were there.

"Without grid cells, it is likely that humans would frequently get lost or have to navigate based only on landmarks," Jacobs said. "Grid cells are thus critical for maintaining a sense of location in an environment."

The researchers made the discovery using electrodes implanted in the brains of 14 patients scheduled for surgery for severe epilepsy. The patients volunteered to play a video game in which they navigated a virtual environment. As they played, the patterns characteristic of rodent grid cells were found, showing that humans use the same neural mechanism as other mammals.

Understanding grid cells in humans could have important medical applications, the researchers say. "The area where the grid cells are found, the entorhinal cortex, is a key component of the human memory system, and in fact is the first to be affected in Alzheimer's disease," said Fried. "A better understanding of this system in humans may offer potential for the development of therapeutic measures to treat memory disorders in neurological patients." The scientists also located grid cells in another brain area in humans, the cingulate cortex.

For more, see the New York Times story:
http://www.nytimes.com/2013/08/06/science/navigational-cell-systems-located-in-human-brains.html


Micro-Machines for the Human Body
8/7/2013

TAU researchers adapt microscopic technology for bionic body parts and other medical devices

Tiny sensors and motors are everywhere, telling your smartphone screen to rotate and your camera to focus. Now, a team of researchers at Tel Aviv University has found a way to print biocompatible components for these micro-machines, making them ideal for use in medical devices, like bionic arms.

Microelectromechanical systems, better known as MEMS, are usually produced from silicon. The innovation of the TAU researchers — engineering doctoral candidates Leeya Engel and Jenny Shklovsky under the supervision of Prof. Yosi Shacham-Diamand of the School of Electrical Engineering and Slava Krylov of the School of Mechanical Engineering — is creating a novel micro-printing process that works a highly flexible and non-toxic organic polymer. The resulting MEMS components can be more comfortably and safely used in the human body and they expend less energy.

A two-way street

As their name suggests, MEMS bridge the worlds of electricity and mechanics. They have a variety of applications in consumer electronics, automobiles, and medicine. MEMS sensors, like the accelerometer that orients your smartphone screen vertically or horizontally, gather information from their surroundings by converting movement or chemical signals into electrical signals. MEMS actuators, which may focus your next smartphone's camera, work in the other direction, executing commands by converting electrical signals into movement.

Both types of MEMS depend on micro- and nano-sized components, such as membranes, either to measure or produce the necessary movement.

For years, MEMS membranes, like other MEMS components, were primarily fabricated from silicon using a set of processes borrowed from the semiconductor industry. TAU's new printing process, published in Microelectronic Engineering and presented at the AVS 59th International Symposium in Tampa, FL, yields rubbery, paper-thin membranes made of a particular kind of organic polymer. This material has specific properties that make it attractive for micro- and nano-scale sensors and actuators. More importantly, the polymer membranes are more suitable for implantation in the human body than their silicon counterparts, which partially stems from the fact that they are hundreds of times more flexible than conventional materials.

The unique properties of the polymer membranes have unlocked unprecedented possibilities. Their flexibility could help make MEMS sensors more sensitive and MEMS motors more energy efficient. They could be key to better cameras and smartphones with a longer battery life.

Giving patients a hand

But the printing process may deliver the biggest jolt to the field of medicine, where polymer membranes could be used in devices like diagnostic tests and smart prosthetics. There are already bionic limbs that can respond to stimuli from an amputee's nervous system and the external environment, and prosthetic bladders that regulate urination for people paralyzed below the waist. Switching to MEMS made with the polymer membranes could help make such prosthetics more comfortable, efficient, and safer for use on or inside the body.

"The use of new, soft materials in micro devices stretches both the imagination and the limits of technology," Engel says, "but introducing polymer MEMS to industry can only be realized with the development of printing technologies that allow for low cost mass production. The team's new polymer membranes can already be quickly and inexpensively produced."

The next step, she says, is to use the printing process to make functional sensors and actuators almost entirely out of the polymer at the micro- and nano-scales. Such flexible machines could be put to use in things like artificial muscles and screens so flexible that you can roll them up and put them in your pocket.


Eating a Big Breakfast Fights Obesity and Disease
8/5/2013

A high-calorie breakfast protects against diabetes, hypertension, and cardiovascular problems, says TAU researcher

Whether you hope to lose weight or just stay healthy, what you eat is a crucial factor. The right nutrients can not only trim your waistline, but also provide energy, improve your mood, and stave off disease. Now a Tel Aviv University researcher has found that it's not just what you eat — but when.

Metabolism is impacted by the body's circadian rhythm — the biological process that the body follows over a 24 hour cycle. So the time of day we eat can have a big impact on the way our bodies process food, says Prof. Daniela Jakubowicz of TAU's Sackler Faculty of Medicine and the Diabetes Unit at Wolfson Medical Center. In a recent study, she discovered that those who eat their largest daily meal at breakfast are far more likely to lose weight and waist line circumference than those who eat a large dinner.

And the benefits went far beyond pounds and inches. Participants who ate a larger breakfast — which included a dessert item such as a piece of chocolate cake or a cookie — also had significantly lower levels of insulin, glucose, and triglycerides throughout the day, translating into a lower risk of cardiovascular disease, diabetes, hypertension, and high cholesterol. These results, published recently in the journal Obesity, indicate that proper meal timing can make an important contribution towards managing obesity and promoting an overall healthy lifestyle.

The study was done in collaboration with Dr. Julio Wainstein of TAU and the Wolfson Medical Center and Dr. Maayan Barnea and Prof. Oren Froy at the Hebrew University of Jerusalem.

A dramatic difference

To determine the impact of meal timing on weight loss and health, Prof. Jakubowicz and her fellow researchers conducted a study in which 93 obese women were randomly assigned to one of two isocaloric groups. Each consumed a moderate-carbohydrate, moderate-fat diet totalling 1,400 calories daily for a period of 12 weeks. The first group consumed 700 calories at breakfast, 500 at lunch, and 200 at dinner. The second group ate a 200 calorie breakfast, 500 calorie lunch, and 700 calorie dinner. The 700 calorie breakfast and dinner included the same foods.

By the end of the study, participants in the "big breakfast" group had lost an average of 17.8 pounds each and three inches off their waist line, compared to a 7.3 pound and 1.4 inch loss for participants in the "big dinner" group. According to Prof. Jakubowicz, those in the big breakfast group were found to have significantly lower levels of the hunger-regulating hormone ghrelin, an indication that they were more satiated and had less desire for snacking later in the day than their counterparts in the big dinner group.

The big breakfast group also showed a more significant decrease in insulin, glucose, and triglyceride levels than those in the big dinner group. More important, they did not experience the high spikes in blood glucose levels that typically occur after a meal. Peaks in blood sugar levels are considered even more harmful than sustained high blood glucose levels, leading to high blood pressure and greater strain on the heart.

Eliminating late night snacking

These findings suggest that people should adopt a well thought-out meal schedule, in addition to proper nutrition and exercise, to optimize weight loss and general health. Eating the right foods at the wrong times can not only slow down weight loss, it can also be harmful. In their study, the researchers found that those in the big dinner group actually increased their levels of triglycerides — a type of fat found in the body — despite their weight loss, reports Prof. Jakubowicz.

Prof. Jakubowicz suggests an end to late night snacking. Mindless eating in front of the computer or television, especially in the late evening hours, is a huge contributor to the obesity epidemic, she believes. It increases not only poundage, but the risk of cardiovascular disease — making that midnight sugar rush more costly than it appears.


Cell Phones Could Increase Cancer Risk
7/29/2013

Saliva from heavy cell phone users shows increased risk factors for cancer, says a TAU researcher

Scientists have long been worried about the possible harmful effects of regular cellular phone use, but so far no study has managed to produce clear results. Currently, cell phones are classified as carcinogenic category 2b — potentially carcinogenic to humans — by the International Agency for Research on Cancer (IARC). A new Tel Aviv University study, though, may bring bad news.

To further explore the relationship between cancer rates and cell phone use, Dr. Yaniv Hamzany of Tel Aviv University's Sackler Faculty of Medicine and the Otolaryngology Head and Neck Surgery Department at the Rabin Medical Center, looked for clues in the saliva of cell phone users. Since the cell phone is placed close to the salivary gland when in use, he and his fellow researchers, including departmental colleagues Profs. Raphael Feinmesser, Thomas Shpitzer and Dr. Gideon Bahar and Prof. Rafi Nagler and Dr. Moshe Gavish of the Technion in Haifa, hypothesized that salivary content could reveal whether there was a connection to developing cancer.

Comparing heavy mobile phone users to non-users, they found that the saliva of heavy users showed indications of higher oxidative stress — a process that damages all aspects of a human cell, including DNA — through the development of toxic peroxide and free radicals. More importantly, it is considered a major risk factor for cancer.

The findings have been reported in the journal Antioxidants and Redox Signaling.

Putting stress on tissues and glands

For the study, the researchers examined the saliva content of 20 heavy-user patients, defined as speaking on their phones for a minimum of eight hours a month. Most participants speak much more, Dr. Hamzany says, as much as 30 to 40 hours a month. Their salivary content was compared to that of a control group, which consisted of deaf patients who either do not use a cell phone, or use the device exclusively for sending text messages and other non-verbal functions.

Compared to the control group, the heavy cell phone users had a significant increase in all salivary oxidative stress measurements studied.

"This suggests that there is considerable oxidative stress on the tissue and glands which are close to the cell phone when in use," he says. The damage caused by oxidative stress is linked to cellular and genetic mutations which cause the development of tumors.

Making the connection

This field of research reflects longstanding concerns about the impact of cell phone use, specifically the effects of radiofrequency non-ionizing electromagnetic radiation on human tissue located close to the ear, say the researchers. And although these results don't uncover a conclusive "cause and effect" relationship between cellular phone use and cancer, they add to the building evidence that cell phone use may be harmful in the long term, and point to a new direction for further research.

One potential avenue of future research would be to analyze a person's saliva prior to exposure to a cell phone, and then again after several intense minutes of exposure. This will allow researchers to see if there is an immediate response, such as a rise in molecules that indicate oxidative stress, Dr. Hamzany says.


Breastfeeding Could Prevent ADHD
7/22/2013

TAU research finds that breastfed children are less likely to develop ADHD later in life

We know that breastfeeding has a positive impact on child development and health — including protection against illness. Now researchers from Tel Aviv University have shown that breastfeeding could also help protect against Attention Deficit/Hyperactivity Disorder (ADHD), the most commonly diagnosed neurobehavioral disorder in children and adolescents.

Seeking to determine if the development of ADHD was associated with lower rates of breastfeeding, Dr. Aviva Mimouni-Bloch, of Tel Aviv University's Sackler Faculty of Medicine and Head of the Child Neurodevelopmental Center in Loewenstein Hospital, and her fellow researchers completed a retrospective study on the breastfeeding habits of parents of three groups of children: a group that had been diagnosed with ADHD; siblings of those diagnosed with ADHD; and a control group of children without ADHD and lacking any genetic ties to the disorder.

The researchers found a clear link between rates of breastfeeding and the likelihood of developing ADHD, even when typical risk factors were taken into consideration. Children who were bottle-fed at three months of age were found to be three times more likely to have ADHD than those who were breastfed during the same period. These results have been published in Breastfeeding Medicine.

Understanding genetics and environment

In their study, the researchers compared breastfeeding histories of children from six to 12 years of age at Schneider's Children Medical Center in Israel. The ADHD group was comprised of children that had been diagnosed at the hospital, the second group included the siblings of the ADHD patients, and the control group included children without neurobehavioral issues who had been treated at the clinics for unrelated complaints.

In addition to describing their breastfeeding habits during the first year of their child's life, parents answered a detailed questionnaire on medical and demographic data that might also have an impact on the development of ADHD, including marital status and education of the parents, problems during pregnancy such as hypertension or diabetes, birth weight of the child, and genetic links to ADHD.

Taking all risk factors into account, researchers found that children with ADHD were far less likely to be breastfed in their first year of life than the children in the other groups. At three months, only 43 percent of children in the ADHD group were breastfed compared to 69 percent of the sibling group and 73 percent of the control group. At six months, 29 percent of the ADHD group was breastfed, compared to 50 percent of the sibling group and 57 percent of the control group.

One of the unique elements of the study was the inclusion of the sibling group, says Dr. Mimouni-Bloch. Although a mother will often make the same breastfeeding choices for all her children, this is not always the case. Some children's temperaments might be more difficult than their siblings', making it hard for the mother to breastfeed, she suggests.

Added protection

While researchers do not yet know why breastfeeding has an impact on the future development of ADHD — it could be due to the breast milk itself, or the special bond formed between mother and baby during breastfeeding, for example — they believe this research shows that breastfeeding can have a protective effect against the development of the disorder, and can be counted as an additional biological advantage for breastfeeding.

Dr. Mimouni-Bloch hopes to conduct a further study on breastfeeding and ADHD, examining children who are at high risk for ADHD from birth and following up in six-month intervals until six years of age, to obtain more data on the phenomenon.


A Heart of Gold
7/17/2013

Gold nanofibers in engineered heart tissue can enhance electrical signalling, TAU researchers find

Heart tissue sustains irreparable damage in the wake of a heart attack. Because cells in the heart cannot multiply and the cardiac muscle contains few stem cells, the tissue is unable to repair itself — it becomes fibrotic and cannot contract properly.

In their search for innovative methods to restore heart function, scientists have been exploring cardiac "patches" that could be transplanted into the body to replace damaged heart tissue. Now, in his Tissue Engineering and Regenerative Medicine Laboratory, Dr. Tal Dvir and his PhD student Michal Shevach of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Center for Nanoscience and Nanotechnology, together with their colleagues, are literally setting a gold standard in cardiac tissue engineering.

To meet one of the biggest challenges in the development of cardiac patches — ensuring that engineered tissue can mimic the heart's coordinated electrical system, which controls heartbeat and rhythm — they integrated cardiac cells with nanofibers made of gold particles to form functional engineered tissues. Their goal is to optimize electrical signalling between cells.

Gold has been found to increase the connectivity of biomaterials, explains Dr. Dvir. With the addition of the gold particles, cardiac tissues contract much faster and stronger as a whole, he reports, making them more viable for transplants. The research was recently published in the Journal of Materials Chemistry B.

Lending nature a helping hand

On their surface, heart cells contain proteins that are responsible for transferring electrical signals. But the process of tissue engineering itself leads to the loss of these proteins. And while the cells will start to produce them again naturally, says Dr. Dvir, they take time to develop — time which a patient may not have. Gold nanofibers can fill the role of electrical connectors until the cells are able to produce their own connectors once more.

New tissues are created by placing cells taken from patients or animals onto a three-dimensional scaffolding made of biomaterials — any matter or surface that interacts with biological systems — which organize the cells into the proper formation as they grow. Dr. Dvir and his team used various chemical and physical processes to integrate gold nanoparticles into their scaffolds. The cells then interacted with each other through these gold nanoparticles.

The researchers used a scanning electron microscope and various measures of electrical activity in order to observe the nanoparticles on the fibers and check conductivity. Cells placed on the gold-embedded scaffolding had significantly stronger contractions compared to those on a scaffolding without gold. Importantly, the cells contracted in unison, demonstrating effective electrical signalling between them.

A golden opportunity

Because 50 percent of heart attack victims die within five years of their initial attack, new treatment options are sorely needed. A functioning, transplantable tissue could not only save lives, but improve a patient's quality of life overall.

Having demonstrated the electrical signalling capability of these gold infused cardiac patches, Dr. Dvir will next evaluate their potential to improve function after heart attack through pre-clinical tests in the lab and, eventually, clinical trials with patients. He says that the ideal method would be to use a patient's own cells when building the new tissue, therefore avoiding the risk of rejection.


Israel Makes Dramatic Advance in Blindness Protection
7/10/2013

Lessons from Israel's healthcare system could optimize eye health around the world, says a TAU researcher

According to the World Health Organization, 80% of blindness is preventable or treatable — but it remains a severe health concern across the globe, even in industrialized countries.

