Tag: Medicine

Stress Makes Vaccines Less Effective

Written by AUFTAU on 26 July 2023. Posted in Newsroom.

Researchers at Tel Aviv University demonstrated for the first time that there is a significant link between behavioral stress and the effectiveness of vaccines. They found that acute stress in lab models 9-12 days after vaccination increases antibody response to the vaccine by 70% compared to the unstressed control group. This, however, comes at the price of reduced antibody breadth, which results in diminished protection against the pathogen’s variants.

“Our study was the first to investigate the possible effects of acute stress. We found that this mental state has a dramatic impact – not only on the vaccine’s effectiveness, but also on how it works.” – Dr. Natalia Freund

The “Dramatic Impact” of Stress

The study was carried out in Tel Aviv University and led by Ph.D. student Noam Ben-Shalom from the lab of Dr. Natalia Freund at the Faculty of Medicine and Ph.D. student Elad Sandbank from the Neuro-immunology Lab of Prof. Shamgar Ben-Eliyahu at The School of Psychological Sciences and the Sagol School of Neuroscience. The paper was published on July 6th in the leading scientific journal Brain, Behavior, and Immunity.

Dr. Freund explains: “In this study we examined, for the first time, the correlation between stress and the body’s ability to develop an immune response following vaccination. The prevailing assumption is that the effectiveness of a vaccine is determined mainly by its own quality. However, over the years, professional literature has reported influences of other factors as well, such as the age, genetics, and microbiome of the outcomes of vaccination. Our study was the first to investigate the possible effects of acute stress. We found that this mental state has a dramatic impact – not only on the vaccine’s effectiveness, but also on how it works.”

Classical ‘Fight or Flight’ Response

Acute stress is a mental state caused by immediate threat (either real or imagined), involving the secretion of adrenaline and stimulation. In this study, Dr. Freund and her colleagues vaccinated mice with two different vaccines: the model protein Ovalbumin and a fragment of the SARS-CoV-2 spike protein also used in the COVID-19 vaccine. Nine days later, just as the adaptive immunity became active and the production of antibodies began, the mice were subjected to a widely used behavioral paradigm simulating acute stress. Two and a half weeks after exposure to stress, namely 30 days after vaccination, the level of antibodies in the blood of vaccinated animals that had experienced stress was 70% higher compared to the control group. This phenomenon was observed in animals vaccinated with either type of vaccine.

At the same time, the researchers discovered that the immune system of the animals that had experienced stress was not cross reactive to variants of the protein used in the vaccine. In other words, following stress the immune system was focused entirely on the original vaccine, showing no response to proteins that were only slightly different – such as variants of concern (VOC) of SARS-CoV-2.

Dr. Natalia Freund

“In general, the purpose of vaccination is not only protection against a specific pathogen, but also creating a long-lasting immunological memory for protection against future mutations of that pathogen.” – Dr. Natalia Freund

“Initially, we were surprised to find out that the response to the vaccine was much more effective in animals that had experienced stress,” says Dr. Freund, “we would have assumed just the opposite – that stressful situations would have a negative impact on the immune system. Nevertheless, with both types of vaccines, we observed a stronger immune response after stress, both in the blood and in B cells (the lymphocytes that produce antibodies) derived from the spleen and lymph nodes of the immunized mice. The enhancement of the antibodies’ activity following stress was mediated by the cellular receptor that identifies adrenaline – the beta2 adrenergic receptor. When we blocked this receptor, either pharmacologically or by means of genetic engineering, the effects of stress were completely eliminated. On the other hand, to our great surprise, the breadth of the immune response generated by the vaccine was reduced by about 50% following stress. In general, the purpose of vaccination is not only protection against a specific pathogen, but also creating a long-lasting immunological memory for protection against future mutations of that pathogen. In this sense, the vaccines appeared to lose much of their effectiveness after exposure to stress.”

According to the researchers, this is in fact a classical ‘fight or flight’ response, however this time demonstrated at the molecular level. During stress, the immune system produces large quantities of antibodies and stronger antibodies, to address the immediate infection, and this large energetic investment in the here and now comes at the expense of future immunological memory.

Does It Apply to Humans?

Dr. Freund adds: “In the second part of the study we wanted to test whether humans also display the post-stress immune impairment observed in vaccinated mice. For this purpose, we cultured B cells obtained from blood of people who had contracted COVID-19 in the first wave. We then induced stress in these cultures using an adrenaline-like substance that stimulates the beta2 adrenergic receptor, that was identified by us in the first part of the study as a mediator of the response to stress in cells that produce antibodies in mice. B cells express a very high level of these receptors, but until now the receptors’ role in producing antibodies was not known. In fact, it was unclear why these cells need the ability to respond to adrenaline.”

“We discovered that just like in mice, human cells also exhibit a zero-sum game between the intensity and breadth of the immune response. When the adrenaline receptor is activated during stress, the entire immune system is stimulated, generating antibodies that are 100-fold stronger than antibodies produced in cells that had not undergone stress. But here too, the response was narrower: the diversity of antibodies was reduced by 20-100%, depending on the individual from whom the cells were taken.

