Tag: Medicine

Half the Tumors Gone: TAU Scientists Remove a Cancer Gene with CRISPR

Written by Hilary on 11 March 2025. Posted in Newsroom.

This gene-editing success from TAU could change cancer treatment forever.

Researchers from Tel Aviv University utilized CRISPR to cut a single gene from cancer cells of head and neck tumors – and successfully eliminated 50% of the tumors in model animals. This groundbreaking study was led by Dr. Razan Masarwy, MD, Ph.D. from the lab of Prof. Dan Peer – a global pioneer in mRNA-based drugs, Director of the Laboratory of Precision Nanomedicine, VP for Research and Development and member of the Shmunis School of Biomedicine and Cancer Research – all at TAU. The findings were published in the prestigious journal Advanced Science.

A New Approach to Treating Head and Neck Cancers

“Head and neck cancers are prevalent, ranking fifth in cancer mortality”, says Prof. Peer. “These are localized cancers, typically starting in the tongue, throat, or neck, which can later metastasize. If detected early, localized treatment can effectively target the tumor. We aimed to use genetic editing of a single gene expressed in this type of cancer to collapse the entire pyramid of the cancerous cell. This gene is the cancer-specific SOX2, also expressed in other types of cancer and overexpressed in these particular tumors”.

Prof. Dan Peer.

Prof. Peer and his colleagues are global pioneers in developing mRNA-based drugs encased in synthetic lipid particles that mimic biological membranes. In this study, the researchers synthesized special lipids that encapsulate the delivered CRISPR system in an RNA format. An antibody targeting a receptor against a protein named EGF was attached to the surface of these particles.

“These tumors are highly targeted”, explains Prof. Peer. “We targeted EGF because the cancer cells express the EGF receptor. Using our nano-lipid delivery system, we injected the drug directly into the tumor in a tumor model and successfully took out the gene – cutting it out from the cancer cell’s DNA with the CRISPR ‘scissors’. We were happy to observe the domino effect we had predicted. Following three injections spaced one week apart, 50% of the cancerous tumors simply disappeared after 84 days – which did not happen in the control group”.

Prof. Dan Peer & research team.

TAU Pioneers CRISPR for Cancer Treatment

In 2020, Prof. Peer and his team were the first in the world to use CRISPR to cut genes from cancer cells in mice and a cell-specific manner, and this is the first time they have applied it to head and neck cancers.

“Generally, CRISPR isn’t used for cancer because the assumption is that knocking out one gene wouldn’t collapse the whole pyramid. In this study we demonstrated that there are some genes without which a cancer cell cannot survive, making them excellent targets for CRISPR therapy. Since cancer cells sometimes compensate with other genes, it’s possible that additional genes need to be cut out, or perhaps not. Theoretically, this approach could be effective against many types of cancer cells, and we are already working on additional cancer types, including myeloma, lymphoma, and liver cancer”.

This study was supported in part by the EXPERT project (European Union’s Horizon 2020 research and innovation programme (under grant agreement # 825828), and the Shmunis Fund for gene editing.

First of Its Kind: mRNA Drugs Delivered Straight to the Gut

Written by Hilary on 9 February 2025. Posted in Newsroom.

Potential new therapy for Crohn’s, colitis, and other inflammatory diseases.

Researchers at Tel Aviv University have achieved a breakthrough in drug delivery: they have successfully transported lipid nanoparticles encapsulating messenger RNA (mRNA) to the immune system of the small and large intestines — bypassing the liver upon systemic administration. By simply altering the composition of the nanoparticles, the researchers demonstrated that mRNA-based drugs can be directed straight to target cells, avoiding the liver.

The groundbreaking Tel Aviv University study was led by post-doctoral fellow Dr. Riccardo Rampado together with Vice President for R&D Prof. Dan Peer, a pioneer in the development of mRNA therapeutics and Director of the Laboratory of Precision Nano-Medicine at the Shmunis School of Biomedicine and Cancer Research. The study was published on the cover of the prestigious journal Advanced Science.

Prof. Dan Peer.

Targeting Drugs More Precisely with Lipid Nanoparticles

“Everything injected into the bloodstream eventually ends up in the liver — that’s just how our anatomy works”, explains Prof. Peer. “This poses two challenges. First, drugs intended to target specific cells in particular organs may be toxic to the liver. Second, we don’t want drugs to get ‘stuck’ in the liver. Ideally, the drug would reach the target organ first, and any remnants would then break down in the liver. We discovered that altering the proportions of lipids comprising the nanoparticles determines their destination in the bloodstream. This is a general phenomenon, meaning it works regardless of the specific lipids, which makes this a significant breakthrough”.

To demonstrate the concept, Prof. Peer and his team encoded the anti-inflammatory protein interleukin-10 into mRNA, encapsulated it in lipid nanoparticles with a composition different from those typically used (such as in mRNA COVID-19 vaccines), and successfully delivered it to the intestines of animal models with Crohn’s disease and colitis via intravenous injection.

“Not only were we able to deliver an mRNA-based anti-inflammatory drug directly to the inflamed intestine and improve all markers of colitis and Crohn’s disease, but we also transformed the immune cells in the intestine into factories for producing the anti-inflammatory interleukin-10”, Prof. Peer explains. “But this is just a proof of concept study. By tweaking the nanoparticle composition, we could deliver other RNA-based drugs to different organs. There’s a saying in American English: ‘It’s all in the formulation’. That’s exactly what this is about”.

