Tag: Medicine

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”.

Could Cancer Vulnerabilities Be Hidden in Chromosome Changes?

Written by AUFTAU on 23 September 2024. Posted in Newsroom.

Two complementary studies from the Faculty of Medical and Health Sciences at Tel Aviv University, in collaboration with the European Institute of Oncology in Milan, have extensively examined the characteristics of cells with an abnormal number of chromosomes – known as aneuploid cells – and raised findings that may advance new cancer treatments.

Targeting Aneuploid Cancer Cells

According to the researchers: “a significant portion of cancer cells are aneuploid, and this trait distinguishes them from healthy cells. Our work focuses on the vulnerabilities of aneuploid cells, with the aim of promoting new strategies for eliminating cancerous tumors”.

The researchers: “In our studies, we found that aneuploidy increases the sensitivity of cancer cells to certain types of anticancer drugs”.

The studies were led by Prof. Uri Ben-David and doctoral student Johanna Zerbib from the Department of Human Molecular Genetics and Biochemistry at the Faculty of Medical and Health Sciences at Tel Aviv University, in collaboration with Professor Stefano Santaguida and doctoral student Marica Rosaria Ippolito from the University of Milan in Italy, along with researchers from both laboratories. Additional contributors included research teams in Israel, Italy, the USA, and Germany. Two articles based on the research were published in the prestigious journals Cancer Discovery and Nature Communications.

Prof. Ben-David explains: “In the nucleus of a healthy human cell, there are 23 pairs of chromosomes – half from the father and half from the mother, totaling 46. One of the characteristics of cancer cells, which distinguishes them from healthy cells, is an abnormal number of chromosomes, resulting from improper cell division – a phenomenon known as aneuploidy. We believe that if we can identify specific vulnerabilities of aneuploid cells, we can promote new cancer treatments that target these weaknesses and do not harm healthy cells. About three years ago, we published a comprehensive study in the journal Nature, in which we classified approximately 2,000 malignant cells from various cancer types according to their level of aneuploidy, and examined how they respond to various existing treatments. In that study, we found new vulnerabilities in aneuploid cells. However, the study had a limitation: because the cells came from different types of cancer, it was difficult to isolate the impact of aneuploidy itself from the effect of other genetic differences between the tumors”.

Consequently, the researchers chose to conduct a new study using human cell cultures that are all genetically identical (i.e., derived from the same individual). The researchers added a substance to the cultures that disrupts the separation of chromosomes, causing some of them to become aneuploid. Since the cells were genetically identical, the only difference between them after the procedure was the level of aneuploidy – i.e., the number of chromosomes. To thoroughly examine the effects of aneuploidy, the cells underwent various characterization processes: DNA and RNA sequencing, measuring the levels of all the proteins in the cell, assessing the response to 6,000 different drugs, as well as a process known as CRISPR screening – systematically impairing each gene in the genome to identify genes that are essential in the cells. The researchers noted: “In this way, an extensive and unique database of the characteristics of aneuploid cells was established, which can serve as a foundation for future studies, as well as for developing biological markers that predict cancer patients’ responses to specific drugs and treatments”.

How to Exploit Cell Vulnerabilities for Cancer Therapy?

As part of the comprehensive survey, a mechanism called MAPK (mitogen-activated protein kinase) was observed, which is especially crucial for repairing DNA damage in aneuploid cells. The study also showed that this mechanism is relevant for various types of aneuploid cells—among them cancer cells in cultures and in human tumors. Prof. Ben-David: “We found that aneuploid cancer cells increase the activity of DNA repair mechanisms due to the large amount of DNA damage present; and we discovered a mechanism that could allow us to exploit this characteristic to target these cancer cells”.

To test their hypothesis, the researchers disrupted the MAPK pathway in the cells and then examined their sensitivity to chemotherapy. The findings were promising: aneuploid cells in which this mechanism was disrupted were much more sensitive to chemotherapy (which causes DNA damage) compared to cells with a normal number of chromosomes. The researchers then sought to determine whether there is a correlation between this pathway and the clinical response of cancer patients to chemotherapy treatments. For this purpose, they relied on data from clinical treatments and experiments where human tumors were implanted in mice, and the results were clear: the higher the activity of the pathway in the aneuploid tumors, the greater their resistance to chemotherapy.

The comprehensive characterization of aneuploid cells also revealed another significant finding: these cells, which contain more chromosomes than normal cells, also necessarily include a larger amount of DNA, leading to excess production of RNA and proteins. The cell, seeking to compensate for this overproduction, attempts to silence and degrade excess RNA and proteins.