Now hope is on the horizon — especially if countries are willing to emulate Israel's approach to eye health, says Prof.Michael Belkin of the Goldschleger Eye Research Institute at Tel Aviv University's Sackler Faculty of Medicine and Sheba Medical Center in a new study published in the American Journal of Ophthalmology. In the last decade, rates of preventable blindness in Israel have been cut by more than half — from 33.8 cases of blindness per 100,000 residents in 1999 to 14.8 in 2010. This improvement, found across all four main causes of avoidable blindness — age-related deterioration, glaucoma, diabetes, and cataract — is unmatched anywhere else in the world, he says.

The secret is not only the innovative methods of treatment that were added to the Israeli medical system, but their universal availability and accessibility, as well as good patient compliance with treatment regimens, including the correct use of prescribed medications.

Israel also offers community-based programs, such as dedicated diabetes clinics, which promote early prevention and timely treatment for diabetes-related complications that can lead to blindness. Prof. Belkin notes that such programs save public and private health care money in the long term.

Advancing eye care

To evaluate the effectiveness of eye health care in Israel, Prof. Belkin and his fellow researchers Alon Skaat, Angela Chetrit and Ofra Kalter-Leibovici from TAU and Sheba, conducted a statistical study measuring rates of blindness in the Israeli population over twelve years. They discovered that Israel has emerged as a world leader in preventing avoidable blindness, reducing rates by over 56%. The rates of untreatable genetic causes of blindness remained steady over the same period.

Several solutions are employed by Israel, which approaches the problem of blindness from medical, public health, and cultural perspectives. For example, age-related macular degeneration, one of the leading causes of blindness in the industrialized world, is treated with a drug therapy originally approved for colon cancer tumors. By diluting the drug to create smaller doses for the eye — an idea that originated in the United States — it is possible to provide inexpensive therapy to thousands of patients.

From the public policy standpoint, Prof. Belkin notes that the decline in blindness due to cataracts is due to a change in health care policy rather than any technical advance. Since the 1990's, patients have been able to choose their doctors privately for cataract surgery. This practically eliminated wait times for surgery and prevented the condition from growing worse over the long term.

Long term savings

Prof. Belkin believes that it's possible for any country to adopt Israel's strategies for reducing blindness. Although the initial costs can be daunting — such as the price of top-notch medications and setting up clinics — it's a worthwhile investment. Treating blindness as it develops rather than preventing it from the start is much more expensive for the healthcare system in the long term. Diabetes clinics in Israel pay for themselves in about two years' time, he says, factoring in their impact on preventing greater health concerns.

But even the most advanced and widely available treatments can't be effective if patients are not examined by an ophthalmologist and don't adhere to the treatment regimen. In Israel, an exceptionally high rate of adherence to these regimens is a major contributor to the prevention of blindness.


Newly Identified Bone Marrow Stem Cells Reveal Markers for ALS
7/9/2013

Genes could give new direction for diagnostics and therapeutics research, says a TAU researcher

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease that rapidly atrophies the muscles, leading to complete paralysis. Despite its high profile — established when it afflicted the New York Yankees' Lou Gehrig — ALS remains a disease that scientists are unable to predict, prevent, or cure.

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

Now, using samples of stem cells derived from the bone marrow of non-genetic ALS patients, Prof. Miguel Weil of Tel Aviv University's Laboratory for Neurodegenerative Diseases and Personalized Medicine in the Department of Cell Research and Immunology and his team of researchers have uncovered four different biomarkers that characterize the non-genetic form of the disease. Each sample shows similar biological abnormalities to four specific genes, and further research could reveal additional commonalities. "Because these genes and their functions are already known, they give us a specific direction for research into non-genetic ALS diagnostics and therapeutics," Prof. Weil says. His initial findings were reported in the journal Disease Markers.

Giving in to stress

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

To hunt for these biomarkers, Prof. Weil and his colleagues turned to samples of bone marrow collected from ALS patients. Though more difficult to collect than blood, bone marrow’s stem cells are easy to isolate and grow in a consistent manner. In the lab, he used these cells as cellular models for the disease. He ultimately discovered that cells from different ALS patients shared the same abnormal characteristics of four different genes that may act as biomarkers of the disease. And because the characteristics appear in tissues that are related to ALS — including in muscle, brain, and spinal cord tissues in mouse models of genetic ALS — they may well be connected to the degenerative process of the disease in humans, he believes.

Searching for the biological significance of these abnormalities, Prof. Weil put the cells under stress, applying toxins to induce the cells' defense mechanisms. Healthy cells will try to fight off threats and often prove quite resilient, but ALS cells were found to be overwhelmingly sensitive to stress, with the vast majority choosing to die rather than fight. Because this is such an ingrained response, it can be used as a feature for drug screening for the disease, he adds.

The hunt for therapeutics

Whether these biomarkers are a cause or consequence of ALS is still unknown. However, this finding remains an important step towards uncovering the mechanisms of the disease. Because these genes have already been identified, it gives scientists a clear direction for future research. In addition, these biomarkers could lead to earlier and more accurate diagnostics.

Next, Prof. Weil plans to use his lab's high-throughput screening facility — which can test thousands of compounds' effects on diseased cells every day — to search for drug candidates with the potential to affect the abnormal expression of these genes or the stress response of ALS cells. A compound that has an impact on these indicators of ALS could be meaningful for treating the disease, he says.

Prof. Weil is the director of the new Cell Screening Facility for Personalized Medicine at TAU. The facility is dedicated to finding potential drugs for rare and Jewish hereditary diseases.


Disrupting Memories Could Help Alcoholics Stay on the Wagon
7/2/2013

TAU researcher discovers that manipulating memories associated with addiction can prevent relapse

For alcoholics and other addicts who've gotten clean, avoiding a relapse is a difficult task. According to Dr. Segev Barak of Tel Aviv University's Sagol School of Neuroscience, 70-80% of alcohol and drug addicts return to their substance of choice, even a year after a successful detox. And memory, he says, has a lot to do with it.

"One of the main causes of relapse in alcoholics is memories that link objects and places connected to alcohol consumption, such as shops, liquor bottles, and of course the smell and taste of alcohol," Dr. Barak says. Now he and his fellow researchers from the University of California at San Francisco (UCSF) have discovered that by "disengaging" memories associated with alcohol, it is possible to significantly cut the recidivism rate for alcoholics. In a UCSF lab, researchers were able to identify and deactivate a brain pathway in rats linked to cravings from alcohol, ultimately preventing the animals from seeking alcohol and drinking it.

In the study, researchers offered the rats a choice between water and 40 proof (20 percent) alcohol, which the rats drank in large quantities for two months. At the same time, the researchers trained the rats to press a lever to obtain alcohol. The rats were then put through a 10-day detoxification regimen, tempting them with the smell and taste of alcohol in their food.

Scanning the brains of the rodents, they discovered that memories of alcohol consumption, often prompted by external stimuli, caused activation of mTORC1 — a protein which plays an important role in memory — in specific areas of the brain responsible for memory processing, emotional memories, and emotional symptoms related to withdrawal. The activation of this protein made relapse for the rats far more likely.

However, in rats that were given a drug called rapamycin, administered immediately after exposure to the memory cue, the pathway was deactivated and there was no relapse. The rats' drinking was suppressed until the end of the study.

Dr. Barak is now working on a behavioral treatment to find the best ways to implement memory disruption and end alcohol and drug recidivism, without the need for pharmaceutical intervention. "If we can develop an efficient treatment without the use of drugs, it would be a real revolution," he said.

For the full story on Dr. Barak's study, see the Times of Israel story:
http://www.timesofisrael.com/israeli-researcher-helps-alcoholics-stay-on-the-wagon/


Video Games an Effective Tool for Stroke Rehabilitation
6/27/2013

Video game-based therapy elicits more purposeful movement than traditional therapy, says TAU researcher

In the months following a stroke, patients undergo hours of rehabilitation to restore movement, speech, and overall functionality. But many still return home without the ability to perform daily tasks, such as dressing, cooking or driving.

Now occupational therapist Dr. Debbie Rand of Tel Aviv University's Stanley Steyer School of Health Professions at the Sackler Faculty of Medicine, has turned to common interactive video games as an affordable and effective alternative to traditional therapy. In a recent study, done in collaboration with a team from Sheba Medical Center and funded by the Marie Curie International Reintegration Grant, she found that people recovering from stroke who use video games as a therapeutic method are more physically active during rehabilitation sessions, making more movements overall than those who experience traditional motor therapy.

The results were presented at the 9th International Conference on Disability, Virtual Reality and Associated Technologies (ICDVRAT 2012).

Goal-directed movement

Interactive game consoles require players to move continuously to interact with the virtual games, Dr. Rand explains. In her study, not only did the players perform double the number of arm movements during each session compared to patients in traditional therapy, but all of their movements were purposeful or "goal-directed" and not just repetitive exercises.

When individuals plan their movements and move deliberately in order to accomplish a specific goal, it is likely to have a positive impact on brain plasticity — changes in the brain that are crucial for recovery from brain damage caused by stroke, Dr. Rand notes. Players' movements require precision and balance, and there is a cognitive benefit in that video games require strategy and planning. And because the individuals are motivated and enjoy the activity, it's more likely that they will continue the treatment regime long-term, she believes.

To test the effectiveness of interactive video games compared to traditional therapy, individuals who had experienced a stroke one to seven years before the study began were randomly assigned to one of two groups of 20 participants each — a traditional therapy group, who completed traditional rehabilitation exercises, and a video games group which played video games using Xbox Kinect, Sony PlayStation and Nintendo Wii gaming consoles. Each group received two sessions a week with occupational therapists for a period of three months.

Although both groups showed improvement in functions such as grip strength of their weaker and stronger hands and gait speed, participants in the video games group continued to improve their grip strength for three months following the intervention, while the traditional group did not.

Having fun with therapy

Beyond the physical advantages, Dr. Rand believes that video games could be an excellent alternative to traditional therapy simply because they’re more fun. In the video game group, 92 percent of participants reported enjoying the experience "extremely" or "very much," opposed to 72 percent of the traditional group. If patients are enjoying the therapy experience, it's more likely that they will adhere to the therapy regime long-term, noting that game consoles are now widely available and fairly inexpensive. Participants who were in the video game playing group reported: "It was lots of fun," "it stimulated all of my senses," and "I finished the sessions wet from sweat, which proves that I really worked hard."

The group environment also contributed to the success of the therapy, Dr. Rand says. Often, individuals with stroke are isolated and don't have a very active social life. This program allowed them to connect with people like themselves, and encourage and support one another's efforts.

In future studies, she intends to investigate whether these interactive video games will be as effective if they are used independently by patients at home to keep up activity levels — a crucial element of rehabilitation following a stroke.


Artificial Sweetener a Potential Treatment for Parkinson's Disease
6/17/2013

TAU researcher says mannitol could prevent aggregation of toxic proteins in the brain

Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it's approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.

Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson's disease.

These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson's and other neurodegenerative diseases. The research was funded by a grant from the Parkinson's Disease Foundation and supported in part by the Lord Alliance Family Trust.

Seeing a significant difference

After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins' ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.

Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the "climbing assay," in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.

The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.

These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.

Delivering therapeutic compounds to the brain

The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson's in humans is needed, Prof. Segal says.

For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson's but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to "piggy-back" on mannitol's ability to open this barrier into the brain.

Although the results look promising, it is still not advisable for Parkinson's patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.


A Peptide to Protect Brain Function
6/13/2013

TAU researcher develops a protein to protect and restore nerve cell communications

A structure called "the microtubule network" is a crucial part of our nervous system. It acts as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer's, ALS, and Parkinson's, this network breaks down, hindering motor abilities and cognitive function.

Now Prof. Illana Gozes of Tel Aviv University's Sackler Faculty of Medicine has developed a new peptide in her lab, called NAP or Davunetide, that has the capacity to both protect and restore microtubule function. The peptide is a compound derived from the protein ADNP, which regulates more than 400 genes and is essential for brain formation, memory, and behavior.

Prof. Gozes and her team of researchers, including Dr. Yan Jouroukhin and graduate student Regin Ostritsky of TAU, observed that in animal models with microtubule damage, NAP was able to maintain or revive the transport of proteins and other materials in cells, ameliorating symptoms associated with neurodegeneration. These findings, which were reported in the journal Neurobiology of Disease, indicate that NAP could be an effective tool in fighting some of the most debilitating effects of neurodegenerative diseases.

Prof. Gozes is the director of TAU's Adams Super Center for Brain Studies and holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.

Securing passage through the brain

In their investigation, the researchers used two different animal models with microtubule damage. The first group was made up of normal mice whose microtubule system was broken down through the use of a compound. The second group were genetically-engineered mouse models of ALS, in which the microtubule system was chronically damaged. In both groups, half the mice were given a single NAP injection, while the control half were not.

To determine the impact of NAP on nerve cell communications, the researchers administered the chemical element manganese to all animal models and tracked its movement through the brain using an MRI. In the mice treated with NAP, researchers observed that the manganese was able to travel through the brain normally — the microtubule system had been protected from damage or restored to normal use. Those mice that did not receive the peptide experienced the usual breakdown or continued dysfunction of the microtubule system.

These findings were corroborated by a subsequent study conducted in the UK, published in the journal Molecular Psychiatry, which found that NAP was able to ameliorate damage in fruit fly models of microtubule deficiency, repairing nerve cell dysfunction.

Slowing down cognitive dysfunction

NAP appears to have widespread potential in terms of neuroprotection, says Prof. Gozes, who was recently awarded the Meitner-Humblodt Research Award for her lifelong contribution to the field of brain sciences.

Previous studies on the peptide, conducted through a collaboration between Allon Therapeutics and Ramot, TAU's technology transfer arm, have shown that patients suffering from cognitive dysfunction — a precursor to Alzheimer's Disease — showed significant improvements in their cognitive scores when treated with NAP. Additional studies have also shown that NAP has a positive impact on rectifying microtubule deficiencies in schizophrenia patients.

Prof. Gozes notes that more research must be conducted to discover how to optimize the use of NAP as a treatment, including which patients can benefit most from the intervention.


Understanding the Heart's Rhythm
6/11/2013

TAU research discovers an unknown channel in the heart could illuminate unsolved cases of arrhythmia

The heart's regular rhythm is crucial to the delivery of oxygenated blood and nutrients to all the organs of the body. It is regulated by a bundle of cells called "the pacemaker," which use electrical signals to set the pace of the heart. Dysfunction in this mechanism can lead to an irregular heartbeat, known as arrhythmia, and often necessitates the implantation of an artificial pacemaker.

Previously, scientists found that many cases of inherited arrhythmias originating in the pacemaker could be attributed to functional defects in the channels responsible for the flow of sodium and calcium. Now Prof. Bernard Attali of Tel Aviv University's Sackler Faculty of Medicine and his fellow researchers have discovered a previously unidentified potassium channel in the cardiac pacemaker which helps to regulate the heartbeat. He hypothesizes that some cases of unexplained arrhythmia could be traced back to irregularities in this channel.

Developing therapies to target this potassium channel could be a significant step towards circumventing artificial pacemakers in favor of biological options, says Prof. Attali. This research has been reported in the journal PNAS.

A cellular heart model

To further investigate the workings of the biological pacemaker, Prof. Attali and his fellow researchers turned to embryonic stem cells isolated from human subjects. Once coaxed into differentiating into cardiac tissue, these cells began to beat automatically, like a small human heart.

While observing and recording the cells' electrical activity, researchers discovered the existence of a new channel in the pacemaker. Facilitating the flow of potassium from the pacemaker cells, this channel triggers the repolarization of the cells — returning the cell membrane from a "beating" to a "resting" state — and automatically renews or "restarts" the cycling of the heart.

Since discovering this channel in the embryonic heart, the researchers have shown that the channel exists in the adult heart as well. This finding deepens medicine's understanding of the heart's pacemaker function, which has been the subject of scientific research for over a century.