Higher Phospholipids, Faster Delivery

In general, lipid-based drugs are encased in synthetic lipid nanoparticles, which mimic biological membranes. One of these lipids is phospholipid named phosphatidylcholine, a component found in all biological membranes. In vaccines like the COVID-19 vaccine, the mRNA is encapsulated in lipid particles containing about 10% of this phospholipid. Prof. Peer and his team increased the phospholipid ratio to 30% and demonstrated that this adjustment caused the particles to float through the bloodstream like oil on water.

“That’s the whole trick”, Prof. Peer concludes. “We adjusted the lipid composition and found that at 30% phospholipid, the drug is directed straight to the intestine. Of course, this wasn’t a blind trial-and-error approach. We understand the mechanism, at least partially, and recognize that this ratio more closely resembles a natural biological membrane, which intestinal cells are better suited to absorb. Now, we are exploring further adjustments to target the pancreas and other organs that can only be reached by fine-tuning the lipid nanoparticle composition. This direct delivery method for mRNA drugs opens up broad possibilities for developing new and more precise therapies than ever before”.

What Happens When the Brain Learns Two Behaviors at Once?

Written by Hilary on 29 December 2024. Posted in Newsroom.

TAU researchers reveal the brain resolves conflict by blocking dual learning.

A new study from Tel Aviv University could reshape our scientific understanding of how humans learn and form memories, particularly through classical and operant conditioning. The research team found that our brain engages in fierce competition between these two learning systems and that only one can prevail at any given time. If we try to learn two conflicting actions for the same situation simultaneously, the result will be confusion, making it difficult to perform either action when re-encountering the situation. In their study, the researchers demonstrated this phenomenon in fruit flies. When the flies were trained to associate a smell with a randomly delivered electric shock (classical conditioning) and also to connect their actions to the smell and shock (operant conditioning), the flies became confused and failed to exhibit a clear response to the shock.

The intriguing research was led by Prof. Moshe Parnas and PhD student Eyal Rozenfeld from the Laboratory for Neural Circuits and Olfactory Perception at Tel Aviv University’s Faculty of Medical and Health Sciences. The findings were published in the prestigious journal Science Advances.

The researchers explain that humans learn in a variety of ways. A well-known example of learning is Ivan Pavlov’s famous experiment, where a dog learns to associate the sound of a bell with food. This type of learning is called classical conditioning and involves passive associations between two stimuli. On the other hand, humans can also learn from their own actions: if a specific action produces a positive outcome, we learn to repeat it, and if it harms us, we learn to avoid it. This type of learning is called operant conditioning and involves active behavior.

Freeze or flee? Cracking the brain’s decision code

For many years, scientists believed that these types of memory work together in the brain. But what happens if the two memories dictate conflicting actions? For instance, mice can be trained to fear a certain smell using both conditioning methods, but their responses will differ depending on which method is employed. Under classical conditioning, the mice will freeze in place, while under operant conditioning, they will flee. What happens if both memories are present simultaneously? Will the mice freeze, flee, or simply continue behaving as if nothing happened?

In a unique study conducted on fruit flies (Drosophila), researchers at Tel Aviv University discovered that the brain cannot learn using both classical and operant conditioning simultaneously. The brain actively suppresses the formation of both types of memories at the same time, using this strategy to determine which behavior to execute. During the experiment, the researchers taught the flies to associate a smell with an electric shock. When classical conditioning was used flies learned to freeze when they smelled the conditioned odor. In contrast, when operant conditioning was used, flies learned to flee from the smell to avoid the electric shock. They demonstrated that the flies could not learn both lessons together and that attempts to teach both types of learning simultaneously led to no learning at all. Furthermore, they identified the brain mechanisms that prioritize one type of learning over the other.

“Our research completely changes the way we have thought for decades about how our brain learns,” explains Prof. Parnas. “You can think of the brain as engaging in a ‘mental tug-of-war’: if you focus on learning through your actions, the brain blocks the formation of automatic associations. This helps avoid confusion but also means you can’t learn two things simultaneously”.

Why multitasking makes you forget

Prof. Parnas adds: “Fruit flies have simple brains, which makes them easy to study, but their brains are surprisingly similar to those of mammals—and thus to our own. Using powerful genetic tools, the researchers gained a deep understanding of how different learning systems compete for ‘space in the brain.’ They found that the brain’s ‘navigation center’ intervenes to ensure that only one type of memory is active at any given moment, preventing clashes between the two systems. This discovery can help us understand why multitasking sometimes leads to forgetting important details”.

Eyal Rozenfeld concludes: “Not only does this discovery reshape what we know about human learning, but it could also lead to the development of new strategies for treating learning disorders. By better understanding how memories are formed in individuals with conditions like ADHD or Alzheimer’s, we might be able to create new treatments. It’s fascinating that our brain selects between different learning systems to avoid confusion—all without us even being aware of it”.

GPS for Cancer: Directing Drugs to the Tumor

Written by Hilary on 23 December 2024. Posted in Newsroom.

A breakthrough method delivers two drugs straight to the cancer site.