Paving the Way for Future Treatments

Johanna Zerbib noted: “Here we found another vulnerability of aneuploid cells, based on our hypothesis that these cells are more sensitive to existing drugs that inhibit protein degradation. To validate this hypothesis, we exposed cell cultures to such drugs and analyzed clinical data from patients treated with a drug that inhibits protein degradation in the cells. The findings supported the hypothesis – that aneuploidy increases the sensitivity of cancer cells to these drugs”.

Prof. Ben-David concluded: “In our research, we identified two significant vulnerabilities characterizing aneuploid cells – cells with chromosomal changes, commonly found in cancer cells. The first is a mechanism essential for repairing DNA damage, where impairment significantly increases the sensitivity of aneuploid cells to chemotherapy; the second is the increased degradation of excess RNA and proteins, which can be targeted, among other things, with inhibitors that are already in clinical use. We also created an extensive database of characteristics of aneuploid cells that can serve to predict cancer patients’ responses to various drugs and treatments. We believe that our research findings will benefit many researchers, oncologists, and patients in the years to come”.

Spotting Parkinson’s Early: A New TAU Breakthrough

Written by AUFTAU on 17 September 2024. Posted in Newsroom.

Researchers at Tel Aviv University cooperated with three major Israeli medical centers to develop a new method for detecting protein aggregation in cells – a hallmark of Parkinson’s disease. The technology can enable diagnosis up to 20 years before the first motor symptoms appear, facilitating treatment or even prevention of the severe disease which is currently incurable. The novel approach is based on super-resolution microscopy combined with computational analysis, allowing for precise mapping of the aggregates’ molecules and structures. The researchers: “Our method can be used to identify early signs and enable preventive treatment in young people at risk for developing Parkinson’s later on in their lives. In the future, the technology may also be adapted for early diagnosis of other neurodegenerative diseases, including Alzheimer’s”.

The study was piloted by researchers from the School of Neurobiology, Biochemistry & Biophysics at the Wise Faculty of Life Sciences, the Sagol School of Neuroscience and the Faculty of Medical and Health Sciences at Tel Aviv University, led by Prof. Uri Ashery and PhD candidate Ofir Sade. Other participants included: Prof. Anat Mirelman, Prof. Avner Thaler, Prof. Nir Giladi, Prof. Roy Alcalay, Prof. Sharon Hassin, Prof. Nirit Lev, Dr. Irit Gottfried, Dr. Dana Bar-On, Dr. Meir Kestenbaum, Dr. Saar Anis, Dr. Shimon Shahar, Daphna Fischel, Dr. Noa Barak-Broner, Shir Halevi, and Dr. Aviv Gour – all from Tel Aviv University, with some also affiliated with the Tel Aviv Sourasky (Ichilov), Sheba, or Meir Medical Centers. Researchers from Germany and the USA also contributed to the study. The paper was published in Frontiers in Molecular Neuroscience.

Spotting Parkinson’s Before Symptoms Appear

Prof. Ashery: “Parkinson’s disease is the second most prevalent neurodegenerative disease in the world after Alzheimer’s – with about 8.5 million people with Parkinson’s living worldwide today, and 1,200 new sufferers diagnosed annually in Israel. The debilitating disease is characterized by the destruction of dopaminergic (dopamine-producing) neurons in the brain’s Substantia Nigra area. Today, diagnosis of Parkinson’s disease is based mainly on clinical symptoms such as tremors or gait dysfunctions, alongside relevant questionnaires. However, these symptoms usually appear at a relatively advanced stage of the disease, when over 50% and up to 80% of the dopaminergic neurons in the Substantia Nigra are already dead. Consequently, available treatments are quite limited in their effect and usually address only motor problems. In this study, we began to develop a research tool to enable diagnosis of Parkinson’s at a much earlier stage, when it is still treatable, and deterioration can be prevented”.

Ofir Sade: “One known feature of Parkinson’s is cell death resulting from aggregates of the alpha-synuclein protein. The protein begins to aggregate about 15 years before symptoms appear, and cells begin to die 5-10 years before diagnosis is possible with the means available today. This means that we have an extensive time window of up to 20 years for diagnosis and prevention before symptoms appear. If we can identify the process at an early stage, in people who are 30, 40, or 50 years old, we may be able to prevent further protein aggregation and cell death”. Past studies have shown that alpha-synuclein aggregates form in other parts of the body as well, such as the skin and digestive system. In the current work, the researchers examined skin biopsies from 7 people with and 7 without Parkinson’s disease, received from the Sheba, Ichilov, and Meir Medical Centers.

