Tel Aviv University researchers decipher the mechanism that enables skin cancer to metastasize to the brain - delaying its spread by 80%
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Research
Sep 22nd, 2022
Slowing Down Skin Cancer
- Medicine
Once melanoma, or skin cancer, spreads to the brain, it becomes extremely aggressive. Individuals with this stage of cancer are given an average 15 months to live, and that is following surgery, radiation, and chemotherapy. Researchers from Tel Aviv University deciphered, for the first time, a mechanism that enables skin cancer to metastasize to the brain and managed to delay the spread of the disease by 60% to 80% (depending on the stage of the intervention) using existing treatments.
The encouraging study was led by Prof. Ronit Satchi-Fainaro and Ph.D. student Sabina Pozzi of the Sackler Faculty of Medicine at Tel Aviv University. The results were published in the scientific journal JCI Insight.
"In an advanced stage, 90% of melanoma patients will develop brain metastases. This is a puzzling statistic. We expect to see metastases in the lungs and liver, but the brain is supposed to be a protected organ."
How do the Cancer Cells Infiltrate the Brain?
"In an advanced stage, 90% of melanoma [/skin cancer] patients will develop brain metastases," explains Prof. Satchi-Fainaro. "This is a puzzling statistic. We expect to see metastases in the lungs and liver, but the brain is supposed to be a protected organ. The blood-brain barrier keeps harmful substances from entering the brain, and here it supposedly doesn't do the job—cancer cells from the skin circulate in the blood and manage to reach the brain. We asked ourselves with ‘whom’ the cancer cells 'talk' to in the brain to infiltrate it."
The researchers found that in melanoma patients with brain metastases, the cancer cells "recruit" cells called 'astrocytes', star-shaped cells found in the spinal cord and brain which are responsible for maintaining stable conditions (/homeostasis) in the brain.
"The astrocytes are the first to come to correct the situation in the event of a stroke or trauma, for example," says Prof. Satchi-Fainaro, "and it is with them that the cancer cells interact, exchanging molecules and corrupting them."
Protecting the Brain's Border Guards
"Moreover, the cancer cells recruit the astrocytes so that they do not inhibit the spread of the metastases. As such, they create local inflammation in the melanoma cells-astrocytes interaction areas that increase the permeability through the blood-brain barrier, as well as the division and migration of the cancer cells."
"The communication between them is reflected in the fact that the astrocytes begin to secrete a protein that promotes inflammation called MCP-1 (also known as CCL2), and in response to this, the cancer cells begin to express its receptors CCR2 and CCR4, which we suspected to be responsible for the destructive communication with the astrocytes."
"Both the antibody and the small molecule we used (…) have already been tested on humans as part of clinical trials. Therefore, these treatments are considered safe, and we can try to repurpose them for melanoma."
To test their hypothesis, Prof. Satchi-Fainaro and her team tried to inhibit the expression of the protein and its receptors in genetically engineered lab models and in 3D models of primary melanoma and brain metastases. To this end, the researchers used both an antibody (biological molecule) and a small molecule (synthetic), designed to block the MCP-1 protein. They also employed CRISPR technology, a gene-editing technique, to genetically edit the cancer cells and cut out the two genes that express the two relevant receptors, CCR2 and CCR4. With each of the methods, the researchers were able to delay the spread of metastases.
"These treatments succeeded in delaying the penetration of the cancer cells into the brain and their subsequent spread throughout the brain,” says Prof. Satchi-Fainaro. The team succeeded in achieving a 60% to 80% delay, depending on the stage of the intervention. They achieved the best results with the treatment conducted immediately after surgery to remove the primary melanoma and were able to prevent the metastases from penetrating the brain.
"I believe that the treatment is suitable for the clinic as a preventive measure," says Satchi-Fainaro. "Both the antibody and the small molecule we used—which are primarily intended to treat sclerosis, diabetes, liver fibrosis, and cardiovascular diseases, as well as serve as a biomarker for other types of cancer—have already been tested on humans as part of clinical trials. Therefore, these treatments are considered safe, and we can try to repurpose them for melanoma."
The research was conducted in collaboration with additional scientists and physicians from Tel Aviv University, including Prof. Adi Barzel, Dr. Asaf Madi, Prof. Iris Barshack, Prof. Eran Perlson, and Prof. Inna Slutsky. International researchers also participated in the study, including Prof. Eytan Ruppin from the US National Institutes of Health (NIH), Prof. Henry Brem and Thomas Hyde from Johns Hopkins University-, and Prof. Helena Florindo from the University of Lisbon.