Researchers at Tel Aviv University have developed a new platform using polymeric nanoparticles to deliver drug pairs to specific cancer types, including skin and breast cancer. The researchers explain that having both drugs arrive at the tumor site significantly amplifies their therapeutic effects and safety profiles.

The study was led by Prof. Ronit Satchi-Fainaro and doctoral student Shani Koshrovski-Michael from the Department of Physiology and Pharmacology at Tel Aviv University’s School of Medicine, in collaboration with other members of Prof. Satchi-Fainaro’s lab: Daniel Rodriguez Ajamil, Dr. Pradip Dey, Ron Kleiner, Dr. Yana Epshtein, Dr. Marina Green Buzhor, Rami Khoury, Dr. Sabina Pozzi, Gal Shenbach-Koltin, Dr. Eilam Yeini, and Dr. Rachel Blau. They were joined by Prof. Iris Barshack from the Department of Pathology at Tel Aviv University’s School of Medicine, Prof. Roey Amir and Shahar Tevet from the School of Chemistry at Tel Aviv University, and researchers from the Israel Institute of Biological Research, Italy, Portugal, and the Netherlands. The study was published in the prestigious journal Science Advances.

Bringing Precision to Drug Partnerships

Prof. Satchi-Fainaro explains: “Currently, cancer treatment often involves a combination of multiple drugs that work synergistically to enhance their anti-cancer effect. However, these drugs differ in their chemical and physical properties – such as their rate of degradation, their circulation time in the bloodstream, and their ability to penetrate and accumulate in the tumor. Therefore, even if multiple drugs are administered simultaneously, they don’t arrive together at the tumor, and their combined effects are not fully realized. To ensure maximal efficacy and minimal toxicity, we sought a way to deliver two drugs simultaneously and selectively to the tumor site without harming healthy organs”.

The researchers developed biodegradable polymeric nanoparticles (which break down into water and carbon dioxide within one month) capable of encapsulating two different drugs that enhance each other’s activity. These nanoparticles are selectively guided to the cancer site by attaching them to sulfate groups that bind to P-selectin, a protein expressed at high levels in cancer cells as well as on new blood vessels formed by cancer cells to supply them with nutrients and oxygen.

The researchers loaded the platform with two pairs of drugs approved by the FDA: BRAF and MEK inhibitors used to treat melanoma (skin cancer) with a BRAF gene mutation (present in 50% of melanoma cases), and PARP and PD-L1 inhibitors intended for breast cancer with a BRCA gene mutation or deficiency. The novel drug delivery system was tested in two environments: in 3D cancer cell models in the lab and in animal models representing both primary tumor types (melanoma and breast cancer) and their brain metastases.

The findings showed that the nanoparticles, targeted toward P-selectin, accumulated selectively in primary tumors and did not harm healthy tissues. Furthermore, the nanoparticles successfully penetrated the blood-brain barrier, reaching metastases in the brain with precision without harming healthy brain tissue.

Additionally, the combination of two drugs delivered simultaneously was far more effective than administering the drugs separately, even at 30 times lower doses than prior preclinical studies. The nanoparticle treatment significantly reduced tumor size, prolonging time to progression by 2.5 times than standard treatments, and extended the lifespan of mice treated with the nanoparticle platform. Mice had a 2-fold higher median survival compared to those receiving the free drugs and a 3-fold longer survival compared to the untreated control group.

A New Approach to Cancer Treatment

Prof. Satchi-Fainaro summarized: “In our study, we developed an innovative platform using biodegradable polymeric nanoparticles to deliver pairs of drugs to primary tumors and metastases. We found that drug pairs delivered this way significantly enhanced their therapeutic effect in BRAF-mutated skin cancers and BRCA-mutated breast cancers and their brain metastases. Since our platform is versatile by design, it can transport many different drug pairs that enhance each other’s effects, thereby improving treatment for a variety of primary tumors and metastases expressing the P-selectin protein, such as glioblastoma (brain cancer), pancreatic ductal adenocarcinoma, and renal cell carcinoma”.

The project received competitive research grants from Fundación “La Caixa”, the Melanoma Research Alliance (MRA), the Israel Science Foundation (ISF), and the Israel Cancer Research Fund (ICRF). It is also part of a broader research effort in Prof. Satchi-Fainaro’s lab supported by an Advanced Grant from the European Research Council (ERC), ERC Proof of Concept (PoC), EU Innovative Training Networks (ITN), and the Kahn Foundation.

Is Treatment for Genetic Autism on the Horizon?

Written by Hilary on 25 November 2024. Posted in Newsroom.

New study reveals brain mechanisms involved in genetically based autism which may lead to effective treatment

A groundbreaking study from Tel Aviv University expands the understanding of the biological mechanism underlying genetically-based autism, specifically mutations in the SHANK3gene, responsible for nearly one million cases of autism worldwide. Based on these discoveries, the research team applied a genetic treatment that improved the function of cells affected by the mutation, laying a foundation for future treatments for SHANK3-related autism.

The study was led by the lab of Prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and the School of Psychological Sciences at Tel Aviv University, in collaboration with the labs of Prof. Ben Maoz from the Department of Biomedical Engineering at Fleischman Faculty of Engineering at Tel Aviv University and Prof. Shani Stern from the Department of Neurobiology at the University of Haifa. The article was published in the prestigious journal Science Advances.