She continues: “We examined the samples under a unique microscope, applying an innovative technique called super-resolution imaging, combined with advanced computational analysis – enabling us to map the aggregates and distribution of alpha-synuclein molecules. As expected, we found more protein aggregates in people with Parkinson’s compared to people without the disease. We also identified damage to nerve cells in the skin, in areas with a large concentration of the pathological protein”.

Parkinson’s Detection Boosted by AI

With proof of concept obtained through the study, the researchers now plan to expand their work, supported by the Michael J. Fox Foundation for Parkinson’s Research. In the next phase, they will increase the number of samples to 90 – 45 from healthy subjects and 45 from people without Parkinson’s disease – to identify differences between the two groups. Ofir Sade: “We intend to pinpoint the exact juncture at which a normal quantity of proteins turns into a pathological aggregate. In addition, we will collaborate with Prof. Lior Wolf of TAU’s School of Computer Science to develop a machine learning algorithm that will identify correlations between the results of motor and cognitive tests and our findings under the microscope. Using this algorithm, we will be able to predict the future development and severity of various pathologies”.

Prof. Ashery: “In this study, we identified differences between tissues taken from people with and without Parkinson’s disease, using super-resolution microscopy and computational analysis. In future studies, we will increase the number of samples and develop a machine-learning algorithm to spot relatively young individuals at risk for Parkinson’s. Our main target population is relatives of Parkinson’s patients who carry mutations that increase the risk for the disease. Specifically, we emphasize two mutations known to be widespread among Ashkenazi Jews. A clinical trial is already underway to test a drug expected to hinder the formation of the aggregates that cause Parkinson’s disease. We hope that in the coming years, it will be possible to offer preventive treatments while tracking the effects of medications under the microscope. It is important to note that the method we’ve developed can also be suitable for early diagnosis of other neurodegenerative diseases associated with protein aggregates in neurons, including Alzheimer’s”.

How Can We See Through Closed Eyes?

Written by AUFTAU on 16 September 2024. Posted in Newsroom.

Tel Aviv University tech tracks pupil changes in sleep and anesthesia.

A new technological development allows for the first time to monitor changes in pupil size and gaze direction behind closed eyes using touchless infrared imaging. In the future, tracking changes in pupil size will help identify a state of wakefulness in sleep, anesthesia, and intensive care and help track the depth of sedation, detect seizures and nightmares, and recognize pain or responsiveness that may occur after trauma and in intensive care departments. The investigators anticipate that this technology has strong potential to become an important tool in clinical care.

The breakthrough was achieved by a team of investigators from Tel Aviv University led by doctoral student Omer Ben Barak-Dror, under the joint supervision of Prof. Yuval Nir from the Department of Physiology and Pharmacology, Faculty of Medical and Health Sciences, Sagol School of Neuroscience, and the Department of Biomedical Engineering; and Prof. Israel Gannot from the Department of Biomedical Engineering. Other team members include Dr. Michal Tepper, Dr. Barak Hadad, Dr. Hani Barhum, and David Haggiag. The research was published in the journal Communications Medicine.

An Eye-Opening Discovery

Prof. Nir explains: “It is often said that the eyes are the windows to the soul”. Indeed, pupil size changes constantly, dilating or contracting to regulate the amount of incoming light, while providing valuable clinical information. We all know that our pupils get smaller in bright light and larger in darkness, but this is only one reason why pupils change size. They also dilate when we’re stimulated, for example when we react to a sudden event or when we are in pain. In such cases, our autonomic nervous system serves as an alarm and prepares us to take action. Tracking pupil size and eye movements can be critical in many clinical situations. However, until now this has been limited to open-eye scenarios. No method allowed anyone to do this when their eyes were closed.

The new research describes innovative technology that combines short-wave infrared (SWIR) imaging with deep learning algorithms to perform touchless pupillometry and eye tracking behind closed eyelids. “To establish and validate our technology, we focused on the pupillary light reflex (PLR) when the pupil constricts in response to a sudden flash of light, and then dilates back to normal. This is a basic reflex that occurs symmetrically across the two eyes in healthy people. We performed experiments testing our technology on the closed eye while comparing the results to the open-eye data,” said Omer Ben Barak-Dror, lead author of the study at Tel Aviv University.

Eye Spy: Monitoring Pupils While You Sleep

Profs. Nir and Gannot add: “Our method can successfully track the precise dynamics of the pupillary light reflex in closed-eye conditions, revealing the changes in pupil size following each light flash in individual subjects, and also accurately estimating where the eye gaze is directed to, within a few degrees accuracy. The system operates at wavelengths where light has its maximum depth of penetration in biological tissue, and by analyzing the data using deep learning algorithms, we can go beyond what is typically possible with standard methods of near-infrared imaging”. Dr. Tepper adds that the information collected using continuous touchless monitoring is a critical element of the patient’s electronic medical record (EMR) and helps with decisions concerning optimal medical treatment.