The study was funded by the European Research Council (ERC), the Melanoma Research Alliance (MRA), the Kahn Foundation, the Israel Cancer Research Fund (ICRF), and the Israel Science Foundation (ISF).
Research
Sep 19th, 2022
Facebook Proven to Negatively Impact Mental Health
New study first to establish causal link between use of the platform and reported worsening in anxiety and depression among college students
- Social Sciences
While many studies have found a correlation between the use of social media and various symptoms related to mental health, so far, it has been challenging to ascertain whether social media was actually the cause of poor mental health. By applying a novel research method, researchers have now succeeded in establishing such a causality: A study led by researchers from Tel Aviv University, MIT Sloan School of Management and Bocconi University reveals new findings about the negative impact of Facebook on the mental health of American college students.
The study was led by Dr. Roee Levy of the Berglas School of Economics at Tel Aviv University, Prof. Alexey Makarin of MIT Sloan School of Management, and Prof. Luca Braghieri of Bocconi University. The paper is forthcoming in the scientific journal American Economic Review, and was awarded a prize at the 2022 Economic Society European Meeting (ESEM).
"Over the last fifteen years, the mental health trends of adolescents and young adults in the United States have worsened considerably,” says Prof. Braghieri. “Since such worsening in trends coincided with the rise of social media, it seemed plausible to speculate that the two phenomena might be related.”
The study was based on data that dates back to the 2004 advent of Facebook at Harvard University, before it took the internet by storm. Facebook was initially accessible only to Harvard students who had a Harvard email address. Quickly spreading to other colleges in and outside the US, the network was made available to the general public in the US and beyond in September 2006. The researchers were able to analyze the impact of social media use by comparing colleges that had access to the platform to colleges that did not. The findings show a rise in the number of students reporting severe depression and anxiety (7% and 20% respectively).
"We hypothesized that unfavorable social comparisons could explain the effects we found, and that students more susceptible to such comparisons were more likely to suffer negative effects."
Here Comes Trouble
The study combined information from two different datasets: the specific dates on which Facebook was introduced at 775 American colleges, and the National College Health Assessment (NCHA), a survey conducted periodically at American colleges.
The researchers built an index based on 15 relevant questions in the NCHA, in which students were asked about their mental health in the past year. They found a statistically significant worsening in mental health symptoms, especially depression and anxiety, after the arrival of Facebook:
- 7% increase in number of students who reported having suffering, at least once during the preceding year, depression so severe that it was difficult for them to function
- 20% increase in number of students who reported anxiety disorders
- 2% increase in number of students expected to experience moderate to severe depression
- 3% increase in number of students experienced impairment to their academic performance due to depression or anxiety
Dr. Roee Levy (Photo: Oren Sarig)
Social Media vs. Social Circumstances
TAU’s Dr. Levy notes, "When studying the potential mechanisms, we hypothesized that unfavorable social comparisons could explain the effects we found, and that students more susceptible to such comparisons were more likely to suffer negative effects.”
“More students believed that others consumed more alcohol, even though alcohol consumption had not changed significantly."
In other words, the methodology also considered any differences in mental health over time or across colleges that were not related to Facebook. This approach enabled conditions similar to those of a 'natural experiment,' which would be impossible today now that billions of people around the world use many different social networks.
To test this interpretation, the team investigated more data from the NCHA. They found, for example, a greater negative impact on the mental health of students who lived off-campus and were consequently less involved in social activities, and a greater negative impact on students with credit card debts who saw their supposedly wealthier peers on the network.
“We also found evidence that Facebook had changed students’ beliefs about their peers,” adds Levy. “More students believed that others consumed more alcohol, even though alcohol consumption had not changed significantly."
Research
Sep 18th, 2022
Are Corals in Deep Trouble?
Reproductive capacity of coral decreases with water depth
- Life Sciences
Today, when coral reefs around the world are being severely damaged by climate change and other human impacts, many are pinning their hopes on deeper reefs to provide a ’lifeline’ of support for shallow-water coral reefs, which may be more exposed to some hazards. A new Tel Aviv University study, in collaboration with the Interuniversity Institute for Marine Sciences in Eilat, suggests that this hope might have been overestimated.