PhD student Inbar Fischer.

Prof. Barak: “Autism is a relatively common neurodevelopmental disorder. According to current data, 1-2% of the global population and one in every 36 boys in the U.S. are diagnosed with autism spectrum disorder (ASD), with numbers rising over time. Autism is caused by a wide range of factors – environmental, genetic, and even social and cultural (such as the rise in parental age at conception). In my lab, we study the genetic causes of autism. Among these are mutations in a gene called SHANK3. The impact of these mutations on the function of brain neurons has been extensively studied, and we know that the protein encoded by SHANK3 plays a central role in binding receptors in the neuron, essential for receiving chemical signals (neurotransmitters and others) by which neurons communicate. Thus, damage to this gene can disrupt message transmission between neurons, impairing the brain’s development and function. In this study we sought to shed light on other, previously unknown mechanisms, through which mutations in the SHANK3 gene disrupt brain development, leading to disorders manifested as autism”.

Specifically, the research team focused on two components in the brain that have not yet been studied extensively in this context: non-neuronal brain cells (glia) called oligodendrocytes and the myelin they produce. Myelin tissue is a fatty layer that insulates nerve fibers (axons), similar to the insulating layer that coats electrical cables. When the myelin is faulty, the electrical signals transmitted through the axons may leak, disrupting the message transmission between brain regions and impairing brain function.

How a Gene Mutation Impacts the Brain

The team employed a genetically engineered mouse model for autism, introducing a mutation in the Shank3 gene that mirrors the mutation found in humans with this form of autism. Inbar Fischer: “Through this model, we found that the mutation causes a dual impairment in the brain’s development and proper function: first, in oligodendrocytes, as in neurons, the SHANK3 protein is essential for the binding and functioning of receptors that receive chemical signals (neurotransmitters and others) from neighboring cells. This means that the defective protein associated with autism disrupts message transmission to these vital support cells. Secondly, when the function and development of oligodendrocytes is impaired, their myelin production is also disrupted. The faulty myelin does not properly insulate the neuron’s axons, thereby reducing the efficiency of electrical signal transmission between brain cells, as well as the synchronization of electrical activity between different parts of the brain. In our model, we found myelin impairment in multiple brain areas and observed that the animals’ behavior was adversely affected as a result”.

The researchers then sought a method for fixing the damage caused by the mutation, with the hope of ultimately developing a treatment for humans. Inbar Fischer: “We obtained oligodendrocytes from the brain of a mouse with a Shank3 mutation, and inserted DNA segments containing the normal human SHANK3 sequence. Our goal was to allow the normal gene to encode a functional and normal protein, which, replacing the defective protein, would perform its essential role in the cell. To our delight, following treatment, the cells expressed the normal SHANK3 protein, enabling the construction of a functional protein substrate to bind the receptors that receive electrical signals. In other words, the genetic treatment we had developed repaired the oligodendrocytes’ communication sites, essential for the cells’ proper development and function as myelin producers”.

To validate findings from the mouse model, the research team generated induced pluripotent stem cells from the skin cells of a girl with autism caused by a SHANK3 gene mutation identical to that in the mice. From these stem cells, they derived human oligodendrocytes with the same genetic profile. These oligodendrocytes displayed impairments similar to those observed in their mouse counterparts.

Autism and Myelin Damage: New Hope for Treatment

Prof. Barak concludes: “In our study, we discovered two new brain mechanisms involved in genetically induced autism: damage to oligodendrocytes and, consequently, damage to the myelin they produce. These findings have important implications – both clinical and scientific. Scientifically, we learned that defective myelin plays a significant role in autism and identified the mechanism causing the damage to myelin. Additionally, we revealed a new role for the SHANK3 protein: building and maintaining a functional binding substrate for receptors critical for message reception in oligodendrocytes (not just in neurons). We discovered that contrary to the prevailing view, these cells play essential roles in their own right, far beyond the support they provide for neurons — often seen as the main players in the brain. In the clinical sphere, we validated a gene therapy approach that led to significantly improved development and function of oligodendrocytes derived from the brains of mice modeling autism. This finding offers hope for developing genetic treatment for humans, which could improve the myelin production process in the brain. Furthermore, recognizing the significance of myelin impairment in autism—whether linked to the SHANK3 gene or not—opens new pathways for understanding the brain mechanisms underlying autism and paves the way for future treatment development”.

Nasal Spray Revolutionizes COVID Protection

Written by Hilary on 21 November 2024. Posted in Newsroom.

Researchers created an affordable, needle-free nasal spray COVID-19 vaccine.

A breakthrough in vaccine development: Prof. Ronit Satchi-Fainaro’s lab at TAU’s Faculty of Medical and Health Sciences collaborated with Professor Helena Florindo’s lab at the University of Lisbon to produce a novel nano-vaccine for COVID-19. The nano-vaccine, a 200-nanometer particle, trains the immune system against all common COVID-19 variants, just as effectively as existing vaccines. Moreover, unlike other vaccines, it is conveniently administered as a nasal spray and does not require a cold supply chain or ultra-cold storage. These unique features pave the way to vaccinating 3rd-world populations, as well as the development of simpler, more effective, and less expensive vaccines in the future. The revolutionary study was featured on the cover of the prestigious journal Advanced Science.