The investigators concluded: “Our technology, backed by a patent application, paves the way for developing devices with wide-ranging clinical and commercial applications in domains ranging from sleep medicine, through monitoring sedation level and intraoperative awareness in anesthesia, to assessing pain and reactivity in unresponsive patients or neurology intensive care and trauma wards”.

The study was supported by grants from the Zimin Foundation and the breakthrough technology program of the Israeli Ministry of Science and Technology.

Can Parkinson’s Treatment be Enhanced by AI Tech?

Written by AUFTAU on 1 September 2024. Posted in Newsroom.

Researchers at TAU’s Faculty of Medical & Health Sciences invited the international community of machine learning researchers to participate in a contest devised to advance their study and assist neurologists: developing a machine learning model to support a wearable sensor for continuous, automated monitoring and quantification of FOG (freezing of gate) episodes in people with Parkinson’s disease. Close to 25,000 solutions were submitted, and the best algorithms were incorporated into the novel technology.

The study was led by Prof. Jeff Hausdorff from the Department of Physical Therapy at the Faculty of Medical & Health Sciences and the Sagol School of Neuroscience at Tel Aviv University, and the Center for the Study of Movement, Cognition, and Mobility at the Tel Aviv Medical Center, together with Amit Salomon and Eran Gazit from the Tel Aviv Medical Center. Other investigators included researchers from Belgium, France, and Harvard University. The paper was published in Nature Communications and featured in the Editors’ Highlights.

Prof. Hausdorff, an expert in the fields of gait, aging, and Parkinson’s disease, explains: “FOG is a debilitating and so far unexplained phenomenon, affecting 38-65% of Parkinson’s sufferers. A FOG episode can last from a few seconds to more than a minute, during which the patient’s feet are suddenly ‘glued’ to the floor, and the person cannot begin or continue walking. FOG can seriously impair the mobility, independence, and quality of life of people with Parkinson’s disease, causing great frustration, and frequently leading to falls and injuries”.

Amit Salomon adds: “Today the diagnosis and tracking of FOG are usually based on self-report questionnaires and visual observation by clinicians, as well as frame-by-frame analysis of videos of patients in motion. This last method, currently the prevailing gold standard, is reliable and accurate. Still, it has some serious drawbacks: it is time-consuming, requires the involvement of at least two experts, and is impracticable for long-term monitoring in the home and daily living environment. Researchers worldwide are trying to use wearable sensors to track and quantify patients’ daily functioning. So far, however, successful trials have all relied on a very small number of subjects”.

TAU’s AI Challenge Advances FOG Tracking

In the current study, the researchers collected data from several existing studies, relating to over 100 patients and about 5,000 FOG episodes. All data were uploaded to the Kaggle platform, a Google company that conducts international machine learning competitions. Members of the worldwide machine learning community were invited to develop models that would be incorporated into wearable sensors to quantify various FOG parameters (e.g. duration, frequency, and severity of episodes). A prize of $100,000, funded by Kaggle and the Michael J. Fox Foundation for Parkinson’s Research, was offered for the best solutions. 1,379 groups from 83 countries rose to the challenge, ultimately submitting a total of 24,862 solutions. The results of the best models were very close to those obtained through the video analysis method, and significantly better than previous experiments relying on a single wearable sensor.

Moreover, the models led to a discovery: an interesting relationship between FOG frequency and the time of day. Co-author Eran Gazit notes: “We observed, for the first time, a recurring daily pattern, with peaks of FOG episodes at certain hours of the day, that may be associated with clinical phenomena such as fatigue, or effects of medications. These findings are significant for both clinical treatment and continued research about FOG”.

Prof. Hausdorff: “Wearable sensors supported by machine learning models can continuously monitor and quantify FOG episodes, as well as the patient’s general functioning in daily life. This gives the clinician an accurate picture of the patient’s condition at all times: has the illness improved or deteriorated? Does it respond to prescribed drugs? The informed clinician can respond promptly, while data collected through this technology can support the development of new treatments. In addition, our study demonstrates the power of machine learning contests in advancing medical research. The contest we initiated brought together capable, dynamic teams all over the world, who enjoyed a friendly atmosphere of learning and competition for a good cause. Rapid improvement was gained in the effective and precise quantification of FOG data. Moreover, the study laid the foundations for the next stage: long-term 24/7 FOG monitoring in the patient’s home and real-world environment”.

Tag: Medicine

Is Treatment for Genetic Autism on the Horizon?