“Stress 9 to 12 days after vaccination, at the time when B cells are generating high affinity antibodies, enhances short-term immunity and damages long-term memory.” – Dr. Natalia Freund

RNA sequencing of the cells in which the beta 2 adrenergic receptor was activated, compared to regular cells, indicated that the receptor’s activation caused antibody-producing cells to work at maximum capacity (by activating the PI3 kinase protein and phosphorylation of AKT) – at the expense of antibody breadth and diversity.”

“From the evolutionary perspective,” concludes Dr. Freund, “stress can be caused by different factors. We tend to think of mental stress, but physical illness also causes a form of stress. When the body contracts a virus or bacteria it experiences stress, and signals to the immune system that the top priority is getting rid of the pathogen, while investing energy in long-term immunological memory is a second priority. Therefore, stress 9 to 12 days after vaccination, at the time when B cells are generating high affinity antibodies, enhances short-term immunity and damages long-term memory.”

Researchers Induce Cancer Cell “Suicide”

Written by AUFTAU on 17 July 2023. Posted in Newsroom.

For the first time in the world: researchers at Tel Aviv University encoded a toxin produced by bacteria into mRNA (messenger RNA) molecules and delivered these particles directly to cancer cells, causing the cells to produce the toxin – which eventually killed them with a success rate of 50%.

“Our idea was to deliver safe mRNA molecules encoded for a bacterial toxin directly to the cancer cells – inducing these cells to actually produce the toxic protein that would later kill them. It’s like placing a Trojan horse inside the cancer cell.” – Prof. Dan Peer

“It’s like placing a Trojan horse inside the cancer cell”

The groundbreaking study was led by PhD student Yasmin Granot-Matok and Prof. Dan Peer, a pioneer in the development of RNA therapeutics and Head of the Nanomedicine Laboratory at The Shmunis School of Biomedicine and Cancer Research, also serving as TAU’s VP R&D. The study’s results were published in Theranostics.

Prof. Peer explains: “Many bacteria secrete toxins. The most famous of these is probably the botulinum toxin injected in Botox treatments. Another classic treatment technique is chemotherapy, involving the delivery of small molecules through the bloodstream to effectively kill cancer cells. However, chemotherapy has a major downside: it is not selective, and also kills healthy cells. Our idea was to deliver safe mRNA molecules encoded for a bacterial toxin directly to the cancer cells – inducing these cells to actually produce the toxic protein that would later kill them. It’s like placing a Trojan horse inside the cancer cell.”

Prof. Dan Peer

Impressive Results

First, the research team encoded the genetic info of the toxic protein produced by bacteria of the pseudomonas family into mRNA molecules (resembling the procedure in which genetic info of COVID-19’s ‘spike’ protein was encoded into mRNA molecules to create the vaccine). The mRNA molecules were then packaged in lipid nanoparticles developed in Prof. Peer’s laboratory and coated with antibodies – to make sure that the instructions for producing the toxin would reach their target, the cancer cells. The particles were injected into the tumors of animal models with melanoma skin cancer. After a single injection, 44-60% of the cancer cells vanished.

“With a simple injection to the tumor bed, we can cause cancer cells to ‘commit suicide’, without damaging healthy cells. Moreover, cancer cells cannot develop resistance to our technology as often happens with chemotherapy – because we can always use a different natural toxin.” – Prof. Dan Peer

“In our study, the cancer cell produced the toxic protein that eventually killed it,” says Prof. Peer. “We used pseudomonas bacteria and the melanoma cancer, but this was only a matter of convenience. Many anaerobic bacteria, especially those that live in the ground, secrete toxins, and most of these toxins can probably be used with our method. This is our ‘recipe’, and we know how to deliver it directly to the target cells with our nanoparticles. When the cancer cell reads the ‘recipe’ at the other end it starts to produce the toxin as if it were the bacteria itself and this self-produced toxin eventually kills it. Thus, with a simple injection to the tumor bed, we can cause cancer cells to ‘commit suicide’, without damaging healthy cells. Moreover, cancer cells cannot develop resistance to our technology as often happens with chemotherapy – because we can always use a different natural toxin.”

Other contributors to the study included: Dr. Assaf Ezra, Dr. Srinivas Ramishetti, Dr. Preeti Sharma Dr. Gonna Somu Naidu and Prof. Itai Benhar, Head of the Antibody Engineering Lab at the Shmunis School of Biomedicine and Cancer Research at TAU. The study was funded by the Shmunis Family Foundation for Biomedicine and Cancer Research.

Metabolomics – A New Frontier in Preventive Medicine

Written by AUFTAU on 13 July 2023. Posted in Newsroom.

Tel Aviv University’s new Metabolite Medicine Division at the BLAVATNIK Center for Drug Discovery poised to revolutionize the field.