Prof. Ronit Satchi-Fainaro.

Prof. Satchi-Fainaro explains: “The new nano-vaccine’s development was inspired by a decade of research on cancer vaccines. When the COVID-19 pandemic began, we set a new goal: training our cancer platform to identify and target the coronavirus. Unlike Moderna and Pfizer, we did not rely on full protein expression via mRNA. Instead, using our computational bioinformatics tools, we identified two short and simple amino acid sequences in the virus’s protein, synthesized them, and encapsulated them in nanoparticles”. Eventually, this nano-vaccine proved effective against all major variants of COVID-19, including Beta, Delta, Omicron, etc.

“Our nano-vaccine offers a significant advantage over existing vaccines because it is needle-free and administered as a nasal spray,” notes Prof. Satchi-Fainaro. “This eliminates the need for skilled personnel such as nurses and technicians to administer injections, reducing contamination risks and sharp waste. Anyone can use a nasal spray, with no prior training”.

Room-Temperature Storage, Same Effectiveness

Another major advantage of the revolutionary nano-vaccine is its minimal storage requirements. Moderna’s sensitive mRNA-based vaccine must be kept at -20°C and Pfizer’s at -70°C, generating great logistic and technological challenges, such as shipping in special aircraft and ultra-cold storage – from the factory to the vaccination station. Prof. Satchi-Fainaro’s novel synthetic nanoparticles are far more durable and can be stored as a powder at room temperature. “There’s no need for freezing or special handling,” she says. “You just mix the powder with saline to create the spray. For testing purposes, as part of the EU’s ISIDORe (Integrated Services for Infectious Disease Outbreak Research feasibility program), we shipped the powder at room temperature to the INSERM infectious diseases lab in France. Their tests showed that our nano-vaccine is at least as effective as Pfizer’s vaccine”.

These important advantages—ease of nasal administration and regular storage and shipping — pave the way towards vaccinating at-risk populations in low-income countries and remote regions, which existing vaccines are unable to reach. Moreover, the novel platform opens the door for quickly synthesizing even more effective and affordable vaccines for future pandemics. “This is a plug-and-play technology,” explains Prof. Satchi-Fainaro. “It can train the immune system to fight cancer or infectious diseases like COVID-19. We are currently expanding its use to target a range of additional diseases, enabling the rapid development of relevant new vaccines when needed”.

The groundbreaking project has received competitive research grants from the Israel Innovation Authority and Merck under the Nofar program, as well as funding from Spain’s “La Caixa” Foundation Impulse as an accelerated program, and support from the ISIDORe feasibility program. It is also part of a broader vaccine platform development program at Professor Satchi-Fainaro’s lab, supported by a European Research Council (ERC) Advanced Grant.

Is There a Way to Stop Parkinson’s Disease at Its Source?

Written by Hilary on 14 November 2024. Posted in Newsroom.

TAU Researchers discovered a potential new target for developing effective treatments for Parkinson’s disease.

Researchers at Tel Aviv University discovered a new factor in the pathology of Parkinson’s disease, which in the future may serve as a target for developing new treatments for this terrible ailment, affecting close to 10 million people worldwide.

The researchers: “We found that a variant of the TMEM16F protein, caused by a genetic mutation, enhances the spread of Parkinson’s pathology through nerve cells in the brain”.

The study was led by Dr. Avraham Ashkenazi and PhD student Stav Cohen Adiv Mordechai from the Department of Cell and Developmental Biology at TAU’s Faculty of Medical and Health Sciences and the Sagol School of Neuroscience. Other contributors included: Dr. Orly Goldstein, Prof. Avi Orr-Urtreger, Prof. Tanya Gurevich and Prof. Nir Giladi from TAU’s Faculty of Medical and Health Sciences and the Tel Aviv Sourasky Medical Center, as well as other researchers from TAU and the University of Haifa. The study was backed by the Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease at TAU. The paper was published in the scientific journal Aging Cell.

Doctoral student Stav Cohen Adiv Mordechai explains: “A key mechanism of Parkinson’s disease is the aggregation in brain cells of the protein α-synuclein (in the form of Lewy bodies), eventually killing these cells. For many years, researchers have tried to discover how the pathological version of α-synuclein spreads through the brain, affecting one cell after another, and gradually destroying whole brain sections. Since α-synuclein needs to cross the cell membrane to spread, we focused on the protein TMEM16F, a regulator situated in the cell membrane, as a possible driver of this lethal process”.

α-synuclein spread in the mouse brain.

At first, the researchers genetically engineered a mouse model without the TMEM16F gene, and derived neurons from the brains of these mice for an in-vitro cellular model. Using a specially engineered virus, they caused these neurons to express the defective α-synuclein associated with Parkinson’s and compared the results with outcomes from normal brain cells containing TMEM16F. They found that when the TMEM16F gene had been deleted, the α-synuclein pathology spread to fewer healthy neighboring cells compared to the spread from normal cells. The results were validated in-vivo in a living mouse model of Parkinson’s disease.