Screening for mutations

The next step is to conduct screening for mutations in the gene encoding the potassium channel, a process already underway at the TAU-affiliated Sheba Medical Center. "We would like to understand if there are genetic diseases linked to this channel," such as a previously unknown cause of arrhythmia, explains Prof. Attali. If a mutation is found, researchers can begin the hunt for drug compounds, which target this channel. The ultimate goal, he adds, is to be able to treat heart arrhythmias biologically by altering the properties of the pacemaker bundle, rather than relying on a man-made electric pacemaker.

One possible solution could be transplanting healthy pacemaker cells — developed from a patient's own stem cells — to replace dysfunctional cells and restore proper heart rhythm. This method would circumvent a common risk of the body rejecting a mechanical transplant.


Manipulating Memory in the Hippocampus
6/3/2013

Protein modification may help control Alzheimer's and epilepsy, TAU researchers find

In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.

Dr. Boaz Barak of Tel Aviv University's Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain's activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.

"This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain," says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer's. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer's patient may help increase cognition and combat memory loss.

A maze of memory loss

The researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.

In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. During the first five days of testing, researchers found that the test group with an over-production of tomosyn had a significant problem in learning and memorizing the location of the platform, compared to a control group that received a placebo injection. And when the platform was removed from the maze, the test group spent less time swimming around the area where the platform once was, indicating that they had no memory of its existence. In comparison, the control group of mice searched for the missing platform in its previous location for two or even three days after its removal, notes Dr. Barak.

These findings were further verified by measuring electrical activity in the brains of both the test group and the control group. In the test group, researchers found decreased levels of transmissions between neurons in the hippocampus, a physiological finding that may explain the results of the behavioral tests.

Correcting neuronal processes

In the future, Dr. Barak believes that the ability to modify proteins directly in the brain will allow for more control over brain activities and the correction of neurodegenerative processes, such as providing stricter regulation in neuronal activity for epileptic patients or stimulating neurotransmitters to help with learning and memory loss in Alzheimer's patients. Indeed, a separate study conducted by the researchers demonstrates that mouse models for Alzheimer's disease do have an over-production of tomosyn in the hippocampus region, so countering the production of this protein could have a beneficial effect.

Now Dr. Barak and Prof. Ashery are working towards a method for artificially decreasing levels of the protein, which they believe will have the opposite effect on the cognitive ability of the mice. "We hypothesize that with an under-production in tomosyn, the mice will show a marked improvement in their performance in behavioral testing," he says.


Low Doses of THC Can Halt Brain Damage
5/30/2013

Extremely low doses of marijuana's psychoactive component protect brain before and after injury, says TAU researcher

Though marijuana is a well-known recreational drug, extensive scientific research has been conducted on the therapeutic properties of marijuana in the last decade. Medical cannabis is often used by sufferers of chronic ailments, including cancer and post-traumatic stress disorder, to combat pain, insomnia, lack of appetite, and other symptoms.

Now Prof. Yosef Sarne of Tel Aviv University's Adelson Center for the Biology of Addictive Diseases at the Sackler Faculty of Medicine says that the drug has neuroprotective qualities as well. He has found that extremely low doses of THC — the psychoactive component of marijuana — protects the brain from long-term cognitive damage in the wake of injury from hypoxia (lack of oxygen), seizures, or toxic drugs. Brain damage can have consequences ranging from mild cognitive deficits to severe neurological damage.

Previous studies focused on injecting high doses of THC within a very short time frame — approximately 30 minutes — before or after injury. Prof. Sarne's current research, published in the journals Behavioural Brain Research and Experimental Brain Research, demonstrates that even extremely low doses of THC — around 1,000 to 10,000 times less than that in a conventional marijuana cigarette — administered over a wide window of 1 to 7 days before or 1 to 3 days after injury can jumpstart biochemical processes which protect brain cells and preserve cognitive function over time.

This treatment, especially in light of the long time frame for administration and the low dosage, could be applicable to many cases of brain injury and be safer over time, Prof. Sarne says.

Conditioning the brain

While performing experiments on the biology of cannabis, Prof. Sarne and his fellow researchers discovered that low doses of the drug had a big impact on cell signalling, preventing cell death and promoting growth factors. This finding led to a series of experiments designed to test the neuroprotective ability of THC in response to various brain injuries.

In the lab, the researchers injected mice with a single low dose of THC either before or after exposing them to brain trauma. A control group of mice sustained brain injury but did not receive the THC treatment. When the mice were examined 3 to 7 weeks after initial injury, recipients of the THC treatment performed better in behavioral tests measuring learning and memory. Additionally, biochemical studies showed heightened amounts of neuroprotective chemicals in the treatment group compared to the control group.

The use of THC can prevent long-term cognitive damage that results from brain injury, the researchers conclude. One explanation for this effect is pre- and post-conditioning, whereby the drug causes minute damage to the brain to build resistance and trigger protective measures in the face of much more severe injury, explains Prof. Sarne. The low dosage of THC is crucial to initiating this process without causing too much initial damage.

Preventative and long-term use

According to Prof. Sarne, there are several practical benefits to this treatment plan. Due to the long therapeutic time window, this treatment can be used not only to treat injury after the fact, but also to prevent injury that might occur in the future. For example, cardiopulmonary heart-lung machines used in open heart surgery carry the risk of interrupting the blood supply to the brain, and the drug can be delivered beforehand as a preventive measure. In addition, the low dosage makes it safe for regular use in patients at constant risk of brain injury, such as epileptics or people at a high risk of heart attack.

Prof. Sarne is now working in collaboration with Prof. Edith Hochhauser of the Rabin Medical Center to test the ability of low doses of THC to prevent damage to the heart. Preliminary results indicate that they will find the same protective phenomenon in relation to cardiac ischemia, in which the heart muscle receives insufficient blood flow.


Common Food Supplement Fights Degenerative Brain Disorders
5/21/2013

Nutritional supplement delays advancement of Parkinson's and Familial Dysautonomia, TAU researchers discover

Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it's a popular treatment for older people experiencing memory impairment. Now a team headed by Prof. Gil Ast and Dr. Ron Bochner of Tel Aviv University's Department of Human Molecular Genetics has discovered that the same supplement improves the functioning of genes involved in degenerative brain disorders, including Parkinson's disease and Familial Dysautonomia (FD).

In FD, a rare genetic disorder that impacts the nervous system and appears almost exclusively in the Ashkenazi Jewish population, a genetic mutation prevents the brain from manufacturing healthy IKAP proteins — which likely have a hand in cell migration and aiding connections between nerves — leading to the early degeneration of neurons. When the supplement was applied to cells taken from FD patients, the gene function improved and an elevation in the level of IKAP protein was observed, reports Prof. Ast. These results were replicated in a second experiment which involved administering the supplement orally to mouse populations with FD.

The findings, which have been published in the journal Human Molecular Genetics, are very encouraging, says Prof. Ast. "That we see such an effect on the brain — the most important organ in relation to this disease — shows that the supplement can pass through the blood-brain barrier even when administered orally, and accumulate in sufficient amounts in the brain."

Slowing the death of nerve cells

Already approved for use as a supplement by the FDA, phosphatidylserine contains a molecule essential for transmitting signals between nerve cells in the brain. Prof. Ast and his fellow researchers decided to test whether the same chemical, which is naturally synthesized in the body and known to boost memory capability, could impact the genetic mutation which leads to FD.

Researchers applied a supplement derived from oysters, provided by the Israeli company Enzymotec, to cells collected from FD patients. Noticing a robust effect on the gene, including a jump in the production of healthy IKAP proteins, they then tested the same supplement on mouse models of FD, engineered with the same genetic mutation that causes the disease in humans.

The mice received the supplement orally, every two days for a period of three months. Researchers then conducted extensive genetic testing to assess the results of the treatment. "We found a significant increase of the protein in all the tissues of the body," reports Prof. Ast, including an eight-fold increase in the liver and 1.5-fold increase in the brain. "While the food supplement does not manufacture new nerve cells, it probably delays the death of existing ones," he adds.

Therapeutic potential for Parkinson's

That the supplement is able to improve conditions in the brain, even when given orally, is a significant finding, notes Prof. Ast. Most medications enter the body through the blood stream, but are incapable of breaking through the barrier between the blood and the brain.

In addition, the researchers say the supplement's positive effects extend beyond the production of IKAP. Not only did phosphatidylserine impact the gene associated with FD, but it also altered the level of a total of 2400 other genes — hundreds of which have been connected to Parkinson's disease in previous studies.

The researchers believe that the supplement may have a beneficial impact on a number of degenerative diseases of the brain, concludes Prof. Ast, including a major potential for the development of new medications which would help tens of millions of people worldwide suffering from these devastating diseases.


Reversing Paralysis with a Restorative Gel
5/13/2013

TAU researchers develop implant to regenerate nerves

Some parts of the body, like the liver, can regenerate themselves after damage. But others, such as our nervous system, are considered either irreparable or slow to recover, leaving thousands with a lifetime of pain, limited mobility, or even paralysis.

Now a team of Tel Aviv University researchers, including Dr. Shimon Rochkind of TAU's Sackler Faculty of Medicine and Tel Aviv Sourasky Medical Center and Prof. Zvi Nevo of TAU's Department of Human Molecular Genetics and Biochemistry, has invented a method for repairing damaged peripheral nerves. Through a biodegradable implant in combination with a newly-developed Guiding Regeneration Gel (GRG) that increases nerve growth and healing, the functionality of a torn or damaged nerve could ultimately be restored.

This innovative project is now gaining international recognition. Its initial successes were reported recently at several renowned scientific congresses, including the World Federation of Neurological Societies and the European Neurological Society. And the therapy, already tested in animal models, is only a few years away from clinical use, says Dr. Rochkind.

Like healing in the womb

A nerve is like an electrical cable. When severed or otherwise damaged, power can no longer be transferred and the cable loses its functionality. Similarly, a damaged nerve loses the ability to transfer signals for movement and feeling through the nervous system.

But Dr. Rochkind and Prof. Nevo found a way to breach the gap. In their method, two severed ends of a damaged nerve are reconnected by implanting a soft, biodegradable tube, which serves as a bridge to help the nerve ends connect. The innovative gel which lines the inside of the tube nurtures nerve fibers' growth, encouraging the nerve to reconnect the severed ends through the tube, even in cases with massive nerve damage, Dr. Rochkind says.

The key lies in the composition of the gel, the researchers say, which has three main components: anti-oxidants, which exhibit high anti-inflammatory activities; synthetic laminin peptides, which act as a railway or track for the nerve fibers to grow along; and hyaluronic acid, commonly found in the human fetus, which serves as a buffer against drying, a major danger for most implants. These components allow the nerve to heal the way a fetus does in the womb — quickly and smoothly.

Keeping cells safe for transplant

The implant has already been tested in animal models, and the gel by itself can be used as a stand-alone product, acting as an aid to cell therapy. GRG is not only able to preserve cells, it can support their survival while being used for therapy and transplantation, says Dr. Rochkind. When grown in the gel, cells show excellent development, as well as intensive fiber growth. This could have implications for the treatment of diseases such as Parkinson's, for which researchers are actively exploring cell therapy as a potential solution.


Positive Social Support at Work Shown to Reduce Risk of Diabetes
5/9/2013

Work conditions can predict development of diabetes in otherwise healthy employees, TAU research finds

Cases of type 2 diabetes continue to rise in the US. And while the development of the disease is more commonly associated with risk factors such as obesity, high blood pressure, and physical inactivity, research has shown that stress can also have a significant impact.

Now Dr. Sharon Toker of Tel Aviv University's Faculty of Management has found that low levels of social support and high levels of stress in the workplace can accurately predict the development of diabetes over the long term — even in employees who appear to be healthy otherwise. Published in the Journal of Occupational Health Psychology, the study contributes to an ongoing body of research linking work conditions to physical and mental health.

The researchers' 3.5-year-long study of male and female employees established that work conditions had a preventative or predictive effect on the development of type 2 diabetes. Participants who reported having a high level of social support at work had a 22 percent lesser chance of developing diabetes over the course of the study. And those who described themselves as either over- or under-worked were 18 percent more likely to develop the disease. The results were controlled for various risk factors including age, family history, activity level, and body mass index.

Dr. Toker says these findings paint a grim picture, with a worrying rise in the rate of diabetes in the researchers' middle-aged study cohort, which had a mean age of 48. "You don't want to see working populations have an increasing rate of diabetes. It's costly to both employees and employers, resulting in absenteeism and triggering expensive medical insurance," she explains.

Assessing work conditions

For the study, conducted in collaboration with Prof. Arie Shirom of TAU, Dr. Galit Armon of the University of Haifa, and Dr. Samuel Melamed of the Tel Aviv Yaffo Academic College, researchers recruited 5,843 individuals who visited a health center in Tel Aviv for a routine physical examination sponsored by their employer. On these initial visits, all participants were healthy and had no indication of diabetes.

To assess whether physical and psychological strain caused by the work environment could predict the development of diabetes, Dr. Toker and her fellow researchers surveyed the participants according to an "expanded job strain model," which takes into account measures of social support, perceived workload, and perceived control over work pace and objectives.

After the initial interview and examination, the health of all participants was followed for a period of 41 months, over which time 182 participants developed diabetes, reports Dr. Toker. When these results were analyzed in relation to reported work conditions, social support emerged as a strong protective factor against the development of the disease, with supported individuals significantly less at risk for diabetes than their unsupported peers. Workload was also correlated with disease development, with employees who felt either overworked or underworked being at increased risk.

Promoting the right balance

The results highlight some of the negative effects of our changing work environment, in which employees are putting in more hours than ever before, says Dr. Toker. Beyond the hours spend in the office, technology now allows us to be constantly connected, heightening expectations that work will be completed in non-working hours, ultimately increasing workloads. This takes a heavy toll on our health, she warns.

One of the most interesting findings of the study — that a too-small workload is as harmful as a too-large workload — shows that dramatically reducing the load of a busy employee may not have the desired effect. Employees will be stressed when overloaded, but they still need to feel challenged to be satisfied in their jobs, notes Dr. Toker.

She suggests that employers focus on finding the right balance in terms of workload and take the initiative to ensure their employees receive the necessary social support, whether that includes a network of emotional support, praising good work performance, or finding ways to improve office communication.


Sniffing Out Schizophrenia
4/29/2013

Neurons in the nose could be the key to early, fast, and accurate diagnosis, says a TAU researcher

A debilitating mental illness, schizophrenia can be difficult to diagnose. Because physiological evidence confirming the disease can only be gathered from the brain during an autopsy, mental health professionals have had to rely on a battery of psychological evaluations to diagnose their patients.

Now, Dr. Noam Shomron and Prof. Ruth Navon of Tel Aviv University's Sackler Faculty of Medicine, together with PhD student Eyal Mor from Dr. Shomron's lab and Prof. Akira Sawa of Johns Hopkins Hospital in Baltimore, Maryland, have discovered a method for physical diagnosis — by collecting tissue from the nose through a simple biopsy. Surprisingly, collecting and sequencing neurons from the nose may lead to "more sure-fire" diagnostic capabilities than ever before, Dr. Shomron says.

This finding, which was reported in the journal Neurobiology of Disease, could not only lead to a more accurate diagnosis, it may also permit the crucial, early detection of the disease, giving rise to vastly improved treatment overall.

From the nose to diagnosis

Until now, biomarkers for schizophrenia had only been found in the neuron cells of the brain, which can't be collected before death. By that point it's obviously too late to do the patient any good, says Dr. Shomron. Instead, psychiatrists depend on psychological evaluations for diagnosis, including interviews with the patient and reports by family and friends.

For a solution to this diagnostic dilemma, the researchers turned to the olfactory system, which includes neurons located on the upper part of the inner nose. Researchers at Johns Hopkins University collected samples of olfactory neurons from patients diagnosed with schizophrenia and a control group of non-affected individuals, then sent them to Dr. Shomron's TAU lab.

Dr. Shomron and his fellow researchers applied a high-throughput technology to these samples, studying the microRNA of the olfactory neurons. Within these molecules, which help to regulate our genetic code, they were able to identify a microRNA which is highly elevated in those with schizophrenia, compared to individuals who do not have the disease.