Even the simplest blood tests of today – which monitor about 20 substances in our body – have powerful predictive and diagnostic power. For example, high cholesterol suggests possible heart trouble, and abnormal glucose could indicate pre-diabetes.

Now imagine that routine and low-cost bloodwork could check for thousands of compounds all at once, as well as calculate the balance between them. Such a real-time status check would provide doctors with unparalleled knowledge for diagnosing patients and creating personalized profiles for the most effective treatment of disease.

“Metabolomics is poised to revolutionize the field of preventive medicine. It holds tremendous potential (…) not only for detecting diseases but also for enabling individuals to proactively monitor their overall physiological well-being even before the onset of illness.” – Prof. Ehud Gazit

The Super Blood Test

We are entering such an era at TAU’s new Metabolite Medicine Division at the BLAVATNIK CENTER for Drug Discovery. This suite of labs is the most advanced at an Israeli university for the emerging science of metabolomics – the study of small molecules called metabolites that our bodies produce every second of our lives as part of ongoing cell processes. Sometimes, all that is required is to identify the one metabolite culprit that is throwing the body off balance.

“Metabolomics is poised to revolutionize the field of preventive medicine. It holds tremendous potential as a cornerstone and indispensable tool, not only for detecting diseases but also for enabling individuals to proactively monitor their overall physiological well-being even before the onset of illness,” explains Prof. Ehud Gazit, the Founding Director of the Metabolomic Medicine division.

“Unlike genetics, which cannot be easily altered, the composition of metabolites provides a valuable reflection of the body’s physiological state, making it possible to optimize towards an ideal state through dietary interventions, physical activity, and lifestyle modifications,” he says.

“The establishment of the Metabolite Medicine division at the BLAVATNIK CENTER for Drug Discovery is highly important for the entire biomed framework of Tel Aviv University.” – Dr. Ludmila Bozhansky

Driving Real-Life Implementation

Using state-of-the-art equipment, scientists will be able to identify specific metabolic signatures in laboratory and patient cell culture samples, learn about their mechanisms of action, and develop AI-aided data analysis tools. The ultimate aim of the Metabolite Division is to connect promising university discoveries with Israeli hospitals for clinical samples and testing, and with the pharma industry for creating or repurposing drugs.

“The establishment of the Metabolite Medicine division at the BLAVATNIK CENTER for Drug Discovery is highly important for the entire biomed framework of Tel Aviv University,” says Dr. Ludmila Buzhansky, the Managing Director of the BLAVATNIk Center for Drug Discovery. “By leveraging the capabilities of metabolomics and benefiting from the exceptional expertise now available at TAU in this field, our researchers develop interdisciplinary collaborations that drive innovation and knowledge dissemination across diverse domains within the university community and beyond.”

Source: TAU Review

Older Bats do Suffer from Age-related Hearing Loss

Written by AUFTAU on 13 July 2023. Posted in Newsroom.

A new study from Tel Aviv University disproves the prevailing scientific assumption that bats are immune to age-related hearing loss. This assumption led researchers to mistakenly believe that because hearing is so critical to the bats’ echolocation system, they preserve a good hearing ability, enabling orientation even at an advanced age.

“Turn left at the next tree! Hey, did you catch that??”

In the present study the researchers found that the bats’ sense of hearing does in fact deteriorate with age, but at a relatively slow rate – compared to humans and other mammals. Since they live in very noisy colonies, where more rapid hearing loss might have been expected, the researchers hypothesize that the bats may have developed special adaptations that slow down the process.

The study was led by PhD student Yifat Tarnovsky from the laboratory of neuro-ecologist Prof. Yossi Yovel of the School of Zoology at The George S. Wise Faculty of Life Sciences, Head of TAU’s Sagol School of Neuroscience, in collaboration with Prof. Karen Avraham, Dean of TAU’s Faculty of Medicine, Dr. Shahar Taiber from her lab and Prof. Jerry Wilkinson from the University of Maryland. The paper was published in Life Science Alliance.

Prof. Yovel explains that the ability to discern high frequencies is critical for the survival of bats, which rely on it to orient themselves in their surroundings. However, to date no study has systematically examined the effects of aging on hearing in bats.

The researchers used DNA methylation accumulation to assess the age of 47 wild Egyptian fruit bats (Rousettus aegyptiacus), and then tested their hearing by monitoring auditory brainstem responses to sounds of varying frequency and intensity. The recordings clearly indicated age-related hearing loss, and just like in humans, this deterioration was more marked in the higher frequencies. The rate of deterioration was found to be similar to hearing loss observed in aging humans.

Prof. Yossi Yovel with two winged friends

Additional tests showed that like in humans, hearing loss in bats is related to the structure and function of the cochlea, alongside slower processing by the auditory nerve. Tarnovsky explains: “In humans, this last symptom can affect speech comprehension. In older bats it can be detrimental to echolocation. The Egyptian fruit bats we studied rely on echolocation to perform various tasks, but whenever possible they also rely substantially on eyesight. Therefore, our tests should be replicated in bats with poor eyesight, that rely almost exclusively on echolocation to orient themselves.”