TMEM16F Mutation Linked to Parkinson’s Risk in Ashkenazi Jews

In addition, in collaboration with the Neurological Institute at the Tel Aviv Sourasky Medical Center, the researchers looked for mutations (variants) in the TMEM16F gene that might increase the risk for Parkinson’s disease. Dr. Ashkenazi explains: “The incidence of Parkinson’s among Ashkenazi Jews is known to be relatively high, and the Institute conducts a vast ongoing genetic study on Ashkenazi Jews who carry genes increasing the risk for the disease. With their help, we were able to identify a specific TMEM16F mutation which is common in Ashkenazi Jews in general, and in Ashkenazi Parkinson’s patients in particular”. Cells carrying the mutation were found to secrete more pathological α-synuclein compared to cells with the normal gene. The researchers explain that the mechanism behind increased secretion has to do with the biological function of the TMEM16F protein: the mutation increases the activity of TMEM16F, thereby affecting membrane secretion processes.

Stav Cohen Adiv Mordechai: “In our study, we discovered a new factor underlying Parkinson’s disease: the protein TMEM16F, which mediates secretion of the pathological α-synuclein protein through the cell membrane to the cell environment. Picked up by healthy neurons nearby, the defective α-synuclein forms Lewy bodies inside them, and gradually spreads through the brain, damaging more and more brain cells. Our findings mark TMEM16F as a possible new target for the development of effective treatments for Parkinson’s disease. If, by inhibiting TMEM16F, we can stop or reduce the secretion of defective α-synuclein from brain cells, we may be able to slow down or even halt the spread of the disease through the brain”.

Dr. Ashkenazi emphasizes that research on the new Parkinson’s mechanism has only begun, and quite a number of questions still remain to be explored: Does inhibiting TMEM16F actually reduce the symptoms of Parkinson’s disease? Does the lipid composition of cell membranes play a part in spreading the disease in the brain? Is there a link between mutations in TMEM16F and the prevalence of Parkinson’s in the population? The research team intends to continue the investigation in these directions and more.

How Does the Brain Keep Calm?

Written by Hilary on 14 November 2024. Posted in Newsroom.

New Insight into Brain Stability: The Key Role of NMDA Receptors

Researchers at Tel Aviv University have made a fundamental discovery: the NMDA receptor (NMDAR)—long studied primarily for its role in learning and memory—also plays a crucial role in stabilizing brain activity. By setting the “baseline” level for activity in neural networks, the NMDAR helps maintain stable brain function amidst continuous environmental and physiological changes. This discovery may lead to innovative treatments for diseases linked to disrupted neural stability, such as depression, Alzheimer’s disease, and epilepsy.

The study was led by Dr. Antonella Ruggiero, Leore Heim, and Dr. Lee Susman from Prof. Inna Slutsky’s lab at the Faculty of Medical and Health Sciences at Tel Aviv University. Prof. Slutsky, who is also affiliated with the Sagol School of Neuroscience, heads the Israeli Society for Neuroscience and directs the Sieratzki Institute for Advances in Neuroscience. Additional researchers included Dr. Ilana Shapira, Dima Hreaky, and Maxim Katsenelson from the Faculty of Medical and Health Sciences at Tel Aviv University, and Prof. Kobi Rosenblum from the University of Haifa. The study was published in the prestigious journal Neuron.

“In recent decades, brain research has mainly focused on processes that allow information encoding, memory, and learning, based on changes in synaptic connections between nerve cells”, says Prof. Slutsky.

“But the brain’s fundamental stability, or homeostasis, is essential to support these processes. In our lab, we explore the mechanisms that maintain this stability, and in this study, we focused on the NMDAR—a receptor known to play a role in learning and memory”, Slutsky continues.

This comprehensive project used three primary research methods: electrophysiological recordings from neurons in both cultured cells (in vitro) and living, behaving mice (in vivo) within the hippocampus, combined with computational modeling (in silico). Each approach provided unique insights into how NMDARs contribute to stability in neural networks.

Dr. Antonella Ruggiero studied NMDAR function in cultured neurons using an innovative technique called “dual perturbation”, developed in Prof. Slutsky’s lab. “First, I exposed neurons to ketamine, a known NMDAR blocker”, she explains. “Typically, neuronal networks recover on their own after disruptions, with activity levels gradually returning to baseline due to active compensatory mechanisms. But when the NMDAR was blocked, activity levels stayed low and didn’t recover. Then, with the NMDAR still blocked, I introduced a second perturbation by blocking another receptor. This time, the activity dropped and recovered as expected, but to a new, lower baseline set by ketamine, not the original level”. This finding reveals the NMDAR as a critical factor in setting and maintaining the activity baseline in neuronal networks. It suggests that NMDAR blockers may impact behavior not only through synaptic plasticity but also by altering homeostatic set points.

Building on this discovery, Dr. Ruggiero sought to uncover the molecular mechanisms behind the NMDAR’s role in tuning the set point. She identified that NMDAR activity enables calcium ions to activate a signaling pathway called eEF2K-BDNF, previously linked to ketamine’s antidepressant effects.

How NMDARs Set the Brain’s Activity Baseline

Leore Heim investigated whether the NMDAR similarly affects baseline activity in the hippocampus of living animals. A major technical challenge was administering an NMDAR blocker directly to the hippocampus without affecting other brain areas, while recording long-term activity at the individual neuron level. “Previous studies often used injections that delivered NMDAR blockers across the entire brain, leading to variable and sometimes contradictory findings,” he explains. “To address this, I developed a method combining direct drug infusion into the hippocampus with long-term neural activity recording in the same region. This technique revealed a consistent decrease in hippocampal activity across states like wakefulness and sleep, with no compensatory recovery as seen with other drugs. This strongly supports that NMDARs set the activity baseline in hippocampal networks in living animals”.