The findings of the study show that coral spawning events in the Gulf of Aqaba and Eilat, Red Sea, at the deep end of the focal species’ depth range (~30–45 m) occur at much lower intensities than those at shallow water (0–30 m). While in shallow water about half of the corals engaged in each reproductive event, this proportion dropped to only 10–20 percent in the deeper part of the reef.
According to the researchers, the significance of this finding is that there is an insufficient basis for the prevalent hope that deep reefs can serve as a ‘lifeline’ for degraded shallow reefs. In fact, they suggest that for some coral species, the opposite is true—to survive through time, deeper coral populations may more often rely on shallow-reef coral more than vice versa.
The study also demonstrates that sharp increases in water temperature within a day or two affected the onset of the breeding events in the examined species.
The study was led by PhD candidate Ronen Liberman from Tel Aviv University’s School of Zoology and Dr. Tom Shlesinger from Florida Institute of Technology; and supervised by Prof. Yehuda Benayahu of Tel Aviv University’s School of Zoology and Steinhardt Museum of Natural History. Prof. Yossi Loya, also of TAU’s Zoology School and Steinhardt Museum, participated in the study as well. The research was recently published in the prominent journal Ecology, the study partially funded by the European Commission as part of its Horizon 2020 program.
Capturing the Moment
The uniqueness of the study lies within the long-term and intensive examination of coral reproduction throughout a wide depth gradient spanning 0–50 m. The study was conducted over the course of five years to include five breeding seasons. It examined the reproduction of soft corals, also called “Octocorallia,” some of which live throughout a wide depth range in the Gulf of Aqaba and Eilat. Specifically, the researchers focused on a species of a soft coral, called Rhytisma fulvum, which reproduces by “surface-brooding”—a reproductive mode by which the coral brood, or hatch, their strikingly yellow larvae glued externally to the coral surface for several days. This unique reproductive mode helps scientists overcome many of the difficulties in examining and monitoring coral reproductive events, especially in the more challenging-to-work depths.
Ronen Liberman explains: “Most coral species are hermaphrodites, meaning that each individual functions as both male and female, and they reproduce by brief and synchronous spawning events, which usually occur once a year in the summer months. During this synchronized event, many corals simultaneously release a huge amount of sperm and eggs which meet externally in the water, where they undergo fertilization and form embryos. In other species, male corals release sperm into the water, and these cells migrate into female corals and fertilize the eggs internally, so that fertilization and embryonic development occurs within the coral. In both cases, the event lasts only a few minutes, mostly at night, so it is very difficult for researchers to ‘capture the moment,’ especially at great depths where divers cannot remain for a long time. Therefore, very little is known about coral reproduction at depths greater than approximately 15 m.”
A Colorful Event
In the present study, the researchers focused on the soft coral Rhytisma fulvum which lives in the Gulf of Eilat and Aqaba along a large depth range: from reef flats close to the sea surface and down to 50m. A particular reason for the choice of this species is its unique reproductive strategy, called “surface-brooding”. This reproductive process begins when male colonies release sperm cells in a synchronized manner, which later reach female colonies where internal fertilization occurs.
Unlike in other coral species, however, in this species, embryos do not proceed to develop internally within the coral. Instead, the fertilized eggs are released and cling to the colony via mucus for six days, where they develop into larvae. “The developing embryos have such a vibrant yellow color that makes it a very colorful event, lasting for several days. Thanks to that fact, we were able to monitor rather easily a large number of colonies along a large depth range throughout five annual reproductive seasons,” says Ronen.
Trying to create their own sunshine? (Photo: Tom Shlesinger)
Corals Like it Hot
The researchers dove to various depths, positioned temperature sensors, and examined several characteristics of the breeding events–timing, duration, and intensity of the events.
They sought to understand which environmental factors influence the onset of reproductive events:
The study showed that the timing and synchronization of reproduction events, at any given depth are associated with a clear and fast increase in water temperature of 1–1.5 degrees Celsius within 24-48 hours – a kind of a “heat wave” that is typical in the waters of the Gulf of Aqaba and Eilat in early summer. In shallow water (approx. 5-15 m), the reproductive events always occurred days to weeks before they were observed at the greater depths. The researchers attributed this phenomenon to the short-term “heat waves” in the deeper water usually occurred only several days to weeks after they occurred in the shallow water.
The reproductive intensity was measured by the number of colonies that reproduced and released embryos at each event. “We found that the number of colonies releasing embryos was significantly smaller at a depth greater than 30 meters,” Ronen adds. “Whereas at a shallow depth, about half of the colonies participated in each spawning event, in the deeper water the participation rate dropped to only 10–20 percent.”