New Discoveries About the Process of Hearing Loss

The researchers assume that one cause of hearing loss in Egyptian fruit bats could be cumulative exposure to high noise levels in their environment. Like many other bat species, Egyptian fruit bats live in large colonies and use loud and frequent social vocalizations to communicate. By placing several microphones inside the fruit bats’ cave, Tarnovsky and her colleagues discovered that the bats are frequently exposed to a sound intensity of over 100 dB, equal to that of a motorcycle or power saw. Surprisingly, the loudest noise was found in low frequencies, while the tests indicated that hearing loss occurs mostly in high frequencies.

“The relatively slow rate of age-related hearing loss (similar to the rate in humans) despite lifelong exposure to very high noise levels may indicate that bats have developed special adaptations for coping with their noisy surroundings,” says Prof. Yovel. The researchers hope that understanding these adaptations can provide new insights about the mechanisms of age-related hearing loss in humans.

Operation Guardian of the Walls: Women, Young People and Residents of the South Paid the Heaviest Price

Written by AUFTAU on 12 July 2023. Posted in Newsroom.

During Operation Guardian of the Walls, which took place in May 2021, researchers from Tel Aviv University carried out a groundbreaking study by equipping Israelis with smartwatches and a dedicated mobile application. The study aimed to examine the impact of the operation on the well-being of citizens by monitoring various objective and subjective indicators. The findings revealed that residents of Israel’s southern region suffered significantly more than the rest of the population.

Assessing Impacts, as well as Resilience

The innovative study was conducted by a team of researchers from Tel Aviv University: Prof. Erez Shmueli, Prof. Dan Yamin, and Ph.D. students Merav Mofaz and Matan Yechezkel of The Iby and Aladar Fleischman Faculty of Engineering; Prof. Noga Kronfeld-Schor of The George S. Wise Faculty of Life Sciences; and Prof. Haim Einat of the Academic College of Tel Aviv-Yafo. The findings of the groundbreaking study were published in the journal Communication Medicine from the Nature group.

According to Prof. Erez Shmueli, the study was part of a broader initiative called PerMed (Personalized Medicine), aimed at early diagnosis of infectious diseases like COVID-19. However, the timing of Operation Guardian of the Walls presented a unique opportunity to examine the physiological and mental changes experienced by civilians during wartime.

By May 2021, the researchers had enrolled 954 Israelis in the experiment, equipping them with smartwatches to assess the impact of the war on the home front. The data collected from the smartwatches and participants’ reports through the app revealed a significant deterioration in various metrics during the war compared to normal circumstances. Notably, after the war ended, all indicators returned to their previous levels on average, showcasing the mental resilience of Israelis. Nevertheless, the researchers observed notable differences among Israeli citizens: with residents of the southern areas (near Gaza), exposed to frequent and dangerous rocket attacks, enduring more significant mental and physiological effects compared to those in the central regions. Furthermore, central region residents suffered more than those in the north.

“In future research, it is crucial to identify individuals who experienced significant adversity during the war and did not fully recover following its conclusion. We believe that providing prompt and targeted support to these individuals may prevent the development of post-traumatic stress disorder (PTSD).” – Prof. Erez Shmueli

The findings highlighted several key differences among the citizens. For example, residents of the southern areas spent more time (6.2 hours) looking at their screens compared to central region residents (5.3 hours), and central region residents spent more screen time than those in the north (5 hours). Similar patterns emerged in other metrics, such as mood (3.24 in the south versus 3.45 in the center and 3.75 in the north, on a scale of 1 to 5), stress (2.8 in the south versus 2.6 in the center and 2.3 in the north, on a scale of 1 to 5), physical activity (20 minutes in the south compared to about 34 minutes in the center and in the north), sleep duration (6.1 hours in the south compared to 6.2 hours in the center and 6.5 hours in the north) and quality of sleep (2.9 in the south compared to 3.3 in the center and 3.5 in the north, on a scale of 1 to 5). Women and young people experienced more deviation from their normal patterns during the conflict compared to men and adults.

Since Operation Guardian of the Walls, there have been subsequent rounds of fighting between Israel and factions in Gaza, as well as Russia’s invasion of Ukraine. Prof. Shmueli believes that wearable technology holds immense potential in monitoring the consequences of such conflicts and providing aid to populations in need: “In the past, wars were fought at the borders,” says Prof. Shmueli. “Today, they are fought deep within the country. Therefore, monitoring the resilience of citizens is crucial, both as groups and as individuals. The state needs to know what happens to its citizens during war, as well as provide special support to groups that are more prone to harm. In future research, it is crucial to identify individuals who experienced significant adversity during the war and did not fully recover following its conclusion. We believe that providing prompt and targeted support to these individuals may prevent the development of post-traumatic stress disorder (PTSD).”

Discovery May Lead to Personalized Medicine for Infectious Diseases

Written by AUFTAU on 12 July 2023. Posted in Newsroom.