Mathematician Dr. Lee Susman created computational models to answer a longstanding question: Is brain stability maintained at the level of the entire neural network, or does each neuron individually stabilize itself? “Based on the data from Antonella and Leore’s experiments, I found that stability is maintained at the network level, not within single neurons,” he explains. “Using models of neural networks, I showed that averaging activity across many neurons provides computational benefits, including noise reduction and enhanced signal propagation. However, we need to better understand the functional significance of single-neuron drift in future studies”.

Prof. Slutsky adds: “We know that ketamine blocks NMDARs, and in 2008, it was FDA-approved as a rapid-acting treatment for depression. Unlike typical antidepressants like Cipralex and Prozac, ketamine acts immediately by blocking NMDARs. However, until now, it wasn’t fully understood how the drug produced its antidepressant effects. Our findings suggest that ketamine’s actions may stem from this newly discovered role of NMDAR: reducing the activity baseline in overactive brain regions seen in depression, like the lateral habenula, without interfering with homeostatic processes. This discovery could reshape our understanding of depression and pave the way for developing innovative treatments”.

Hyperbaric Oxygen Therapy: A Promising Treatment for PTSD Symptoms

Written by Hilary on 11 November 2024. Posted in Newsroom.

Biological damage in PTSD sufferers can be treated with a specialized protocol.

Researchers at Tel Aviv University and the Sagol Center for Hyperbaric Medicine and Research at the Shamir Medical Center have demonstrated that hyperbaric oxygen therapy (HBOT) improves the condition of PTSD sufferers who have not responded to psychotherapy or psychiatric medications. The researchers: “Our unique therapeutic protocol affects the biological brain ‘wound’ associated with PTSD, and effectively reduces typical symptoms such as flashbacks, hypervigilance, and irritability. We believe that our findings give new hope to millions of PTSD sufferers and their families, all over the world”.

The study was led by Prof. Shai Efrati and Dr. Keren Doenyas-Barak from the Faculty of Medical and Health Sciences at Tel Aviv University and the Sagol Center for Hyperbaric Medicine and Research at the Shamir Medical Center. Other contributors include Dr. Ilan Kutz, Gabriela Levi, Dr. Erez Lang, Dr. Amir Asulin, Dr. Amir Hadanny, and Dr. Ilia Beberashvili from the Shamir Medical Center, and Dr. Kristoffer Aberg and Dr. Avi Mayo from the Weizmann Institute. The paper was published in The Journal of Clinical Psychiatry.

“At present, we treat hundreds of PTSD sufferers every day”

Prof. Efrati: “Due to our unfortunate circumstances, Israel has become a global leader in the field of PTSD. Before the Hamas attack on Oct. 7, 2023, approximately 6,000 IDF veterans had been recognized as PTSD sufferers, with many others, both soldiers and citizens, not yet acknowledged by the authorities. Following Oct. 7 and the ensuing war, these numbers have risen sharply. Tens of thousands of soldiers, and much larger numbers of civilians, are likely to be diagnosed with PTSD. The world-leading Sagol Center for Hyperbaric Medicine, the largest of its kind in the world, is rising to the challenge – with a comprehensive therapeutic array comprising hyperbaric facilities combined with diverse mental health professionals, psychologists and psychiatrists. At present, we treat hundreds of PTSD sufferers every day, aiming to reach one thousand patients per year”.

Dr. Doenyas-Barak: “PTSD (Post-Traumatic Stress Disorder) is defined as the mental outcome of exposure to a life-threatening event. About 20% of those who have undergone such an experience will develop PTSD, which can lead to substantial social, behavioral, and occupational dysfunctions. In extreme cases, the disorder can severely impact their quality of life, family life, and professional performance. Symptoms include a range of emotional and cognitive changes, nightmares and flashbacks, hypervigilance, irritability, and avoidance – so as not to trigger traumatic experiences. In many cases, PTSD is resistant to psychotherapy and common psychiatric medications. Past studies on therapy-resistant sufferers have found changes in the structure and function of brain tissues, or a ‘biological wound’ that explains such treatment resistance. In our study, we wanted to determine whether hyperbaric therapy can help these patients”.

Testing HBOT for PTSD Relief

The study, which began in 2019 and ended in the summer of 2023, included 98 male IDF veterans diagnosed with combat-associated PTSD, who had not responded to either psychotherapy or psychiatric medications. Participants were divided into two groups: one group received HBOT treatment, breathing pure high-pressure oxygen, while the other underwent the same procedure, but received a placebo treatment, breathing regular air. 28 members of each group completed the process and the following evaluation.

Dr. Doenyas-Barak: “The HBOT was administered in accordance with a unique treatment protocol developed at our Center. Every patient is given a series of 60 two-hour treatments in our hyperbaric chamber, during which they are exposed to pure 100% oxygen at a pressure of 2 atmospheres (twice the normal air pressure at sea level). Our protocol specifies alternately breathing oxygen and regular air: every 20 minutes the patient removes the oxygen mask and breathes regular air for five minutes. The drop in oxygen level, at the tissue level, activates healing processes and thus enhances the therapeutic effect”.