Considering these findings, the researchers believe that the deep-water coral populations are less likely to thrive on their own and are reliant to some extent on populations from the shallower reef. Because of their lower breeding intensity, it appears that the deep-water coral population requires the contribution of the larvae from the corals found in the shallower water. The researchers suggest that this ‘weakness’ among the deep corals may be linked to the much lower intensity of sunlight that reaches their habitat. Sunlight is necessary for photosynthesis, in which symbiotic algae found within the coral tissue convert light energy to provide the coral host with the chemical energy it needs.
Protecting those at High Risk
The researchers conclude: “Today, when coral reefs around the world are being severely damaged by climate change and other human impacts, many are pinning their hopes on deeper reefs to provide a ’lifeline’ of support for shallow-water coral reefs, which may be more exposed to some hazards. While we do not wish to diminish the optimism, our research suggests that this hope might have been overestimated. Rather, it looks like it is the deeper coral populations that need the shallow ones to persist more than vice versa. Therefore, these hidden deep reefs require attention and protection on their own right, perhaps even more than the shallow reefs.”
Research
Sep 12th, 2022
Making Wheat Rust-Resistant
Researchers respond to the global food crisis by enabling resistance of wheat to rust diseases
- Life Sciences
Wheat supplies about one fifth of all calories and proteins consumed by humanity. However, through the millennia, the process of cultivation has reduced the diversity of wheat varieties, and consequently modern wheat varieties are more vulnerable than their predecessors to diseases, pests, and climate hazards. The escalating climate crisis creates an urgent need to produce wheat varieties capable of thriving in extreme environmental and climatic conditions and withstanding pests and diseases.
An international research team that includes researchers from Tel Aviv University has isolated three disease-resistance genes from wild grasses, enabling resistance to rust diseases that cause severe damage to wheat yields worldwide.
It's in The Genes
The project was facilitated by several technological innovations that drastically cut down the time needed to identify and isolate genes from wild plant species and transfer them into cultivated plants.
"Since wheat first originated in our part of the world, wild cereals growing in our region are the progenitors of cultivated wheat, still carrying a rich variety of genetic traits that can be used to develop improved wheat varieties."
The three genes were isolated from plants preserved in the Liberman Okinow Gene Bank of Wild Cereals at the Institute for Cereal Crops Research (ICCR) at the George S. Wise Faculty of Life Sciences at Tel Aviv University. Two of the genes, providing immunity against stem rust disease, were isolated by an international team led by researchers from the UK. The third gene, isolated by researchers at TAU, provides resistance against two different diseases – leaf rust and stripe rust, currently exacerbated due to rising temperatures around the world.
Prof. Amir Sharon, Head of ICCR, says that isolating the genes was enabled by several technological breakthroughs, and that these novel technologies can also be used to isolate genes for other beneficial properties. Transferred into the genome of cultivated wheat, such genes will serve to generate better wheat varieties – featuring higher yields, and resistant to diseases, pests, and harsh environmental conditions. "Just as each of us carries only a small part of his/her grandparents' genes, cultivated wheat contains only a remnant of its ancient ancestors' genetic heritage. Since wheat first originated in our part of the world, wild cereals growing in our region are the progenitors of cultivated wheat, still carrying a rich variety of genetic traits that can be used to develop improved wheat varieties," explains Prof. Sharon.
"Certain traits of wild plants have already been incorporated into cultivated wheat over the years, however this great genetic potential remained mostly untapped, since, until recently, it took more than a decade to isolate a single gene. Today, thanks to several technological breakthroughs, especially genome sequencing and bioinformatics, we can isolate new genes in less than a year. Thus, in the past year alone, three genes providing resistance to various rust diseases were isolated from seeds of wild plants preserved in our gene bank. These genes, implanted in cultivated wheat, can significantly reduce damage from the relevant diseases with no need for pesticides - preventing yield losses while also protecting the environment."
In addition to disease resistance, Prof. Sharon's team is collaborating with researchers worldwide to isolate genes for other beneficial traits. Thus, for example, they work with researchers from Ben-Gurion University who recently isolated pest-resistance genes from wild wheat, and in our own Institute they've identified a new gene in wheat progenitors, that may provide endurance in an arid climate.
Prof. Amir Sharon & Dr. Arava Shatil Cohen in the lab
'Safe Box' to Tackle Climate Change
In addition to new methods for isolating genes, great advances have been made in biotechnology, specifically in technologies for gene transfer and genome editing. These technologies enable the transfer of new genes to crop plants, as well as introduction of changes into existing wheat genes.