In the world of healthcare, personalized medicine has made significant strides in certain disease areas, notably cancer. However, when it comes to infection diseases, the application of personalized medicine tools remains largely unexplored. Thanks to a groundbreaking scientific breakthrough, researchers at Tel Aviv University have set their sights on expanding the realm of personalized medicine to encompass infectious diseases as well. This newfound potential holds the promise of delivering more targeted and effective treatments to patients in need.

Until now, the medical world studied the immune response as a single unit, but a team of researchers at Tel Aviv University discovered a way, using experiments and computational tools, to classify two central components of the immune response that operate as a result of severe infectious disease. The importance of the discovery is that it provides a doorway to the world of personalized medicine in the field of infectious diseases and the provision of more effective treatments for patients. For example, instead of deciding to give a uniform medicine to all patients (i.e. an antibiotic like penicillin) the physician will be able to determine precisely which medicine he should give the patient and at what dosage, according to the classification of the infection based on analysis of the ratio between two key markers found in the patient’s blood.

Infectious Disease

An infectious disease is a condition in which a microorganism (virus, bacterium, or parasite) manages to penetrate and multiply in the human body, causing direct damage to the body’s cells.

The damage to the body may also be indirect, as a result of the reaction of the immune system, for example, the creation of inflammation against the same disease-causing agent (pathogen).

Zooming in on the Immune System

The research was led by Prof. Irit Gat-Viks and Prof. Eran Bacharach, with the doctoral students Ofir Cohn and Gal Yankovitz from the Shmunis School of Biomedicine and Cancer Research in The George S. Wise Faculty of Life Sciences. The study was published in the prestigious journal, Cell Systems.

“From simple blood tests, we can learn a lot about the health status of people who became ill and give them more comprehensive treatment according to the development of the infection in their bodies.” – Prof. Irit Gat-Viks

“In the general population, people react differently to infections, and therefore there is a need for medical tools to indicate how each person is expected to react to a certain infectious disease,” explains Prof. Gat-Viks. She explains that, “until now, there have been only very general indicators to characterize these diseases, such as inflammatory markers, fever, urine tests, etc. Based on these indicators, analyses of the response to the infection that appeared rather uniform can be divided into different responses according to the new classification. In extreme cases, as we saw in the Corona epidemic, a person’s immune response to the virus can result in lethality, and preliminary identification of their response can help us save lives. Our new observations and more precise classification of the inflammatory response has allowed us to identify new indicators and markers in our bloodstream. What all this means is that from simple blood tests, we can learn a lot about the health status of people who became ill and give them more comprehensive treatment according to the development of the infection in their bodies.”

Prof. Eran Bacharach and Prof. Irit Gat-Viks

The researchers were able to observe the response of the immune system with high resolution, and identify two main types of responses. Prof. Bacharach outlines the first response as one in which, “the immune system fights a pathogen that has entered the body,” and the other type and one in which “the damage to the body ‘after the war’ with the pathogen is repaired.” In their research, they used disease models in animals, computational tools, and information collected from people with different markers in their bodies that are indicators of the type of response to the pathogen.

“People with extreme reactions to infection with microorganisms such as viruses or bacteria lack an adequate medical response today.” – Prof. Irit Gat-Viks

Prof. Gat-Viks explains that “in fact, personalized medicine exists today for ‘regular’ diseases such as cancer, but there is almost no use of personalized medicine methods in the field of infectious diseases. People with extreme reactions to infection with microorganisms such as viruses or bacteria lack an adequate medical response today. We believe that thanks to our research, doctors will be able to better diagnose the patient’s condition and, as a result, provide effective treatment that will improve the patient’s chances of recovery. We aim to continue the research and discover more subgroups with different reactions among the population so that we can help doctors make their diagnosis more precise and thus provide proper treatment for their patients.”

One Third of Normal-Weight Individuals are Obese

Written by AUFTAU on 12 July 2023. Posted in Newsroom.

Researchers from the School of Public Health at Tel Aviv University’s Faculty of Medicine examined the anthropometric [the scientific study of the measurements and proportions of the human body] data of about 3,000 Israeli women and men and concluded that body fat percentage is a much more reliable indicator of an individual’s overall health and cardiometabolic risk than the BMI index, widely used in clinics today. The researchers suggest that body fat percentage should become the gold standard in this respect and recommend equipping clinics all over Israel with suitable devices.

“BMI (…) is considered a standard indicator of an individual’s general health. However, despite the obvious intuitive connection between excess weight and obesity, the actual measure for obesity is the body’s fat content.” – Prof. Yftach Gepner

‘The Paradox of Obesity with Normal Weight’

The study – the largest of its kind ever conducted in Israel – was led by Prof. Yftach Gepner and PhD student Yair Lahav, in collaboration with Aviv Kfir. It was based on data from the Yair Lahav Nutrition Center in Tel Aviv. The paper was published in Frontiers in Nutrition.