Functional MRI before and after HBOT. Photo credit: The Shamir Medical Center.

The results were encouraging, with improvements observed both at the clinical level and in fMRI imaging. The group that received hyperbaric therapy showed improved connectivity in brain networks, alongside a decline in all typical PTSD symptoms. In the placebo group, on the other hand, no change was observed in either the brain or clinical symptoms. Prof. Efrati: “Our study demonstrated that HBOT induces biological healing in the brain of PTSD sufferers. Curing the biological wound also impacts clinical symptoms. We believe that HBOT, based on the special protocol we have developed, can bring relief to numerous PTSD sufferers worldwide, allowing them to resume a normative life in their community and family”.

Prof. Efrati emphasizes:

“Patients suffering from PTSD should undergo HBOT only at professional hyperbaric centers, where treatment is delivered by multidisciplinary teams experienced in trauma care. Unsupervised, private hyperbaric chambers are unable to provide a proven, effective protocol. Additionally, patients must receive a thorough professional evaluation to ensure they are suitable for HBOT and to determine what additional support is needed throughout their treatment journey”.

Israel’s Ministry of Defense funds HBOT for veterans who need it.

TAU Breakthrough Reveals Mechanism That Eliminates Tumors

Written by Hilary on 3 November 2024. Posted in Newsroom.

Researchers identified a mechanism that eliminates tumors—even those resistant to immunotherapy.

A technological breakthrough by medical researchers at Tel Aviv University enabled the discovery of a cancer mechanism that prevents the immune system from attacking tumors. The researchers were surprised to find that reversing this mechanism stimulates the immune system to fight the cancer cells, even in types of cancer considered resistant to prevailing forms of immunotherapy. The breakthrough was led by Prof. Carmit Levy, Prof. Yaron Carmi, and PhD student Avishai Maliah from TAU’s Faculty of Medical and Health Sciences. The paper was published in the leading journal Nature Communications.

Prof. Levy: “It all happened by coincidence. My lab studies both cancer and the effects of ultraviolet (UV) radiation from the sun on our skin and body – both of which are known to suppress the immune system. Cancer suppresses approaching immune cells and solar radiation suppresses the skin’s immune system. While in most cases, we cancer researchers worldwide focus on the tumor and look for mechanisms by which cancer inhibits the immune system, here we proposed a different approach: investigating how UV exposure suppresses the immune system and applying our findings to cancer. The discovery of a mechanism that inhibits the immune system opens new paths for innovative therapies”.

What Surprising Findings Emerged from the Research?

Prof. Levy adds: “With this idea in mind, I asked my colleague Prof. Yaron Carmi, a global expert on the immune system, to join the study. Avishai Maliah, an MD/PhD candidate in my lab, led the project. The first stage was a comprehensive investigation of changes in the skin induced by exposure to UV, using a mouse model. Avishai examined the behavior of dozens of proteins post-UV exposure and surprisingly discovered a significant rise in the level of a relatively unexplored protein called Ly6a. This unexpected finding led us to investigate further, to understand the protein function and whether it is involved in the immune suppression process”.

Prof. Carmi explains: “It’s important to understand a basic aspect of the immune system’s function. Our natural immune system is very efficient and very powerful, but it contains quite a few brakes and controls, to prevent overactivity that can cause autoimmune diseases – in which the body attacks itself. When our skin is exposed to UV radiation from the sun, our immune system responds immediately: blood vessels expand, DNA is repaired wherever possible, and cells with mutations are identified and removed. At the same time, a strong control system with numerous brakes is also activated to prevent overactivity”.

How Does UV Exposure Affect Immune Response?

Prof. Levy: “The use of sunlight to suppress autoimmune diseases of the skin – when the skin’s immune system overreacts – has been known for years. Phototherapy is basically the application of UV radiation to treat patients with autoimmune diseases, such as psoriasis, vitiligo and more, because ultimately UV suppresses the skin’s immune system”.

Avishai Maliah: “We found that after exposure to UV radiation, the immune system’s T cells – that play a critical role in fighting cancer – begin to express high levels of the protein Ly6a. We suspected that Ly6a serves as a brake through which UV inhibits the immune system, and that by releasing this brake, optimal activation of the immune system might be resumed”.

Prof. Levy: “We were surprised to discover that this protein, Ly6a, is also overexpressed in cancer tumors – apparently inhibiting T cells. Having found this in two types of cancer, melanoma skin cancer and colon cancer, we have reason to believe that the same thing happens in other cancers as well. Evidently, we have discovered a general mechanism through which cancer tumors desensitize the immune system. Avishai treated cancer with Ly6a antibodies, and amazingly the tumors were significantly reduced. Moreover, cancers resistant to known treatments reacted substantially to Ly6a antibodies”. The new discovery can have practical implications in immunotherapy – treating cancer by enhancing the response of the immune system.

Prof. Carmi: “Immunotherapy has revolutionized the treatment of cancer. However, about 50% of the patients do not respond to the currently prevailing treatment – the protein PD1. We discovered a new protein, Ly6a, and found that its antibody eradicated tumors in our model animals – even those resistant to PD1 therapy. We are currently working to translate our findings into a drug for human cancer patients, hoping to offer an effective new treatment”.