"We were able to narrow down the microRNA to a differentially expressed set, and from there down to a specific microRNA which is elevated in individuals with the disease compared to healthy individuals," explains Dr. Shomron. Further research revealed that this particular microRNA controls genes associated with the generation of neurons.

In practice, material for biopsy could be collected through a quick and easy outpatient procedure, using a local anesthetic, says Dr. Shomron. And with microRNA profiling results ready in a matter of hours, this method could evolve into a relatively simple and accurate test to diagnose a very complicated illness.

Early detection, early intervention

Though there is much more to investigate, Dr. Shomron has high hopes for this diagnostic method. It's important to determine whether this alteration in microRNA expression begins before schizophrenic symptoms begin to exhibit themselves, or only after the disease fully develops, he says. If this change comes near the beginning of the timeline, it could be invaluable for early diagnostics. This would mean early intervention, better treatment, and possibly even the postponement of symptoms.

If, for example, a person has a family history of schizophrenia, this test could reveal whether they too suffer from the disease. And while such advanced warning doesn't mean a cure is on the horizon, it will help both patient and doctor identify and prepare for the challenges ahead.


Bursts of Brain Activity May Protect Against Alzheimer's Disease
4/18/2013

TAU reveals the missing link between brain patterns and Alzheimer's

Evidence indicates that the accumulation of amyloid-beta proteins, which form the plaques found in the brains of Alzheimer's patients, is critical for the development of Alzheimer's disease, which impacts 5.4 million Americans. And not just the quantity, but also the quality of amyloid-beta peptides is crucial for Alzheimer's initiation. The disease is triggered by an imbalance in two different amyloid species — in Alzheimer's patients, there is a reduction in a relative level of healthy amyloid-beta 40 compared to 42.

Now Dr. Inna Slutsky of Tel Aviv University's Sackler Faculty of Medicine and the Sagol School of Neuroscience, with postdoctoral fellow Dr. Iftach Dolev and PhD student Hilla Fogel, have uncovered two main features of the brain circuits that impact this crucial balance. The researchers have found that patterns of electrical pulses (called "spikes") in the form of high-frequency bursts and the filtering properties of synapses are crucial to the regulation of the amyloid-beta 40/42 ratio. Synapses that transfer information in spike bursts improve the amyloid-beta 40/42 ratio.

This represents a major advance in understanding that brain circuits regulate composition of amyloid-beta proteins, showing that the disease is not just driven by genetic mutations, but by physiological mechanisms as well. Their findings were recently reported in the journal Nature Neuroscience.

Tipping the balance

High-frequency bursts in the brain are critical for brain plasticity, information processing, and memory encoding. To check the connection between spike patterns and the regulation of amyloid-beta 40/42 ratio, Dr. Dolev applied electrical pulses to the hippocampus, a brain region involved in learning and memory.

When increasing the rate of single pulses at low frequencies in rat hippocampal slices, levels of both amyloid-beta 42 and 40 grew, but the 40/42 ratio remained the same. However, when the same number of pulses was distributed in high-frequency bursts, researchers discovered an increased amyloid-beta 40 production. In addition, the researchers found that only synapses optimized to transfer encoded by bursts contributed towards tipping the balance in favor of amyloid-beta 40. Further investigations conducted by Fogel revealed that the connection between spiking patterns and the type of amyloid-beta produced could revolve around a protein called presenilin. "We hypothesize that changes in the temporal patterns of spikes in the hippocampus may trigger structural changes in the presenilin, leading to early memory impairments in people with sporadic Alzheimer's," explains Dr. Slutsky.

Behind the bursts

According to Dr. Slutsky, different kinds of environmental changes and experiences — including sensory and emotional experience — can modify the properties of synapses and change the spiking patterns in the brain. Previous research has suggested that a stimulant-rich environment could be a contributing factor in preventing the development of Alzheimer's disease, much as crossword and similar puzzles appear to stimulate the brain and delay the onset of Alzheimer's. In the recent study, the researchers discovered that changes in sensory experiences also regulate synaptic properties — leading to an increase in amyloid-beta 40.

In the next stage, Dr. Slutsky and her team are aiming to manipulate activity patterns in the specific hippocampal pathways of Alzheimer's models to test if it can prevent the initiation of cognitive impairment. The ability to monitor dynamics of synaptic activity in humans would be a step forward early diagnosis of sporadic Alzheimer's.

Hila Milshtein, Yevgeny Berdichevsky, and Neta Gazit of Dr. Slutsky's lab at TAU, and Noa Lipstein and Nils Brose of the Max-Planck-Institute for Experimental Medicine in Germany, also contributed to this work.


TAU School of Public Health Hosts Second Summer Institute in Collaboration with Johns Hopkins University
4/15/2013

Israeli-US initiative advances international perspective on public health

From July 7 to 26, 2013, Tel Aviv University's School of Public Health at the Sackler Faculty of Medicine will host the second annual Summer Institute of Advanced Epidemiology and Preventative Medicine in collaboration with Johns Hopkins University's Bloomberg School of Public Health. The program comprises five advanced level courses open to students and professionals in the health care field, as well as others interested in developing advanced skills in Epidemiology and Preventive Medicine and gaining insight into Israel's health system and unique public health challenges.

"The Summer Institute of Advanced Epidemiology and Preventative Medicine, open to students from abroad and inside the country, will address topics of global importance," says Prof. Dani Cohen, Director of TAU's School of Public Health and one of the co-directors of the program along with Prof. Tamy Shohat of TAU and Prof. Jonathan Zenilman of Johns Hopkins University. "It's a rare opportunity to take advanced courses while experiencing this unique country and all the benefits that Tel Aviv has to offer."

Some of the topics on this year's calendar include food security and public health, the development and evaluation of vaccines, and cardiovascular epidemiology. The institute offers a limited number of dormitory rooms to the program's international participants. Registration and other information on the program can be found at http://international.tau.ac.il/prospective-students/summer-programs/summer-eapm.html.

A shared vision

Featuring instructors from universities and research institutions in the United States, Europe, and Israel, the Summer Institute represents the vision and dedication of leading experts in the field of public health. This summer's lecturers will be donating their time to a program — and a country — that they believe in, says Prof. Cohen. The institute is the result of many years of co-operation between TAU researchers and their colleagues in the international arena. "With these interactions, you can truly build special programs," he notes.

Last year, more than 80 Israeli and international students participated in TAU's Summer Institute program, which is based on the Johns Hopkins Bloomberg School of Public Health summer institute initiative. This year, Prof. Cohen predicts that new and exciting course offerings will draw an even higher number. "Faculty and researchers from University of Maryland, University of British Colombia, Emory University, Pasteur Institute, other academic institutions and the World Health Organization will be joining TAU and Johns Hopkins researchers," he says. Among the faculty from Johns Hopkins who will teach at TAU this summer are Prof. Moyses Szklo, Director of the Graduate Summer Institute of Epidemiology and Biostatistics and Prof. Lawrence Appel, Director of the Welch Center for Prevention, Epidemiology and Clinical Research.

Breaking boundaries with public health

The Summer Institute represents the next step in the growth of TAU's School of Public Health, which has been gaining in international recognition and prestige since first opening its doors seven years ago. The Summer Institute of Advanced Epidemiology and Preventative Medicine is the second international program run by the school, joining the International Masters in Public Health in Emergency and Disaster Management program, which also draws students from all over the world.

The organizers are seeking funding for scholarships to support participation of students from all over the world including developing countries. The School of Public Health has long worked to break down boundaries through improving public health in the Middle East, and is part of the Middle East Consortium for Infectious Disease Surveillance, which brings together academic and health organizations in Israel, Jordan, and the Palestinian Authority.


Sustained Stress Heightens Risk of Miscarriage
4/8/2013

TAU researcher finds a 59% increased risk of miscarriage for women living under rocket fire

Several studies have examined the impact of stress on a pregnancy — both chronic stress, such as workload, and acute stress associated with traumatic events like the 9/11 terrorist attacks. They conclude that stress can lead to adverse birth outcomes, including miscarriage and premature birth.

Few studies, however, assess the impact of continuous military or political stress throughout a pregnancy, says Prof. Liat Lerner-Geva of Tel Aviv University's Sackler Faculty of Medicine and the Women and Children's Health Research Unit at The Gertner Institute for Epidemiology and Health Policy Research Ltd, Tel Hashomer. Now her new study, conducted with PhD student Tamar Wainstock and Prof. Ilana Shoham-Vardi of Ben Gurion University, Prof. Eyal Anteby of the Barzilai Medical Center, and Saralee Glasser of Gertner Institute, Tel Hashomer, reveals that living under these sustained stresses significantly increases the risk of miscarriage.

Following the pregnancies of women from the Israeli town of Sderot, which is constantly under threat of rocket bombings from Gaza, and women from nearby Kiryat Gat, which is outside of Gaza's rocket range, the researchers demonstrated that those living under rocket fire were 59 percent more likely to miscarry than their neighbors.

These results, published in the Psychosomatic Medicine Journal of Biobehavioural Medicine, should be a call-to-action for practitioners, advises Prof. Lerner-Geva, who suggests making intervention readily available to pregnant women in stressful and threatening situations.

Studying stress under fire

Sderot has been a constant target of rocket fire from the Gaza Strip since 2001. Rocket attacks are preceded by an alarm warning residents to take shelter. The alarms themselves are loud, sudden, and themselves stress-inducing — once they sound, Sderot residents have only seconds before the rocket hits. Between 2001 and 2008, more than 1,000 alarms were sounded in the vicinity of Sderot. Since 2001, rockets exploding in the town have killed at least 13 residents, wounded dozens, and caused extensive property damage.

To study the impact of such sustained stress on pregnancy, researchers turned to the medical records at Barzilai Medical Center, a hospital which serves both Sderot and Kiryat Gat. They followed the pregnancies of 1,345 women from Sderot who were exposed to alarms and subsequent rocket fire, and 2,143 residents of Kiryat Gat who live out of missile range. The medical records were then cross-referenced to local municipal databases that track the number and location of rocket attacks.

In the unexposed group in Kiryat Gat, miscarriage rates were 4.7 percent, which accords with predictions from existing medical research literature. In the exposed group in Sderot, however, 6.9 percent of women miscarried — a statistically significant increase. The results were controlled for other risk factors for miscarriage, such as age and other medical conditions.

Within the exposed group, the researchers also analyzed the intensity of exposure. Not every neighborhood in Sderot was subject to the same number of attacks, notes Prof. Lerner-Geva, and the researchers originally hypothesized that women in higher stress areas would have a higher probability of miscarriage. However, the results indicate that women in both high-intensity and low-intensity areas were at the same risk. One explanation is that the constant fear of attack is as stressful as the attacks themselves, she concludes.

Prevention through intervention

One advantage that healthcare providers have in dealing with populations under constant threat is that they can make use of early intervention, says Prof. Lerner-Geva. "Most of the Sderot pregnant women receive prenatal care through community health clinics. This presents an opportunity to run preventive interventions to reduce stress or even provide one-on-one counseling."

Currently, she and her fellow researchers are conducting further studies on the same population to determine whether sustained stress had an impact on other negative birth outcomes, such as preterm delivery or low birth weights.


President Obama Puts Much-Needed Money Where the Brain Is
4/4/2013

TAU researcher says that BRAIN Initiative is a welcome step forward

When US President Barack Obama announced a $100 million brain mapping initiative this week, he said that the new project will attempt to "crack the code" of what causes degenerative neurological diseases. Prof. Rivka Inzelberg, a leading neurologist at Tel Aviv University's Sackler Faculty of Medicine, told US News & World Report that she welcomed the funding and the attention it will draw.

"A lot of money is needed because [brain mapping] is expensive," Prof. Inzelberg told the magazine. "Of course, any money invested in this area is welcome, but $100 million is not a lot of money for brain research. It's below what is really needed."

Hundreds of millions of dollars are already being spent in neurological research around the world. The National Institutes of Health, which will receive at least $40 million of the initial funds, already spends $5.5 billion annually on neurosciences, according to the report.

Prof. Inzelberg is a member of TAU's Adams Super Center for Brain Studies. The Center brings together lead scientists to spearhead a multidisciplinary approach to brain research, with participants from TAU's faculties of medicine, engineering, life sciences, and the humanities, among others. Its studies and teaching are aimed at deciphering the secrets of the mind and the brain and finding new approaches to the treatment of devastating neurological diseases.

Prof. Inzelberg says incremental advances have been made in neurology over the past few years, notably in her field of Alzheimer's research. This research is increasingly necessary, she says — the number of people with Alzheimer's disease is expected to triple by 2050. "It's a problem with major implications. We'll not only have the cost of treating these people, but it'll also be a burden for the generation of people who will have to take care of them."

For the full story, see the US News & World Report article:
http://www.usnews.com/news/articles/2013/04/02/obamas-100-million-brain-initiative-barely-makes-a-dent-in-neuroresearch-budget

For more about Tel Aviv University's Adams Super Center for Brain Studies, see the Center's Web site:
http://www.brain.tau.ac.il/


New Relief for Gynecological Disorders
4/3/2013

TAU researchers discover injectable protein to reverse symptoms of dangerous conditions

The creation of new blood vessels in the body, called "angiogenesis," is usually discussed in connection with healing wounds and tumors. But it's also an ongoing process in the female reproductive tract, where the growth and breaking of blood vessels is a normal part of the menstrual cycle. But abnormal growth of blood vessels can have painful consequences and resultant pathologies.

Now, Prof. Ruth Shalgi and research associate Dr. Dana Chuderland of Tel Aviv University's Sackler Faculty of Medicine have found a potential treatment for this abnormal growth in a potent physiological anti-angiogentic factor, PEDF. Administered by simple injection, this protein reverses the symptoms of related diseases without compromising fertility, according to pre-clinical studies.

These new findings, which have been reported in the Journal of Clinical Endocrinology and Metabolism, Human Reproduction, and Molecular Human Reproduction, could provide relief for millions of women worldwide. This work was done in collaboration with Prof. Rafael Ron-El and Dr. Ido Ben-Ami from Assaf Harofeh Hospital.

Dangers of angiogenesis

There are two primary pathologies associated with angiogenesis in the female reproductive system. One is endometriosis, characterized by the passage of uterine cells to other locations in the body during menstruation, which causes severe pain and reduced fertility. The other is ovarian hyperstimulation syndrome (OHSS), a possible side effect of IVF treatments. This is a potentially life-threatening disease with symptoms including abdominal pain and swelling.

Approximately 170 million women suffer from endometriosis worldwide, and about 10 percent of women receiving IVF treatment develop OHSS. Because no treatment currently exists for either of these conditions, affected women have no choice but to suffer through the symptoms.

In the past few decades, scientists have conducted extensive research on both pro-angiogenic factors such as VEGF and anti-angiogenic factors including PEDF. The effect of PEDF in decreasing abnormal angiogenesis has been extensively investigated in the eye and in tumors. Prof. Shalgi and Dr. Chuderland hypothesized that the same protein could play a role in diseases of the female reproductive system related to blood vessels growth.

In both OHSS and endometriosis, rampant VEGF levels allow for the abnormal vascularization that characterises both diseases. To counteract this effect and restore a healthy angiogenic balance in the reproductive system, the researchers turned to PEDF as a replacement therapy agent. In the lab, Prof. Shalgi and Dr. Chuderland developed mouse models of both endometriosis and OHSS. After preparing the PEDF protein, they injected the mice with it.

The researchers noted a "perfect reversal" of all symptoms, including reduced abdominal swelling in OHSS-induced mice and eradicated lesions in endometriosis. When evaluating whether this protein might affect fertility, they confirmed that PEDF had no negative impact on ovulation or pregnancy rate. In fact, it increased the number of ovulated eggs in the endometriosis model, suggesting improved fertility.

Easing the pain

The next step is to commercialize the protein for therapeutic use, say the researchers, who were the first to prove that this anti-angiogenic protein is active in the reproductive system. This discovery has been patent protected and is currently undergoing commercialization by Ramot, the technology transfer company of TAU (www.ramot.org).