“Israel is a leader in childhood obesity and more than 60% of the country’s adults are defined as overweight,” says Prof. Gepner, adding that, “the prevailing index in this respect is BMI, based on weight and height measures, which is considered a standard indicator of an individual’s general health. However, despite the obvious intuitive connection between excess weight and obesity, the actual measure for obesity is the body’s fat content, with the maximum normal values set at 25% for males and 35% for females. Higher fat content is defined as obesity and can cause a range of potentially life-threatening cardiometabolic diseases: heart disease, diabetes, fatty liver, kidney dysfunction, and more. The disparity between the two indexes has generated a phenomenon called ‘the paradox of obesity with normal weight’ – higher than normal body fat percentage in normal-weight individuals. In this study we examined the prevalence of this phenomenon in Israel’s adult population.”

“We recommend equipping all clinics with suitable devices for measuring body fat content, and gradually turning it into the gold standard both in Israel and worldwide, to prevent disease and early mortality.” – Prof. Yftach Gepner

Body Fat Percentage – A More Reliable Indicator

The researchers analyzed the anthropometric data of 3,000 Israeli women and men, accumulated over several years: BMI scores; DXA scans (using X-rays to measure body composition, including fat content); and cardiometabolic blood markers. About one third of the participants, 1,000 individuals, were found to be within the normal weight range. Of these, 38.5% of the women and 26.5% of the men were identified as ‘obese with normal weight’ – having excess fat content despite their normal weight. Matching body fat percentage with blood markers for each of these individuals, the study found a significant correlation between ‘obesity with normal weight’ and high levels of sugar, fat, and cholesterol – major risk factors for a range of cardiometabolic diseases. At the same time, 30% of the men and 10% of the women identified as overweight were found to have a normal body fat percentage.

“Our findings were somewhat alarming, indicating that obesity with normal weight is much more common in Israel than we had assumed,” warns Prof. Gepner. “Moreover, these individuals, being within the norm according to the prevailing BMI index, usually pass ‘under the radar’. Unlike people who are identified as overweight, they receive no treatment or instructions for changing their nutrition or lifestyle – which places them at an even greater risk for cardiometabolic diseases.”

Based on their findings, the researchers concluded that body fat percentage is a more reliable indicator of an individual’s general health than BMI. Consequently, they suggest that body fat percentage should become the prevailing standard of health and recommend some convenient and accessible tools for this purpose: skinfold measurements that estimate body fat based on the thickness of the fat layer under the skin; and a user-friendly device measuring the body’s electrical conductivity, already used in many fitness centers.

Prof. Gepner: “Our study found that obesity with normal weight is very common in Israel, much more than we had previously assumed, and that it is significantly correlated with substantial health risks. And yet, people who are ‘obese with normal weight’ are not identified by today’s prevailing index, BMI. We also found that body fat percentage is a much more reliable indicator than BMI with regard to an individual’s general health. Therefore, we recommend equipping all clinics with suitable devices for measuring body fat content, and gradually turning it into the gold standard both in Israel and worldwide, to prevent disease and early mortality.”

Breakthrough Gene Therapy Offers Hope for Severe Developmental Epilepsy in Children

Written by AUFTAU on 27 June 2023. Posted in Newsroom.

Advancing treatment and improving quality of life.

Researchers at Tel Aviv University, among other institutions, have developed an innovative gene therapy that may help children suffering from Dravet syndrome (DS), a severe developmental epilepsy caused by a random mutation in the SCN1A gene during fetal development. DS is characterized by uncontrollable epilepsy, developmental delays, cognitive impairment, and a high risk of early death. The team’s innovative gene therapy not only improved epilepsy but also protected against early death and enhanced cognitive abilities in DS lab models.

Breakthrough Gene Therapy

The researchers are hopeful that their genetic therapy can be adapted for other genetic epilepsies and may lead to the development of similar treatments for rare diseases. The study involved injecting a virus carrying a normal SCN1A gene into the brains of DS mice. The treatment demonstrated effectiveness in various critical aspects, even after the onset of severe epilepsy. The researchers express optimism that their laboratory technique will eventually reach clinical settings and provide help to children wit this debilitating disease. They also believe that the tools developed during this research will pave the way for similar treatments for other rare diseases.

The study was led by Dr. Moran Rubinstein and graduate student Saja Fadila, along with Anat Mavashov, Marina Brusel and Karen Anderson, all from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University, and Dr. Eric Kremer, from the University of Montpellier in France. Also participating in the study were Bertrand Beucher and Iria González-Dopeso Reyes from Montpellier and other researchers from France, the USA and Spain. The research was published in the Journal of Clinical Investigation.

Dr. Moran Rubinstein

Dravet syndrome affects approximately one in 16,000 births and is considered relatively common among rare genetic diseases. Currently, there are around 70 affected children in Israel. The syndrome presents as thermally-induced seizures around six months of age, with progress to frequent spontaneous epileptic seizures and motor and cognitive developmental delays after one year.

Dr. Rubinstein highlights that existing epilepsy drugs are insufficient for children with DS, who face a significant risk of early death. The syndrome results from a genetic mutation that occurs randomly during fetal development in a gene called SCN1A and is not inherited from the parents. Unfortunately, the disease cannot be predicted or discovered during pregnancy, making early diagnosis challenging.