There are currently no treatment options for women suffering from these diseases, explains Dr. Chunderland, who believes that endometriosis, in particular, is under-diagnosed and usually dismissed as severe menstrual pain. This new treatment could bring long-awaited relief from painful and seemingly uncontrollable symptoms, including severe abdominal pain and infertility issues.

Endometriosis has a negative impact on eggs' quality; 30 percent of women with this disease require fertility treatments in order to conceive, say the researchers. Women who develop OHSS have a lower chance of conception and a higher chance of miscarriage during their IVF treatment cycles. If these diseases could be eradicated, it would ease the sometimes difficult road towards conception, they suggest.


Job Burnout Can Severely Compromise Heart Health
3/12/2013

Top 20% of burnt-out employees have a dramatically increased risk of heart disease, TAU researcher finds

Americans work longer hours, take fewer vacation days, and retire later than employees in other industrialized countries around the globe. With such demanding careers, it's no surprise that many experience job burnout — physical, cognitive, and emotional exhaustion that results from stress at work. Researchers have found that burnout is also associated with obesity, insomnia, and anxiety.

Now Dr. Sharon Toker of Tel Aviv University's Faculty of Management and her fellow researchers — Profs. Samuel Melamed, Shlomo Berliner, David Zeltser and Itzhak Shpira of TAU's Sackler Faculty of Medicine — have found a link between job burnout and coronary heart disease (CHD), the buildup of plaque in the coronary arteries that leads to angina or heart attacks.

Those who were identified as being in the top 20 percent of the burnout scale were found to have a 79 percent increased risk of coronary disease, the researchers reported in the journal Psychosomatic Medicine. Calling the results "alarming," Dr. Toker says that these findings were more extreme than the researchers had expected — and make burnout a stronger predictor of CHD than many other classical risk factors, including smoking, blood lipid levels, and physical activity.

Taking a toll on the heart

Some of the factors that contribute to burnout are common experiences in the workplace, including high stress, heavy workload, a lack of control over job situations, a lack of emotional support, and long work hours. This leads to physical wear and tear, which will eventually weaken the body.

Knowing that burnout has been associated with other cardiovascular risk factors, such as heightened amounts of cholesterol or fat in the bloodstream, the researchers hypothesized that it could also be a risk factor for coronary heart disease.  Over the course of the study, a total of 8,838 apparently healthy employed men and women between the ages of 19 and 67 who presented for routine health examinations were followed for an average of 3.4 years. Each participant was measured for burnout levels and examined for signs of CHD. The researchers controlled for typical risk factors for the disease, such as sex, age, family history of heart disease, and smoking.

During the follow-up period, 93 new cases of CHD were identified. Burnout was associated with a 40% increased risk of developing CHD. But the 20% of participants with the highest burnout scores had a 79% increased risk. Dr. Toker predicts that with a more extended follow-up period, the results would be even more dramatic.

Avoiding long-term damage

These results are valuable for preventative medicine, says Dr. Toker. Healthcare providers who know that their patients are experiencing burnout can closely monitor for signs of coronary heart disease as well.

Once burnout begins to develop, it sparks a downwards spiral and ultimately becomes a chronic condition, she warns. Employers need to prioritize prevention by promoting healthy and supportive work environments and keeping watch for early warning signs of the condition. Simple diagnostic questionnaires that identify burnout are already available online. Workers can contribute to prevention by making healthy lifestyle choices, such as exercising more regularly, getting seven to eight hours sleep per night, and seeking psychological therapy if required.


Study Finds Fat and Bone Mass Are Genetically Linked
3/11/2013

Obesity and osteoporosis should not be treated separately, TAU researcher counsels

When it comes to body shape, diet and exercise can only take us so far. Our body shape and geometry are largely determined by genetic factors. Genetics also have an impact on our body composition — including soft fat tissue and hard bone tissue — and can lead to excess fat or osteoporosis.

Now Prof. Gregory Livshits of Tel Aviv University's Department of Anatomy and Anthropology at the Sackler Faculty of Medicine, working alongside Dr. Michael Korostishevsky, has uncovered a clear genetic link between fat and bone mass. These factors, which contribute to bone metabolism, also affect Body Mass Index (BMI), which often serves as an indicator of overall health.

Reported in the journal Bone, this finding is a step towards understanding how these tissues are inter-related on a biological level, and will help doctors develop better treatment plans for patients dealing with fat or bone related pathologies. "When a patient is prescribed a medication, it is always important to know the potential side effects," says Prof. Livshits. As a result of this genetic connection, "a medication that is prescribed to treat obesity might have a negative impact on skeletal health," he says.

Connections forged in fat and bone

Previous studies revealed that osteocalcin, a protein produced by bone cells, has an impact not only on bone but also on fat tissue metabolism. The protein's function is associated with bone formation and bone mineralization. But recent data suggest that osteocalcin is also involved in the regulation of glucose and fat metabolism and that osteocalcin levels are lower in obese and overweight individuals. Prof. Livshits and Dr. Korostishevsky set out to determine the underlying mechanism of this osteocalcin link — whether it was purely environmental or had a genetic basis.

The researchers conducted their study on a European population called the Chuvasha — descendants of Bulgarian tribes that have lived along the Volga River for more than a thousand years. As a relatively isolated and ethnically homogeneous population, they are highly appropriate for the study of genetic effects. 1,112 participants over the age of 20 hailing from a total of 230 families were tested for variants in the osteocalcin gene. Genetic information was analyzed in connection with measurements that reflect body mass, including BMI, thickness of skin folds, reflecting the amount of fat beneath the skin and others.

"We discovered a statistically significant association between osteocalcin gene variants and measures of body mass, suggesting the involvement of this gene in body mass regulation," says Prof. Livshits. To check the reliability of their findings, they asked researchers at Tulane University in Louisiana to test the same association between genetic variants of the osteocalcin gene and body mass measurements in an extensive sample of 2,244 Americans of European background. The results revealed a very similar pattern.

Balancing treatment

Because the connection between fat and bone mass has been shown to be genetic rather than environmental, related issues can't be addressed separately, Prof. Livshits says. Bisphosphonates, for example, are effective agents for the treatment of bone mineral density loss and are therefore commonly used to treat osteoporosis. However, it is also important to know how this therapy impacts fat tissue. "After a few years of treatment that improves the bones, we don't want to discover that we have harmed the fat tissue in the process," he adds.

In parallel studies, the researchers are also investigating the FTO (fat mass and obesity-associated) gene, which has been shown to impact fat and lean body mass and is suspected to impact bone mineral density too. Their future research will explore the extent to which osteocalcin, FTO, and several other genes impact muscle mass in addition to fat and bone mass. It is important to understand the extent to which these genes contribute to interdependence of all major body composition components, says Prof. Livshits.


Star-Shaped Glial Cells Act as the Brain's "Motherboard"
3/6/2013

New framework for brain communications offers insight into brain disease, says TAU researcher

The transistors and wires that power our electronic devices need to be mounted on a base material known as a "motherboard." Our human brain is not so different — neurons, the cells that transmit electrical and chemical signals, are connected to one another through synapses, similar to transistors and wires, and they need a base material too.

But the cells serving that function in the brain may have other functions as well. PhD student Maurizio De Pittà of Tel Aviv University's Schools of Physics and Astronomy and Electrical Engineering says that astrocytes, the star-shaped glial cells that are predominant in the brain, not only control the flow of information between neurons but also connect different neuronal circuits in various regions of the brain.

Using models designed to mimic brain signalling, De Pittà's research, led by his TAU supervisor Prof. Eshel Ben-Jacob, determined that astrocytes are actually "smart" in addition to practical. They integrate all the different messages being transferred through the neurons and multiplexing them to the brain's circuitry. Published in the journal Frontiers in Computational Neuroscience and sponsored by the Italy-Israel Joint Neuroscience Lab, this research introduces a new framework for making sense of brain communications — aiding our understanding of the diseases and disorders that impact the brain.

Transcending boundaries

"Many pathologies are related to malfunctions in brain connectivity," explains Prof. Ben-Jacob, citing epilepsy as one example. "Diagnosis and the development of therapies rely on understanding the network of the brain and the source of undesirable activity."

Connectivity in the brain has traditionally been defined as point-to-point connections between neurons, facilitated by synapses. Astrocytes serve a protective function by encasing neurons and forming borders between different areas of the brain. These cells also transfer information more slowly, says Prof. Ben-Jacob — one-tenth of a second compared to one-thousandth of a second in neurons — producing signals that carry larger amounts of information over longer distances. Aastrocytes can transfer information regionally or spread it to different areas throughout the brain — connecting neurons in a different manner than conventional synapses.

De Pittà and his fellow researchers developed computational models to look at the different aspects of brain signalling, such as neural network electrical activity and signal transfer by synapses. In the course of their research, they discovered that astrocytes actually take an active role in the way these signals are distributed, confirming theories put forth by leading experimental scientists.

Astrocytes form additional networks to those of the neurons and synapses, operating simultaneously to co-ordinate information from different regions of the brain — much like an electrical motherboard functions in a computer, or a conductor ensuring that the entire orchestra is working in harmony, explains De Pittà.

These findings should encourage neuroscientists to think beyond neuron-based networks and adopt a more holistic view of the brain, he suggests, noting that the two communication systems are actually interconnected, and the breakdown of one can certainly impact the other. And what may seem like damage in one small area could actually be carried to larger regions.

A break in communication

According to Prof. Ben-Jacob, a full understanding of the way the brain sends messages is significant beyond satisfying pure scientific curiosity. Many diseases and disorders are caused by an irregularity in the brain's communication system or by damage to the glial cells, so more precise information on how the network functions can help scientists identify the cause or location of a breakdown and develop treatments to overcome the damage.

In the case of epilepsy, for example, the networks frequently become overexcited. Alzheimer's disease and other memory disorders are characterized by a loss of cell-to-cell connection. Further understanding brain connectivity can greatly aid research into these and other brain-based pathologies.

To read the article, see:
http://www.frontiersin.org/computational_neuroscience/10.3389/fncom.2012.00098/abstract

To learn more about De Pittà's research, visit his home page:
https://sites.google.com/site/mauriziodepitta/home


Walking Away from Back Pain
3/5/2013

Home aerobic program as effective as clinical therapy in treating lower back pain, finds TAU researcher

Lower back pain is a common complaint, and treatment often requires many hours of physical therapy over multiple weekly clinic visits — a costly commitment. Now Dr. Michal Katz-Leurer of Tel Aviv University's Stanley Steyer School of Health Professions at the Sackler Faculty of Medicine says that a simple aerobic walking program is as effective in alleviating lower back pain as muscle strengthening programs that require specialized equipment in rehabilitation clinics. The program includes walking two to three times a week for a period of 20 to 40 minutes.

Dr. Katz-Leurer and her colleague Ilana Shnayderman, a graduate student at the Department of Physical Therapy and a practicing physiotherapist at Maccabi Health Care, say that their treatment option fits easily into a daily routine and allows those with back pain to be more responsible for their own health.

Their study was published in the journal Clinical Rehabilitation.

A simple solution

According to Dr. Katz-Leurer, research has shown that when people walk actively, abdominal and back muscles work in much the same way as when they complete exercises that target these areas. And unlike muscle strengthening programs, which often call for specific equipment and can involve exercises that require expert supervision, walking is a simple activity that can be done alone.

For the study, the researchers recruited 52 patients with lower back pain to participate in a randomized control trial. Through questionnaires, they were initially assessed for pain levels, feelings of disability, and avoidance of daily activities, as well as muscle and walking endurance.

Then, half of the participants completed a typical clinic-based muscle strengthening program, with two to three exercise sessions a week for six weeks. The other half completed a six-week aerobic walking program, walking two to three times weekly. Participants started with 20 minutes of walking, then progressed to 40 minutes as their endurance improved.

Results showed that both groups improved significantly in all areas of assessment, demonstrating that the walking program was "as effective as treatment that could have been received in the clinic," says Dr. Katz-Leurer.

The path to a healthier lifestyle

Dr. Katz-Leurer says that the walking program has the additional advantage of encouraging patients to follow a healthier lifestyle overall. In terms of physical fitness, those in the walking group were able to walk an average of 0.05 miles farther during a six-minute walking test at the end of the program compared to the pre-program assessments.

She also notes that that regularly active people are less likely to suffer typical aches and pains over their lifetime. Walking, a low-impact activity, also lowers blood pressure, boosts brain and immune system functioning, and reduces stress, she says.


Crowd-Sourced Funding Provides Missing Help for Rare Genetic Diseases
2/27/2013

TAU researcher heads first international branch of the Rare Genomics Institute

For the estimated 250 million people worldwide who suffer from rare diseases, there is little hope for diagnosis or treatment. Because each individual disease impacts so few people, hardly any funding is allocated to research, leaving many without medical options. The US-based non-profit organization Rare Genomics Institute (RGI) is working to address this problem by "crowd-funding" — allowing people to donate on the Internet towards genetic testing for individual children who are struggling with a rare disease.

Now, thanks to Dr. Noam Shomron of Tel Aviv University's Sackler Faculty of Medicine, RGI's vital mission has come to Israel — the first international branch of the organization. Its online home is http://raregenomics.org/world_Israel.php, and it has launched its first appeal for two Israeli children at http://raregenomics.org/donors.php.

Based at the TAU-affiliated Sourasky Medical Center and Rabin Medical Center, RGI-Israel will help families with children impacted by rare genetic diseases find support and care through advanced genetic testing. The Israeli branch is run in collaboration with three of Israel's top geneticists, Drs. Lina Basel, Shay Ben-Shachar, and Hagit Baris.

The services that the organization provides are sorely needed in Israel, says Dr. Shomron, who is the director of Israel’s RGI. Both Jewish and Arabic populations in Israel are plagued by a unique pool of genetic diseases. "There are decades of genetic puzzles in the Israeli population, and we are hoping to solve a few of them," he says, hoping that RGI-Israel will help provide the funding to support these families in need.

A community effort

A decade ago, the human genome was sequenced for the first time. The process cost over a billion dollars and took more than ten years to complete. But now a more advanced technology, deep sequencing, can sequence the entire human genome in a matter of days and at a less prohibitive cost. Dr. Shomron's TAU lab is a world leader in this field of research.

RGI's approach is straight-forward. It maintains online donation pages with pictures and personal stories of children in need of genetic testing for mutations as the first step toward treatment or a cure. Donors can then contribute to the cost of DNA testing for each individual child. "Deep sequencing costs around $1,500 per person now, and the fundraising goal for each child is less than $8,000, which is used for sequencing and confirmation of the genomes of the affected child and their relatives, depending on the family's genetic history and the genetics of the disease," says Dr. Shomron, who notes that Israeli families are already reaching out to RGI Israel for help. This allows families to avoid the difficult and expensive process of testing for mutations gene by gene.

One family, for example, has been plagued for generations by what appears to be mental retardation — but the medical cause of this condition remains a mystery. "They have been living for many years without knowing what causes this problem in their family. They don't know whether their DNA is the cause — and if it is, what mutation causes it," he says.

Once the genetic testing has been completed, RGI-Israel's doctors will meet with each family to discuss the results. And the support won't end there. The next phase is to link each family with researchers who study the genes in question, building a network of researchers and patients who work together to investigate these rare diseases. Ultimately, this process assures each patient that they are not facing their disease alone.

Family planning

For many families, simply knowing the cause of their child's disease gives a sense of relief and hope. It also helps doctors to develop better treatment plans, and in a few "miracle" cases, RGI's work has even led to a successful therapeutic management. With the very first child whose genome was sequenced, doctors discovered that he had a mutation in a haematological-related gene, says Dr. Shomron. With a stem cell related transplant, they were able to completely eradicate his disease.

Genetic knowledge can also be invaluable in terms of future family planning. Many affected parents want more children but are afraid of similar complications with subsequent births. Once the genetic mutation is identified, these couples can use IVF and advanced scanning methods such as Preimplantation Genetic Diagnosis (PGD) to ensure that their future children are healthy.

For more information on RGI-Israel or to donate, please visit the website at:
http://raregenomics.org/world_Israel.php


Backs Bear a Heavy Burden
2/21/2013

TAU research finds that heavy loads on the shoulders can cause nerve damage in the hands and fingers

Trudging from place to place with heavy weights on our backs is an everyday reality, from schoolchildren toting textbooks in backpacks to firefighters and soldiers carrying occupational gear. Muscle and skeletal damage are very real concerns. Now Tel Aviv University researchers say that nerve damage, specifically to the nerves that travel through the neck and shoulders to animate our hands and fingers, is also a serious risk.

Prof. Amit Gefen of TAU's Department of Biomedical Engineering and Prof. Yoram Epstein of TAU’s Sackler Faculty of Medicine, along with PhD student Amir Hadid and Dr. Nogah Shabshin of the Imaging Institute of the Assuta Medical Center, have determined that the pressure of heavy loads carried on the back have the potential to damage the soft tissues of the shoulder, causing microstructural damage to the nerves.

The result could be anything from simple irritation to diminished nerve capacity, ultimately limiting the muscles' ability to respond to the brain's signals, inhibiting movement of the hand and the dexterity of the fingers. In practice, this could impact functionality, reducing a worker's ability to operate machinery, compromise a soldiers' shooting response time, or limiting a child's writing or drawing capacity.

The research was published in the Journal of Applied Physiology and partially supported by a grant from TAU's Nicholas and Elizabeth Slezak Super Center for Cardiac Research and Biomedical Engineering.

Modeling impaired nerve function

Focusing their study on combat units in which soldiers must carry heavy backpacks, the researchers discovered that, in addition to complaining of discomfort or pain in their shoulders, soldiers also reported tickling sensations or numbness in the fingers.

Exploring this issue in a non-invasive manner, they used biomechanical analysis methods originally developed for investigating chronic wounds. The analyses show how mechanical loads, defined as the amount of force or deformation placed on a particular area of the body, were transferred beneath the skin to cause damage to tissue and internal organs.

Based on data collected by MRI, Profs. Gefen and Epstein developed anatomical computer models of the shoulders. These showed how pressure generated by the weight of a backpack load is distributed beneath the skin and transferred to the brachial plexus nerves. The models also account for mechanical properties, such as the stiffness of shoulder tissues and the location of blood vessels and nerves in the sensitive areas which are prone to damage.

Extensive mechanical loading was seen to have a high physiological impact. "The backpack load applies tension to these nerves," explains Prof. Gefen. He notes that the resulting damage "leads to a reduction in the conduction velocity — that is, the speed by which electrical signals are transferred through the nerves." With a delay or reduction in the amplitude or the intensity of signals, nerve communication cannot properly function, he says.

A danger to adults and children

These results apply to people from all walks of life, says Prof. Gefen. Many professions and leisure activities, such as hiking or travelling, involve carrying heavy equipment on the back. The researchers plan to extend this study in two directions: first, to study the effects of load on nerve conductivity, and second, to examine the impact of these heavy loads on a child's anatomy.

School bags are a major concern, he warns. It cannot be assumed that children's bodies react to shoulder stress in exactly the same way as adults. Differences in physiology could lead to different consequences, tolerance, and damage levels.


Medicine Gets More Personal
2/12/2013

High-content drug screening could be the key for treatment of rare Jewish diseases, says a TAU researcher

Personalized medicine — tailoring diagnostics and treatment according to individual genetics — is a rapidly growing field. Using advanced screening technologies, the dream of offering customized care to each patient is slowly becoming a reality, offering hope to sufferers of rare diseases, who are often left without medical support. But because each disease impacts only a handful of people worldwide, there is no commercial incentive for pharmaceutical companies to fund drug research and development.

Now Tel Aviv University is bridging the gap. The laboratory of Prof. Miguel Weil of TAU's Department of Cell Research and Immunology is home to a new state-of-the-art high-throughput drug screening facility which can apply thousands of drug compounds a day on diseased cells. This enhances the chance of finding a "hit" — when a compound has a positive impact on a sick cell.

The method could dramatically shorten drug development time, Prof. Weil explains, adding that a compound being tested for viability is simultaneously checked for toxicity. Considering the critical nature of many of these cases, the quicker an effective treatment can be identified, the better.

Finding a needle in a haystack

Prof. Weil was inspired to pursue this field of research after his own son Nir was born with Familial Dysautonomia (FD), a rare genetic disorder of the autonomic nervous system that is prevalent in Ashkenazi Jews. In their research and with the permission of hospital ethics committees, Prof. Weil and his team use live cells isolated from tissue samples of patients with FD and Amyotrophic Lateral Sclerosis. First, they compare the diseased cells with healthy ones to identify the biological differences, including various molecular features or markers of disease. Then, they use the drug screening facility to screen thousands of drug compounds against patient cells, searching for a compound that will affect the cellular markers of the disease.

There are two candidate groups of compounds used in screening, explains Prof. Weil. One category comprises FDA-approved drugs, which can be used for treatment not long after they are discovered to be effective at the cellular level. The other category includes libraries of unknown compounds deemed potentially viable as drug therapies due to their chemical structure.

But even when scientists have identified the genetic mutation that causes a disease, it doesn't necessarily mean that they understand why. Drug development is like searching for a needle in a haystack, Prof. Weil says. "This technology allows you to develop drugs without knowing exactly what you are aiming for, using an unbiased approach to drug screening," he explains.

Drug development for one

Rare diseases are an ideal starting point for personalized medicine development, Prof. Weil believes. Because sufferers make up such a tiny percentage of the population, a compound can be statistically beneficial – even if there are only 10 patients. "Using rare diseases as a proof-of-concept will help us to develop useful technologies for personalized medicine in cancer and other more common diseases," he says.

This research is especially critical for Jewish Ashkenazi population, which is at high risk for a total of 19 rare diseases, including FD, Tay-Sachs, and Cystic Fibrosis. One in five Ashkenazi Jews is a carrier of a disease. TAU's Cell Screening Facility for Personalized Medicine, established by the Mexican Friends of Tel Aviv University, is the first worldwide to deal with drug screening for rare Jewish diseases.

Prof. Weil and his team are currently seeking long-term funding in order to continue their lifesaving work, with the goal of establishing a workable platform for developing individualized therapies. The large range of testing that the screening facility allows will eventually help them to tweak compounds to meet a patient's specific biological needs, uncovering much needed treatment options for people like his son Nir, who too often fall by the wayside of mainstream medicine, says Prof. Weil.


A Privacy Risk in Your DNA
2/7/2013

New policies are needed to safeguard participants' identity in genetic studies, cautions TAU researcher

The growing ease of DNA sequencing has led to enormous advancements in the scientific field. Through extensive networked databases, researchers can access genetic information to gain valuable knowledge about causative and preventative factors for disease, and identify new targets for future treatments. But the wider availability of such information also has a significant downside — the risk of revealing personal information.

Researchers from Tel Aviv University and the Whitehead Institute of Biomedical Research in Cambridge, MA, have developed an algorithm that can identify last names using information gathered from the Y chromosome, which passes from father to son. This finding shows how genetic data can be used to compromise an individual's privacy, says Prof. Eran Halperin of TAU's Blavatnik School of Computer Science and Department of Molecular Microbiology and Biotechnology, who worked on the project with PhD student David Golan of TAU's Department of Statistics and Operations Research and Dr. Yaniv Ehrlich of the Whitehead Institute.

Using chromosomal data drawn from genetic databases, the researchers were able to identify the surname of one in every eight people from a sample of 911 American men. Sometimes other private information could even be discovered, including their geographic locations or the identities of their relatives. Published in the journal Science, this result should serve as a call to action for safeguards, the researchers note.

Weighing science and privacy

"Having such data is critical to scientific research, so we must look for ways to minimize the risk, including better techniques for encrypting genetic data, education for study participants and researchers, and new legislation to protect such information and prevent its misuse," Prof. Helperin says.

Although information about a person's entire genome is often available, this project sought to determine how much can be discovered about an individual using only a small amount of chromosomal data. The researchers chose to focus on the Y chromosome, which is passed down through the male lineage, because of its connection to surnames, which are commonly passed down through the male lineage as well.

Data relating to the Y chromosome of the sample of 911 American men — whose genetic information was collected through a private company — was used to search for their corresponding surnames in public databases. The researchers' algorithm was able to identify the family name of 12 percent of the participants.

Because they were only looking for near-precise matches, this is a very conservative return, notes Prof. Halperin. A broader search would reveal a short-list of possibilities that could reveal even more identities. And with some additional details that are commonly included in study databases, such as age group or geographic location, there is a much higher chance of tracing a person's identity, explains Golan. Those with rarer surnames were also easier to identify accurately than those with more common names.

Mitigating risk

While Prof. Halperin believes there are some positive applications of these findings, such as searching for lost relatives or identifying bodies in mass disasters, there are also serious security issues to consider. Even if the genomic data is originally anonymous, it can still be used to invade an individual's privacy — and that of their family as well. Insurance companies could use this genetic information to determine if you are at higher risk for a particular illness and ultimately deny coverage, suggests Golan.

Steps must be taken to ensure that identities are secure while allowing scientists to access valuable genomic information, the researchers say. As credit cards and other forms of ID are encrypted to extract required information while safeguarding personal details, researchers must find a way to publish genetic data in a way that it maintains individuals' privacy but still has scientific value. Those who publish their genomic information, or participate in such studies, should be made aware of the implications. And new legislation concerning the maintenance of private and public databases, as well as anti-genetic-discrimination laws, should be drafted, conclude Prof. Halperin and Golan.


Can Cancer Be Turned Against Itself?
2/4/2013

Immune system can use melanoma's own proteins to kill off cancer cells, TAU researchers find

Though a small group of proteins, the family called Ras controls a large number of cellular functions, including cell growth, differentiation, and survival. And because the protein has a hand in cellular division, mutated Ras, which can be detected in one-third of all tumors, contributes to many human cancers by allowing for the rapid growth of diseased cells.

Now Prof. Yoel Kloog of Tel Aviv University's Department of Neurobiology, along with Dr. Itamar Goldstein of TAU's Sackler Faculty of Medicine and the Sheba Medical Center and their students Helly Vernitsky and Dr. Oded Rechavi, has found that oncogenic Ras, which promotes cancer development, can also alert the immune system to the presence of cancer cells.

For the first time, the researchers have shown the transfer of oncogenic Ras in human cells from melanoma cells to T cells, which belong to a group of white blood cells that are part of the immune system. This transfer allows the immune cells to gather crucial intelligence on what they are fighting and develop the necessary cytokines, or signalling molecules, to kill the melanoma cells.

Prof. Kloog suggests that a drug that enhances the transfer of the oncogene from the tumor to the immune cells is a potential therapy to augment the anti-cancer immune response. This research has been published in the Journal of Immunology.

Finding the tipping point

Although they found that immune cells often exchange proteins among themselves, the discovery that melanoma cells transfer mutated Ras is an intriguing first. And it's this initial transfer that begins what the researchers call a positive feedback loop.

In the lab, researchers incubated T-cells from patients with human melanoma cells that had originated from tumors to track the process of handing-off various proteins. They uncovered a circuit that runs between the cancer and immune cells. Once the melanoma cells pass oncogenic Ras to the T-cells, the T-cells are activated and begin to produce cytokines, which enhances their capacity to kill cancer cells.

As these melanoma cells pass along the mutated Ras, the immune cells become increasingly active. Eventually, enough oncogenic material is transferred across the immune cells' threshold, causing the T-cells to act on the melanoma cells from which the oncogenic Ras was derived. Ultimately, this transfer tips the scales in favor of the immune cells, the researchers say.

Exploiting the information transfer

The next step is to develop a therapy that can enhance the transfer in patients with cancers linked to oncogenic Ras, says Prof. Kloog. And although their research has so far focused on melanoma, which is known to elicit the response of the immune system, he believes that this finding could be applicable to other types of cancers.

There is a constant balancing act between cancer cells and the immune system, says Dr. Goldstein. Under normal circumstances, the immune system will kill some cancerous cells on a daily basis. The disease becomes critical when the immune system can no longer keep cancer cells in check. Although there are many theories as to how cancer cells break free of this cycle, scientists are still attempting to discover why this occurs.

Prof. Kloog and Dr. Goldstein hope that this research leads to a better understanding of how the immune system fights tumors. "It's a part of the interaction between cancer and the immune system that is not well known," says Dr. Goldstein. "We are trying to gather more comprehensive data on all the proteins that are being passed around, and how this information impacts the immune system's response to cancer."


Discovering the Missing "LINC" to Deafness
1/28/2013

Mutation in a genetic protein prevents hearing, reports a TAU researcher

Because half of all instances of hearing loss are linked to genetic mutations, advanced gene research is an invaluable tool for uncovering causes of deafness — and one of the biggest hopes for the development of new therapies. Now Prof. Karen Avraham of the Sackler Faculty of Medicine at Tel Aviv University has discovered a significant mutation in a LINC family protein — part of the cells of the inner ear — that could lead to new treatments for hearing disorders.

Her team of researchers, including Dr. Henning Horn and Profs. Colin Stewart and Brian Burke of the Institute of Medical Biology at A*STAR in Singapore, discovered that the mutation causes chaos in a cell's anatomy. The cell nucleus, which contains our entire DNA, moves to the top of the cell rather than being anchored to the bottom, its normal place. Though this has little impact on the functioning of most of the body's cells, it's devastating for the cells responsible for hearing, explains Prof. Avraham. "The position of the nucleus is important for receiving the electrical signals that determine proper hearing," she explains. "Without the ability to receive these signals correctly, the entire cascade of hearing fails."

This discovery, recently reported in the Journal of Clinical Investigation, may be a starting point for the development of new therapies. In the meantime, the research could lead towards work on a drug that is able to mimic the mutated protein's anchoring function, and restore hearing in some cases, she suggests.

From human to lab to mouse

Prof. Avraham originally uncovered the genetic mutation while attempting to explain the cause of deafness in two families of Iraqi Jewish descent. For generations, members of these families had been suffering from hearing loss, but the medical cause remained a mystery. Using deep genetic sequencing, a technology used to sequence the entire human genome, she discovered that the hearing impaired members of both families had a mutated version of the protein Nesprin4, a part of the LINC group of proteins that links the cell's nucleus to the inner wall of the cell.

In the lab, Prof. Avraham recreated this phenomenon by engineering the mutation in single cells. With the mutation in place, Nesprin4 was not found in the area around the cell nucleus, as in healthy cells, but was spread throughout the entire cell. Investigating further, she studied lab mice that were engineered to be completely devoid of the protein.

Created in Singapore, the mice were originally engineered to study the biology of LINC proteins. The fact that they were deaf came as a complete surprise to researchers. Without this protein serving as an anchor, the cell nucleus is not located in the correct position within inner ear cells, but seems to float throughout. This causes the cells' other components to reorient as well, ultimately harming the polarity of the cells and hindering electrical signals. It's a mutation that took a heavy toll on the cells' ability to transfer sound signals, explains Prof. Avraham, rendering the mice deaf.

Given the similarity between mouse and human inner ear cells, researchers predict that the same phenomenon is occurring in human patients with a mutation in the Nesprin4 gene.

Looking for a wider impact

Prof. Avraham says that she and her collaborators are the first to reveal this mutation as a cause of deafness. "Now that we have reported it, scientists around the world can test for mutations in this gene," she notes. The mutation could indeed be a more common genetic cause of deafness in a number of populations. And because Nesprin4 belongs to a family of proteins that have been linked to other diseases, such as muscular coordination and degeneration disorders, this could prove a ripe area for further research.

At TAU, the research was supported by the National Institutes of Health — NIDCD and Israeli Center of Research Excellence, I-CORE.