According to the researchers, it is customary nowadays to perform a genetic analysis for children who suffer from complex thermally-induced seizures around the age of six months. However, even if the test detects that the problem is in the SCN1A gene, the final diagnosis is often given after the epilepsy worsens, with the appearance of severe spontaneous convulsions and developmental delays. Although it is important to have an early diagnosis, diagnosis is often delayed, and most children are diagnosed only at the age of one or two years and sometimes even later.

Promising Results in Lab Models

Although genetic therapies have shown promise in DS mice and some of them are undergoing clinical trials in humans, they have only been effective when administered at very early stages, prior to symptom onset. Given the complex and invasive nature of gene therapy, it cannot be administered without a confirmed diagnosis of DS. Hence, the researchers focused on developing a treatment that could be effective after seizure onset, even at a relatively late age. Additionally, since DS involves cognitive impairments, the team aimed to alleviate both epilepsy and cognitive symptoms.

Dr. Rubinstein explains that viruses are commony used as carriers in genetic therapies to introduce normal genetic material into patients, enabling normal cellular function. For this purpose, the virus is engineered: its original genetic material is removed so it cannot cause disease or replicate itself, and instead, the relevant normal gene is packed inside. In the case of Dravet syndrome, since the SCN1A gene is very large, it was not possible to use common viruses that are usually used for this purpose and a virus capable of carrying and transferring large genes was needed. The team solved this problem by using a virus called Canine adeno virus type 2, as a carrier of the normal gene.

The carrier virus was directly injected into the brains of DS mice since its properties prevent it from crossing the blood-brain barrier. The treatment was administered to 31 mice at three weeks of age, after spontaneous convulsions had commenced (equivalent to one to two years of age in children), and to 13 mice at five weeks of age (equivalent to approximately six to eight years of age in children). The injection was performed in multiple brain areas, while an empty virus was injected into the brains of 48 control mice.

Potential for Rare Diseases

Promising results followed, with the highest efficacy observed when the treatment was administered at three weeks of age. In these mice, seizures ceased entirely within 60 hours of injection, life expectancy significantly increased, and cognitive impairment, assessed through spatial memory tests, was completely restored. Even in mice treated at five weeks of age, there was notable improvement, characterized by reduced epileptic activity and protection against thermally-induced seizures. In the control group that received the empty virus, no improvement was observed, and the mice experienced symptoms akin to untreated mice, with approximately 50% succumbing to early death due to severe epilepsy. The treatment was also applied to healthy mice without any adverse effects, demonstrating its safety.

The researchers clarify that their treatment restored normal function to damaged neurons in the brain by introducing a complete, normal gene. This approach is crucial in treating Dravet syndrome since the mutation can occur at different locations within the gene, and administering a complete gene provides a univform treatment suitable for all DS patients. Furthermore, the chosen virus infected numerous nerve cells and spread widely beyond the injection site, enhancing its effectiveness.

Dr. Rubinstein concludes that their treatment is the first proven to be effective for Dravet syndrome after the onset of spontaneous convulsions, offering improvement in cognitive function for DS mice. The team has already registered a patent, and hopes to see the treatment reach clinical settings to benefit children affected by this debilitating disease. They are also exploring its potential applicability to other genetic neurodevelopmental diseases. The developed platform represents a plug-and-play system for genetic therapies, with the possibility of incorporating different types of normal genetic material into the carrier virus for treating additional diseases in the future.

Prof. Isaac P. Witz Honored with 2023 Szent-Györgyi Prize for Progress in Cancer Research

Written by AUFTAU on 26 June 2023. Posted in Magazine.

An Impressive achievement: Professor Isaac P. Witz from the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University’s George S. Wise Faculty of Life Sciences, was chosen by the prize selection committee of the National Foundation for Cancer Research (NFCR) in the US to receive the prestigious Szent-Györgyi Prize for his groundbreaking scientific contributions.

Groundbreaking Discoveries

The prize will be given to Prof. Witz, a distinguished figure in cancer research, whose work has shed light on the crucial role of reciprocal information flow and signaling between cancer cells and the tumor microenvironment (TME) for understanding tumor formation, progression and metastasis. The annual Prize honors scientists whose seminal discovery or pioneering body of work has contributed to cancer prevention, diagnosis, or treatment and has had a lasting impact on understanding cancer, holding the promise of improving or saving lives of cancer patients. In recognition of his achievements, Professor Witz will receive the award at a ceremony scheduled for October 21, 2023, at The National Press Club in Washington, D.C.

“I am filled with immense gratification knowing that my contributions have shaped current understanding of the TME and laid the foundation for life-saving immunotherapies for patients.”– Prof. Isaac Witz

Professor Isaac Witz expressed his profound satisfaction, stating: “I am filled with immense gratification knowing that my contributions have shaped current understanding of the TME and laid the foundation for life-saving immunotherapies for patients. It is an absolute honor, and I am overwhelmed with joy and gratitude towards the 2023 Szent-Györgyi Prize Selection Committee for bestowing upon me this prestigious recognition, allowing me to stand alongside the esteemed previous recipients of the Szent-Györgyi Prize.”