It's True: Medical Cannabis Provides Dramatic Relief for Sufferers of Chronic Ailments
1/24/2013

Treatment can improve appetite, ease chronic pain, and more, say TAU researchers

Though controversial, medical cannabis has been gaining ground as a valid therapy, offering relief to suffers of diseases such as cancer, Post-Traumatic Stress Disorder, ALS and more. The substance is known to soothe severe pain, increase the appetite, and ease insomnia where other common medications fail.

In 2009, Zach Klein, a graduate of Tel Aviv University's Department of Film and Television Studies, directed the documentary Prescribed Grass. Through the process, he developed an interest in the scientific research behind medical marijuana, and now, as a specialist in policy-making surrounding medical cannabis and an MA student at TAU's Porter School of Environmental Studies, he is conducting his own research into the benefits of medical cannabis.

Using marijuana from a farm called Tikkun Olam — a reference to the Jewish concept of healing the world — Klein and his fellow researchers tested the impact of the treatment on 19 residents of the Hadarim nursing home in Israel. The results, Klein says, have been outstanding. Not only did participants experience dramatic physical results, including healthy weight gain and the reduction of pain and tremors, but Hadarim staff saw an immediate improvement in the participants' moods and communication skills. The use of chronic medications was also significantly reduced, he reports.

Klein's research team includes Dr. Dror Avisar of TAU's Hydrochemistry Laboratory at the Department of Geography and Human Environment; Prof. Naama Friedmann and Rakefet Keider of TAU's Jaime and Joan Constantiner School of Education; Dr. Yehuda Baruch of TAU's Sackler Faculty of Medicine and director of the Abarbanel Mental Health Center; and Dr. Moshe Geitzen and Inbal Sikorin of Hadarim.

Cutting down on chronic medications

Israel is a world leader in medical cannabis research, Klein says. The active ingredient in marijuana, THC, was first discovered there by Profs. Raphael Mechoulam and Yechiel Gaoni. Prof. Mechoulam is also credited for having defined the endocannabinoid system, which mimics the effects of cannabis and plays a role in appetite, pain sensation, mood and memory.

In the Hadarim nursing home, 19 patients between the ages of 69 and 101 were treated with medical cannabis in the form of powder, oil, vapor, or smoke three times daily over the course of a year for conditions such as pain, lack of appetite, and muscle spasms and tremors. Researchers and nursing home staff monitored participants for signs of improvement, as well as improvement in overall life quality, such as mood and ease in completing daily living activities.

During the study, 17 patients achieved a healthy weight, gaining or losing pounds as needed. Muscle spasms, stiffness, tremors and pain reduced significantly. Almost all patients reported an increase in sleeping hours and a decrease in nightmares and PTSD-related flashbacks.

There was a notable decline in the amount of prescribed medications taken by patients, such as antipsychotics, Parkinson's treatment, mood stabilizers, and pain relievers, Klein found, noting that these drugs have severe side effects. By the end of the study, 72 percent of participants were able to reduce their drug intake by an average of 1.7 medications a day.

Connecting cannabis and swallowing

This year, Klein is beginning a new study at Israel's Reuth Medical Center with Drs. Jean-Jacques Vatine and Aviah Gvion, in which he hopes to establish a connection between medical cannabis and improved swallowing. One of the biggest concerns with chronically ill patients is food intake, says Klein. Dysphagia, or difficulty in swallowing, can lead to a decline in nutrition and even death. He believes that cannabis, which has been found to stimulate regions of the brain associated with swallowing reflexes, will have a positive impact.

Overall, Klein believes that the healing powers of cannabis are close to miraculous, and has long supported an overhaul in governmental policy surrounding the drug. Since his film was released in 2009, the number of permits for medical cannabis in Israel has increased from 400 to 11,000. His research is about improving the quality of life, he concludes, especially for those who have no other hope.


Oxygen Chamber Can Boost Brain Repair
1/23/2013

Hyperbaric treatment has significantly resuscitated activity in damaged brains, TAU researchers find

Stroke, traumatic injury, and metabolic disorder are major causes of brain damage and permanent disabilities, including motor dysfunction, psychological disorders, memory loss, and more. Current therapy and rehab programs aim to help patients heal, but they often have limited success.

Now Dr. Shai Efrati of Tel Aviv University's Sackler Faculty of Medicine has found a way to restore a significant amount of neurological function in brain tissue thought to be chronically damaged — even years after initial injury. Theorizing that high levels of oxygen could reinvigorate dormant neurons, Dr. Efrati and his fellow researchers, including Prof. Eshel Ben-Jacob of TAU's School of Physics and Astronomy and the Sagol School of Neuroscience, recruited post-stroke patients for hyperbaric oxygen therapy (HBOT) — sessions in high pressure chambers that contain oxygen-rich air — which increases oxygen levels in the body tenfold.

Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to control periods of non-treatment, reported Dr. Efrati in PLoS ONE. Patients experienced improvements such as a reversal of paralysis, increased sensation, and renewed use of language. These changes can make a world of difference in daily life, helping patients recover their independence and complete tasks such as bathing, cooking, climbing stairs, or reading a book.

Oxygen breathes new life into neurons

According to Dr. Efrati, there are several degrees of brain injury. Neurons impacted by metabolic dysfunction have the energy to stay alive, but not enough to fire electric signals, he explains. HBOT aims to increase the supply of energy to these cells.

The brain consumes 20 percent of the body's oxygen, but that is only enough oxygen to operate five to ten percent of neurons at any one time. The regeneration process requires much more energy. The tenfold increase in oxygen levels during HBOT treatment supplies the necessary energy for rebuilding neuronal connections and stimulating inactive neurons to facilitate the healing process, explains Dr. Efrati.

For their study, the researchers sought post stroke patients whose condition was no longer improving. To assess the potential impact of HBOT treatment, the anatomical features and functionality of the brain were evaluated using a combination of CT scans to identify necrotic tissue, and SPECT scans to determine the metabolic activity level of the neurons surrounding damaged areas.

Seventy-four participants spanning 6 to 36 months post-stroke were divided into two groups. The first treatment group received HBOT from the beginning of the study, and the second received no treatment for two months, then received a two-month period of HBOT treatment. Treatment consisted of 40 two-hour sessions five times weekly in high pressure chambers containing oxygen-rich air. The results indicate that HBOT treatment can lead to significant improvement in brain function in post stroke patients even at chronically late stages, helping neurons strengthen and build new connections in damaged regions.

A potential avenue for prevention

Although the study focuses on patients only through three years post-stroke, Dr. Efrati has seen similar improvement in patients whose brain injuries occurred up to 20 years before, belying the concept that the brain has a limited window for growth and change. "The findings challenge the leading paradigm since they demonstrate beyond any doubt that neuroplasticity can still be activated for months and years after acute brain injury, thus revealing that many aspects of the brain remain plastic into adulthood," says Prof. Ben-Jacob.

This study also "opens the gate into a new territory of treatment," adds Dr. Efrati. The researchers are currently conducting a study on the benefits of HBOT for those with traumatic brain injury. This treatment also has potential as an anti-aging therapy, applicable in other disorders such as Alzheimer's disease and vascular dementia at their early stages.

"It is now understood that many brain disorders are related to inefficient energy supply to the brain," explains Dr. Efrati. "HBOT treatment could right such metabolic abnormalities before the onset of full dementia, where there is still potential for recovery."


"Marisol's Mice" Guide Scientists to New Hope for a Rare Genetic Disorder
1/22/2013

One child's battle with Vanishing White Matter Disease inspires breakthrough research at a TAU lab

Vanishing White Matter (VWM) disease is a devastating condition that destroys the brain's white matter. This white matter protects the axons of neurons, and leads to seizures and the progressive loss of motor function, eyesight, and speech. Also known as Childhood Ataxia with Central Nervous System Hypomyelination (CACH), the disease has no cure, and victims do not typically live longer than the early teens.

It's a heartbreaking diagnosis that the O'Brien family of Boston, Massachusetts, knows well. Their daughter Marisol — "a very energetic, funny, beautiful girl who could light up a room," says her father Tom O'Brien — was diagnosed with the disease at the age of three in 2003, sparking a long journey that led to the finest Boston doctors, Lourdes, Bethesda's National Institutes of Health, and finally Tel Aviv University.

For Prof. Orna Elroy-Stein, whose lab at TAU's Department of Cell Research and Immunology is focused on research surrounding VWM disease, Marisol is a daily source of inspiration. She was first alerted to Marisol's condition through Dr. Rafi Schiffman of the National Institutes of Health, one of her research collaborators. Dr. Schiffman took some hair, skin, and blood samples from Marisol at his Maryland clinic and asked Marisol's father for permission to send them along to Prof. Elroy-Stein's lab; he agreed.

Developing "Marisol's mice"

Marisol passed away from the disease in 2008, but her DNA pattern and specific genetic mutation were the basis for Prof. Elroy-Stein's breakthrough development of the first population of laboratory mice — called "Marisol's mice" — with a VWM disease mutation. With this invaluable biological tool in place, researchers have been able to make important progress into understanding how the disease functions.

Through these mice, the researchers were able to discover that VWM disease was in essence a developmental disorder — the mutation causes delayed development of the myelin that forms after birth, they reported in the journal Brain. The researchers' most recent findings, published in the journal PLoS One, add to this understanding.

"Because of these mutations, the brain's response to physiological stress, such as fever or blunt trauma, is not normal. Following damage, the proteins can't be synthesized quickly enough to make a repair," explains Prof. Elroy-Stein, who keeps a photograph of Marisol on her desk to motivate her in this challenging research. "Every morning, she smiles at me and it keeps me going," she said.

What Marisol's mice revealed

In VWM disease, the systematic loss of the brain's myelin is due to a mutation in the translation factor eIF2B, which translates genetic information from our DNA for the use of proteins, explains Prof. Elroy-Stein. But with this mutation, the protein responsible for the production of white matter is faulty.

That's why patients with VWM disease have an impaired ability to cope with physiological stresses that damage the brain. The brain usually responds to such injuries by triggering elevated protein synthesis to make the proteins necessary for repair, says Prof. Elroy-Stein. But the mutated version of elF2B cannot keep up with such acute demand.

"As long as there is no stress, protein production rate is slower but still sufficient," Prof. Elroy-Stein says. The crisis begins when protein production is needed critically and on a large-scale. Because the developmental delay renders immediate response impossible, it leads to more severe and permanent brain damage, findings suggest.

The personal touch

Four years after Marisol's death, Tom O'Brien visited Prof. Elroy-Stein's lab, and what he found had a powerful effect. "I felt Marisol's strong presence in the lab," he said. "And then Orna took me down to where the mice were — there were thousands and thousands of them! It was amazing!

"Prof. Elroy-Stein is a very kind, wonderful person and a beautiful human being," O'Brien recalls. "There were a lot of researchers we met who were specialists and very smart. But she also understands how this research is very personal for us."

In the future, Prof. Elroy-Stein hopes that she and her team will be able to unravel one of the mysteries connected to VWM disease. Unlike patients of other genetic diseases, the severity of a VWM patient's mutation is not necessarily correlated to disease onset and deterioration. The researchers hypothesize that this could be a simple matter of timing. Myelin forms at a specific stage of development, when the brain is the most sensitive. Early trauma may impact the trajectory of the disease.

These discoveries — and the promise of future findings — are only a part of Marisol's legacy, says Prof. Elroy-Stein. "Though they weren't able to save their daughter, the O'Brien family continues to help others through their Foundation for Marisol's Journey. Their courage and unbelievable effort inspires me to continue on in this challenging research, hoping to help patients in the future. Marisol is the spirit that drives us all forward," she says.


Remembering Marisol
1/22/2013

A family tragedy inspires breakthrough research at TAU

Marisol O'Brien, the youngest of four children Patricia and Tom O'Brien of Boston adopted from Latin American countries, "could light up a room," her father remembers with a smile. But at the age of three she started to lose her ability to walk, and the O'Briens were not prepared for the devastating diagnosis of a very rare disorder that has no cure. Victims of Vanishing White Matter (VWM) disease, they were told, rarely live longer than their early teens. "It was every parent's worst nightmare," he says.

"Most families would feel that they couldn't let this happen to their child," O'Brien says, and they were no different, doing whatever was necessary to help Marisol. "We took her everywhere, even though Boston is a very strong place for medical research and has wonderful doctors. We even took her to Lourdes — a long and difficult trip for us, as you can imagine."

One Boston doctor suggested that the O'Briens contact Dr. Rafi Shiffman, a researcher with the National Institutes for Health in Bethesda, MD. "I wrote Dr. Schiffman a long email about VWM, about where Marisol was in the progression of the disease and her symptoms, and at the end I asked, 'Can I come and visit you?' He sent me a one-word reply — 'Yes.'" Although Dr. Schiffman was not able to offer much hope in 2003, he did take some hair, blood, and skin samples and asked the O'Briens if he could share them with a collaborator.

A call from Tel Aviv

A year later, Tom O'Brien was contacted by Schiffman's collaborator, Prof. Orna Elroy-Stein of Tel Aviv University's Department of Cell Research and Immunology, whose research focuses on VWM disease. In Boston for a conference, Prof. Elroy-Stein, a mother herself, sat down with O'Brien to talk about the disease.

"We talked for a number of hours about Marisol and her condition," O'Brien remembers. "Prof. Elroy-Stein had just begun to create these laboratory mice based on Marisol's very unique DNA pattern. She's a very kind, wonderful person — a beautiful human being. There are a lot of researchers you meet in this process who are specialists and very smart, but don't always have the best bedside manner."

Unfortunately, Marisol O'Brien died on December 20, 2008.

Meeting Marisol's many mice

The family continued to support Prof. Elroy-Stein's work through the nonprofit Foundation for Marisol's Journey, which they started within days of Marisol's death. But it wasn't until 2011 that O'Brien met with Prof. Elroy-Stein a second time, when he came to the Tel Aviv University campus as part of a group of Boston businessmen led by Massachusetts Gov. Deval Patrick.

"Tel Aviv University has a beautiful campus, and I visited Prof. Elroy-Stein's lab there on a beautiful sunny day," O'Brien remembers, his voice breaking slightly. "I felt Marisol's presence with me as I walked into her terrific lab, filled with kind and energetic young people. She took me down to a room where the mice were — there were thousands and thousands of them! It was amazing! She's conducting dozens of experiments with these mice, and she's on a path to truly understanding what happens with this disease."

The Foundation for Marisol's Journey remains committed to raise funds to support Prof. Elroy-Stein's research at Tel Aviv University — and Marisol's spirit continues to animate not only the O'Briens, but also all of the researchers at the TAU lab. "Marisol plays a role in our daily lives — she's done so ever since she came to us in 2000," O'Brien says. "Orna Elroy-Stein understands that. She's a superb research doctor, but she also gets the personal side — why this work is so wonderful for us."

More information about the Foundation can be found at its Web site:
http://www.marisolfoundation.org

 

 

Paging Dr. Charles Dickens!
1/16/2013

Author used literature to showcase discrimination against the disabled, says a TAU researcher

Charles Dickens' tales are filled with immortal characters — think of A Christmas Carol's Scrooge and Great Expectations' Miss Havisham. But more than whims of literary invention, his characters and plots often deal with the difficult social realities of Victorian England. His portrayal of the disabled — both in terms of medicine and the social discrimination they faced — is no exception.

"Social attitudes towards the disabled can often be traced through art, from ancient times through today," explains Prof. Avi Ohry of Tel Aviv University's Sackler Faculty of Medicine, a specialist in rehabilitation medicine and a scholar of the medical humanities. In Dickens' works, he says, readers are confronted with the stark realities of the 19th century, including poor medical care and social discrimination against the physically disabled and the mentally ill.

In a recent article for the journal Orthopedia, Traumatologia and Rehabilitacja, Prof. Ohry argues that literature was a way for Dickens to express his ideas for reform and advocate for better treatment of the disabled. Extremely influential, Dickens’ opinions may have gone a long way towards influencing social attitudes — the first step towards improved care and non-discriminatory legislation, he says.

Putting disability in a new light

During Dickens' time, disabled people were still commonly feared and seen as monstrous, explains Prof. Ohry. In the literature of the 19th century, physical deformities were often interpreted as "outward manifestations of inner depravity" or "punishment for moral failings," he says.

And while Dickens does portray some of his disabled characters in this way, such as the greedy and ruthless Smallweed in Bleak House, many of his disabled characters are uniquely sympathetic and inspirational — a surprisingly progressive attitude, considering the era’s social prejudices towards the disabled. Examples include the heart-tugging Tiny Tim from A Christmas Carol and Phil Squod, a loyal and good-hearted servant in Bleak House, both of whom are "crippled." Dickens also took care to differentiate between physical handicaps and mental disabilities or illness, another distinguishing feature of his work.

This kind of advanced thinking was shaped by Dickens' real life experiences, Prof. Ohry explains. The author's own experience of illness and poverty, especially in early adulthood, bred a lifelong interest in medical and social conditions. Deeply committed to alleviating the plight of the poor and a frequent visitor at both hospitals and asylums, Dickens maintained close friendships with some of the most notable reformers and doctors of his time.

Learning from the past

Although attitudes towards the disabled have shifted throughout the centuries, there are still lessons to be learned from Dickens' message. Today's sociologists and anthropologists who have studied reactions to disabled communities can attest that prejudice remains common, says Prof. Ohry. Ask a healthy individual to sit in a disabled person's wheelchair, for instance, and often he will refuse, as though the disability is contagious, he adds.

In many arenas, advocates for the sick and infirm are still fighting the battle for greater acceptance of those who are different. Dickens' passion for social reform and support for those in need resonates even in our modern society, he concludes.


Parkinson's Treatment Can Trigger Creativity
1/14/2013

Patients treated with dopamine-enhancing drugs are developing artistic talents, reports a TAU researcher

Parkinson's experts across the world have been reporting a remarkable phenomenon — many patients treated with drugs to increase the activity of dopamine in the brain as a therapy for motor symptoms such as tremors and muscle rigidity are developing new creative talents, including painting, sculpting, writing, and more.

Prof. Rivka Inzelberg of Tel Aviv University's Sackler Faculty of Medicine first noticed the trend in her own Sheba Medical Center clinic when the usual holiday presents from patients — typically chocolates or similar gifts — took a surprising turn. "Instead, patients starting bringing us art they had made themselves," she says.

Inspired by the discovery, Prof. Inzelberg sought out evidence of this rise in creativity in current medical literature. Bringing together case studies from around the world, she examined the details of each patient to uncover a common underlying factor — all were being treated with either synthetic precursors of dopamine or dopamine receptor agonists, which increase the amount of dopamine activity in the brain by stimulating receptors. Her report will be published in the journal Behavioral Neuroscience.

Giving in to artistic impulse

Dopamine is involved in several neurological systems, explains Prof. Inzelberg. Its main purpose is to aid in the transmission of motor commands, which is why a lack of dopamine in Parkinson's patients is associated with tremors and a difficulty in coordinating their movements.

But it's also involved in the brain's "reward system" — the satisfaction or happiness we experience from an accomplishment. This is the system which Prof. Inzelberg predicts is associated with increasing creativity. Dopamine and artistry have long been connected, she points out, citing the example of the Vincent Van Gogh, who suffered from psychosis. It's possible that his creativity was the result of this psychosis, thought to be caused by a spontaneous spiking of dopamine levels in the brain.

There are seemingly no limits to the types of artistic work for which patients develop talents, observes Prof. Inzelberg. Cases include an architect who began to draw and paint human figures after treatment, and a patient who, after treatment, became a prize-winning poet though he had never been involved in the arts before.

It's possible that these patients are expressing latent talents they never had the courage to demonstrate before, she suggests. Dopamine-inducing therapies are also connected to a loss of impulse control, and sometimes result in behaviors like excessive gambling or obsessional hobbies. An increase in artistic drive could be linked to this lowering of inhibitions, allowing patients to embrace their creativity. Some patients have even reported a connection between their artistic sensibilities and medication dose, noting that they feel they can create more freely when the dose is higher.

Therapeutic value

Prof. Inzelberg believes that such artistic expressions have promising therapeutic potential, both psychologically and physiologically. Her patients report being happier when they are busy with their art, and have noted that motor handicaps can lessen significantly. One such patient is usually wheelchair-bound or dependent on a walker, but creates intricate wooden sculptures that have been displayed in galleries. External stimuli can sometimes bypass motor issues and foster normal movement, she explains. Similar types of art therapy are already used for dementia and stroke patients to help mitigate the loss of verbal communication skills, for example.

The next step is to try to characterize those patients who become more creative through treatment through comparing them to patients who do not experience a growth in artistic output. "We want to screen patients under treatment for creativity and impulsivity to see if we can identify what is unique in those who do become more creative," says Prof. Inzelberg. She also believes that such research could provide valuable insights into creativity in healthy populations, too.


Promising Stem Cell Therapy for Children with Renal Cancer
1/2/2013

TAU researchers discover potential alternative to dangerous chemotherapy treatment

Conventional chemotherapy, which is toxic to the body, can have a particularly devastating impact on children — and even lead to secondary cancers.

Now a team of Tel Aviv University researchers, led by Prof. Benjamin Dekel of TAU's Sackler Faculty of Medicine and the head of the Pediatric Stem Cell Research Institute at Sheba Medical Center, has isolated cancer stem cells that lead to the growth of a tumor usually found in the kidneys of young children. His research may lead to an alternative therapy that circumvents such negative side effects.

A small group of cancer stem cells (CSCs) are responsible for the creation and spread of tumors. The researchers' study, published in EMBO Molecular Medicine, details the identification of CSCs in children suffering from Wilms' tumors, which are the most common form of pediatric kidney tumors and known to spread aggressively.

To specifically target these cells, the team took tissue from pediatric patients and grafted it into genetically engineered mice.  They were then able to identify the CSC's in these tumors, and, after identifying the molecules on the cells' surface, develop an antibody drug that targets one of the molecules.

"The targeted elimination of the CSCs fuelling the tumor led to shrinkage and, in some cases, the complete eradication of the tumors we induced in mice — without causing any toxic side effects," explains Prof. Dexel. He notes that this discovery may make the use of chemotherapy in pediatric renal cancer patients redundant in the very near future. The antibody is currently being tested in clinical trials with adult patients, and if approved, may also be tested on children.

For the full story on this alternative stem cell therapy, see the December 24, 2012, Ha'aretz story:
"Israeli researchers developing stem-cell therapy for children with renal cancer"


Helmsley Charitable Trust Awards $3.3 Million Matching Grant to TAU for Nanomedicine Initiative
12/19/2012

Research will design "theranostic" drugs personalized for individual cancer, cardiovascular, and inflammatory disease patients

The Leona M. and Harry B. Helmsley Charitable Trust has awarded a three-year $3,304,400 grant to the Tel Aviv University Leona M. and Harry B. Helmsley Nanotechnology Research Fund to launch research on personalized "theranostic" nanomedicines for cancer, cardiovascular, and inflammatory diseases. Theranostics, combining diagnostics and therapeutics, are a key component of the rapidly growing field of personalized medicine.

The Helmsley Charitable Trust grant provides matching funds for monies received from the government-supported Israel National Nanotechnology Initiative (INNI). In March 2012, the INNI selected Tel Aviv University from among 30 applicants to launch and lead a research consortium to work on a combined system of diagnostic and therapeutic treatments. The goal of the "Nanomedicines for Personalized Theranostics" team is to design a new class of drugs that can destroy faulty proteins and to deliver these drugs in a way that is safe for each individual patient.

Comprised of 11 laboratories, the consortium is dedicated to accelerating breakthroughs in the field of personalized medicine by developing nano-sized drug delivery systems for detection and treatment. Eight of the labs are TAU-led, with additional participation from Hebrew University Jerusalem, Bar-Ilan University and Ben Gurion University of the Negev.

Prof. Dan Peer, recruited by TAU from Harvard Medical School in 2008, initiated the project, organized the consortium, and has been appointed director of the initiative. INNI awarded him a $5.75 million grant over five years based on a Tel Aviv University commitment to provide one-to-one matching funds from its own operating budget and donor funds, for a total of $11.5 million at $2.3 million per year. Additional funds have already been secured from the National Institutes of Health and the Oakland, CA-based Kenneth Rainin Foundation.

A humanitarian partnership

President of Tel Aviv University Prof. Yossi Klafter has been personally involved in the initiative throughout. "Together, the INNI and Helmsley Charitable Trust awards put the spotlight on the pioneering work being done by Tel Aviv University scientists, and provide greater access to collaborations with similarly talented international communities. That means more progress in the very promising field of nanotechnology — and at a much faster rate."

Prof. Peer, who also heads the Laboratory of NanoMedicine at TAU, adds that "the addition of the Helmsley Charitable Trust grant puts us in a position to translate laboratory research into clinical practice within 10 years at the outside. For patients, that means minimally invasive, extremely efficient and safe nano-based delivery strategies that will specifically target diseased cells while leaving healthy cells untouched."

Prof. Peer has long been at the forefront of research in the field. His work was among the first to demonstrate systemic delivery of RNAi using targeted nanocarriers to the immune system and the first to demonstrate in vivo validation of new drug targets using RNAi in the immune system. With Prof. Rimona Margalit, he developed a nano-sized vehicle with the ability to deliver chemotherapy drugs directly into cancer cells while avoiding interaction with healthy cells — a stealth "submarine" — increasing the efficiency of chemotherapeutic treatment while reducing its side effects.

This is the first gift to Tel Aviv University from the Leona M. and Harry B. Helmsley Charitable Trust, which aspires to improve lives by supporting effective nonprofits in a variety of selected areas. Since 2008, when the Trust began its active grant-making, it has committed over $700 million to a wide range of charitable organizations.

For more information on the Leona M. and Harry B. Helmsley Charitable Trust and its programs, see
www.helmsleytrust.org

For more on the "Nanomedicines for Personalized Theranostics" consortium, see
http://www.aftau.org/site/News2?page=NewsArticle&id=17301

For more on Prof. Peer's work, see
http://www.aftau.org/site/News2?page=NewsArticle&id=8465


Speaking Skills Crucial for Hearing Impaired Children in the Classroom
12/17/2012

Intelligible speech closes the gap between hearing-impaired children and their normal-hearing peers, TAU researcher says

Current special education laws are geared towards integrating special-needs children into the general classroom environment from a young age, starting as early as preschool. Prof. Tova Most of Tel Aviv University's Jaime and Joan Constantiner School of Education and the Department of Communications Disorders at the Stanley Steyer School of Health Professions says that these laws present a unique set of challenges for children with hearing loss, and that a sense of isolation may inhibit a successful education.

While studies show that many children with hearing loss are academically comparable to their peers with normal hearing, active participation in classroom and group activities, as well as social integration, is more complex. Even with advanced sensory devices such as hearing aids and cochear implants, it can be difficult for children to pick up on all the necessary information in a busy atmosphere, leaving them with a sense that they’re being "left out" by hearing classmates.

In a study designed to explore the social competence and the perceived sense of loneliness of children with hearing loss in a regular classroom with normal hearing children, Prof. Most and her fellow researchers discovered that successful integration is dependent on a child's level of speech intelligibility. The results have been reported in the Journal of Deaf Studies and Deaf Education.

Closing the gap

Modern technology has allowed children with hearing loss to access more auditory information and develop better spoken language than ever before. And because advanced screening for hearing loss is now performed at birth, children can receive intervention from a young age. "In the regular classroom, the more they are intelligible, the more their social skills and competence rise, and it’s easier for them to make hearing friends," Prof. Most reports.

In their study, the researchers measured social competence and perceived sense of loneliness in children with hearing loss in two educational settings: individual inclusion where one child with hearing loss joined a regular classroom, and group inclusion, where a number of children with hearing loss joined a regular classroom. Sixty-four children between the ages of 4-7 participated, 22 in the individual inclusion and 42 in the group inclusion. All results were analyzed in light of the child's speech intelligibility.

Researchers discovered that individually integrated children had a higher social competence with the children with normal hearing than those in the group inclusion scenario. Speaking abilities played an important role in both groups, and had specific importance for children who were individually integrated. The poorer their speech intelligibility, the more likely they were to feel lonely in the classroom, something that the group inclusion children did not experience as part of an hearing loss enclave.

These findings suggest that development of intelligible spoken language has the power to close the gap between children with hearing loss and their hearing peers, resulting in increased social interaction, an improvement in group work, and a change in the teachers' and students' perception of the child with hearing loss, adds Prof. Most.

Meeting the needs of each child

Taking her years of research and in-field experience into account, Prof. Most says that there is an advantage to integrating children with hearing loss with hearing children, provided that their special needs are met.  Each child must be assessed on whether to be integrated individually or in a group, she counsels, noting that a "one size fits all" strategy could be harmful for some students.

"I prefer to see kids integrated into the regular school system, allowing them to be closer to home and interact with children in their neighborhood. They would then have access to broader programming and activities," she says. But if a child's spoken language and cognitive abilities indicate that a regular classroom would be difficult for him or her, pushing integration could result in failure.

Children with hearing loss, parents and specialists can aid successful integration by focusing on speech development, advises Prof. Most. And teachers can also do their part to create a more welcoming environment by creating small work groups and setting up meeting points in advance so the child won't be left out. The more children with normal hearing are exposed to those with hearing loss, the more understanding and accepting they will become, she says.


Embracing the Art of Science
12/5/2012

TAU scientists find beauty and win top prize in "genetic art" competition

The fine arts and the exact sciences may appear an unlikely pair, but creativity is a crucial element in both. Prof. Karen Avraham and PhD candidate Shaked Shivatzki of Tel Aviv University's Sackler Faculty of Medicine embraced this truth when creating Hearing and Deafness: Structure and Sequence, their winning submission to the recent American Society of Human Genetics art competition. Their work was awarded first place and graces the cover of the society's most recent journal.

Their creation uses modern techniques in genetic diagnostics. An image of a mouse cochlea, with cells stained with antibodies to denote the different types of cells and their function in the ear, makes up the background. In the foreground are DNA sequences of a gene that, when mutated, causes deafness, which symbolizes deep sequencing, an advanced technique used to reveal variances in cellular DNA or RNA.

The contest rules were simple, explains Prof. Avraham — create a piece that combines genetics and art to reveal the aesthetic beauty in scientific research. "It's very important to teach the public about science, and one of the ways to do this is to show them the beauty of the field. But a picture is worth a thousand words, and can explain scientific concepts in a clearer way," she said.

Essentially, the image is a tribute to deep sequencing, a technology used to describe the major components of the human genome, DNA. It's one of the most important tools in genetic diagnostics today, says Prof. Avraham, revolutionizing the hunt for genetic mutations. By finding the mutations responsible for human disease, scientists can diagnose disorders in a way that was impossible before. Israel has been one of the pioneering countries in the use of this technology.

Before deep sequencing, it would take a number of years and millions of dollars to sequence a genome. Now, it takes a matter of weeks, and can be done for the comparatively low cost of about $1,000. Not only does this mean greater access to genetic diagnosis, family planning, and medical management of disorders caused by genetic mutations, it also puts researchers on the right path in terms of developing therapeutic treatment.

The gene featured in the image is called Connexin 26. It is now known that mutations in this gene are the most common cause for deafness, found in about 30 percent of the hearing impaired population in Israel, says Prof. Avraham. Much of the early work in terms of diagnosing this mutation was done in Israel and at TAU, she adds. The study was supported by the National Institutes of Health NIDCD and I-CORE Gene Regulation in Complex Human Disease.


Fish Oil Helps Heal Bed Sores of the Critically Ill
12/4/2012

TAU research finds a 20-25 percent reduction in pressure ulcers with a fish oil enriched diet

Chock-full of Omega-3 fatty acids and antioxidants, fish oil can help lower blood pressure, reduce inflammation in the skin and joints, and promote healthy fetal development. Now a Tel Aviv University researcher has found that it has a positive effect on bedsores, too.

A common problem in critically ill patients, bedsores result from constant pressure on the skin and underlying tissue due to prolonged sitt