With an outstanding career spanning over fifty years, Professor Witz currently serves as Professor Emeritus at Tel Aviv University and heads the Laboratory of Tumor Microenvironment & Metastasis Research at The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences. Throughout his career, he made significant contributions through breakthrough observations, discoveries, publications, and collaborative efforts, emphasizing the critical role of the TME in cancer cell biology, growth, and metastasis.

Impactful Research

During the early stages of his scientific journey, in the 1960s, Professor Witz pioneered the TME concept by an experimental demonstration that components of the immune system infiltrate the TME, impacting tumor behavior. His research established that humoral immune factors localized in the TME exert pivotal roles on various manifestations of anti-tumor immune responses. These seminal findings laid the groundwork for certain aspects of contemporary life-saving immunotherapies, ultimately benefiting cancer patients and advancing scientific progress towards finding cures for cancer.

Rakesh K. Jain, Ph.D., Chair of the 2023 Selection Committee and the 2022 Prize recipient, expressed his delight at Professor Witz’s selection, highlighting the impact of his work on the development of cancer therapeutics targeting molecules within the TME. Dr. Jain, whose own research encompasses the field of TME, believes that future opportunities for life-saving therapies will continue to emerge from this area of study.

A Step Closer to Beating Melanoma?

Written by AUFTAU on 18 June 2023. Posted in Newsroom.

New study reveals critical insights in fight against skin cancer.

A new study conducted at Tel Aviv University and the Sheba Medical Center reveals how melanoma cancer cells affect their close environment to support their needs – by forming new lymph vessels in the dermis to go deeper into the skin and spread through the body. The researchers believe that the new discovery may contribute to the development of a vaccine against the deadly cancer.

The Hidden Mechanism

The scientific breakthrough was led by Prof. Carmit Levy of Tel Aviv University’s Sackler Faculty of Medicine and Prof. Shoshana Greenberger from the Sheba Medical Center. The study was funded by ICRF (the Israel Cancer Research Fund) and its results appeared in the Journal of Investigative Dermatology published by Nature.

“We demonstrated for the first time that in the first stage, in the epidermis, melanoma cells secrete extracellular vesiculas called melanosomes.” – Prof. Shoshana Greenberger

The researchers (from left): Prof. Carmit Levy and Prof. Shoshana Greenberger

Melanoma, the deadliest of all skin tumors, starts with uncontrolled division of melanocyte cells in the epidermis – the top layer of the skin. In the second stage the cancer cells penetrate the dermis and metastasize through the lymphatic and blood systems.

In previous studies a dramatic rise was observed in the density of lymph vessels in the skin around the melanoma – a mechanism that was not understood by researchers until now.

“Our main research question was how melanoma impacts the formation of lymph vessels, through which it then metastasizes,” explains Prof. Greenberger. “We demonstrated for the first time that in the first stage, in the epidermis, melanoma cells secrete extracellular vesiculas called melanosomes.”

What are these vesiculas and how do they impact their environment? Examining this in human melanomas from the Pathology Institute, the researchers demonstrated that melanosomes could penetrate lymph vessels. They then examined their behavior in the environment of actual lymph vessel cells and found that here too the melanosomes penetrate the cells and give them a signal to replicate and migrate. In other words, the primary melanoma secretes extracellular vesiculas that penetrate lymph vessels and encourage the formation of more lymph vessels near the tumor, enabling the melanoma to advance to the lethal stage of metastasis.

“If we can stop the mechanisms that generate metastases in lymph nodes, we can also stop the disease from spreading” – Prof. Shoshana Greenberger

Melanoma’s Stealth Tactics

Prof. Carmit Levy adds that, “melanoma cells secrete the extracellular vesiculas, termed melanosomes, before cancer cells reach the dermis layer of the skin. These vesicles modify the dermis environment to favor cancer cells. Therefore, melanoma cells are responsible for enriching the dermis with lymph vessels, thereby preparing the substrate for their own metastasis. We have several continuing studies underway, demonstrating that the melanosomes don’t stop at the lymph cells, as they also impact the immune system, for example.”

A Promising Vaccine Hope

Since melanoma is not dangerous at the premetastatic stage, understanding the mechanism by which the metastases spread via the lymphatic and blood systems can hopefully contribute to the development of a vaccine against this deadly cancer.

“Melanoma that remains on the skin is not dangerous,” says Prof. Greenberger. “Therefore, the most promising direction for fighting melanoma is immunotherapy: developing a vaccine that will arouse the immune system to combat the melanosomes, and specifically to attack the lymphatic endothelial cells already invaded by the melanosomes. If we can stop the mechanisms that generate metastases in lymph nodes, we can also stop the disease from spreading.”

Tag: Medicine