"Essentially, the collection serves as a safe box for genes needed to create new, improved varieties of wheat that will give humanity larger crops and meet the challenges of climate change."
ICCR implements these new technologies, offering services of wheat gene transformation and genome editing to researchers in other institutes, as well as commercial companies. "With the support of the Chief Scientist of Israel's Ministry of Agriculture, and the Israeli Center for Genome Editing in Agriculture, we have established a center for wheat transformation and genome editing at ICCR," shares Prof. Sharon. "This is an important milestone, enabling us, for the first time, to perform effective wheat transformation here in Israel,” says Prof. Sharon.
Dr. Arava Shatil Cohen, Head of the wheat transformation unit, adds: “With these technologies we can implant new genes and use genome editing methods to give wheat new properties. We utilize our systems to promote research at ICCR and help companies and researchers from other institutions who wish to use this technology".
Today, ICCR's gene bank includes over 17,000 seeds of 20 different species of wild cereals, collected in Israel over the past 50 years. The collection is unique, both because of its large number of species related to cultivated wheat, and because a large portion of the plants preserved in the gene bank were collected in natural habitats that no longer exist due to rapid urban development in Israel. "Essentially, the collection serves as a safe box for genes needed to create new, improved varieties of wheat that will give humanity larger crops and meet the challenges of climate change," says Prof. Sharon. "The new technologies are the key to the safe box: they enable us to identify and extract the needed genes quickly and incorporate them into cultivated wheat."
Research
Sep 11th, 2022
Like Manna from the Sea
Innovative technology may ease global food crisis: “enriched seaweed” with extremely high nutritional value
- Life Sciences
Researchers from Tel Aviv University and the Israel Oceanographic and Limnological Research Institute in Haifa have developed an innovative technology that enables the growth of “enriched seaweed” infused with nutrients, proteins, dietary fiber, and minerals for human and animal needs.
According to the researchers, the state-of-the-art technology significantly increases the growth rate, protein levels, healthy carbohydrates, and minerals in the seaweed’s tissues – making the “enriched seaweed” a natural superfood with extremely high nutritional value, which can be used in the future for the health food industry and to secure an unlimited food source.
The research was led by Ph.D. student Doron Ashkenazi, under the guidance of Prof. Avigdor Abelson from the School of Zoology, George S. Wise Faculty of Life Sciences at Tel Aviv University and Prof. Alvaro Israel of the Israel Oceanographic and Limnological Research Institute (IOLR) in Tel Shikmona, Haifa. The article was published in the scientific journal Innovative Food Science & Emerging Technologies.
"Seaweed can be regarded as a natural superfood, more abundant in the necessary components of the human diet than other food sources."
A Natural Superfood
Doron Ashkenazi explains that in the study, local species of the algae Ulva, Gracilaria and Hypnea were grown near fish farming systems under different environmental conditions. The special conditions allowed the seaweed to flourish and enabled a significant improvement in their nutritional value to the point of their becoming “enriched seaweed,” a superfood.
“Seaweed can be regarded as a natural superfood, more abundant in the necessary components of the human diet than other food sources,” Ashkenazi adds. “Through the technological approach we developed, a farm owner or entrepreneur will be able to plan in advance a production line of seaweed rich in the substances in which they are interested, which can be used as health foods or nutritional supplements; for example, seaweed with a particularly high level of protein, seaweed rich in minerals such as iron, iodine, calcium, magnesium, and zinc, or in special pigments or anti-oxidants. The enriched seaweed can be used to help populations suffering from malnutrition and nutritional deficiencies, for example disadvantaged populations around the world, as well as supplements to a vegetarian or vegan diet.”
In fact, the use of seaweed as a rich food source that meets all human nutritional needs is reminiscent of the biblical manna that fed the Israelites in the desert.
Layout of the land-based, outdoor, aquaculture system as was stationed at the IOLR institute, Haifa, Israel
“Technologies of this type are undoubtedly a model for a better future for humanity, a future where humans live in idyll and in health in their environment.”
Aquaculture, Tomorrow's Agriculture
Unlike terrestrial agriculture, aquaculture, and in particular the proposed seaweed farming approach, does not require extensive land, fresh water, or large amounts of fertilizer. Environmentally friendly, it preserves nature and the ecological balance by reducing environmental risks. The new methodology, in fact, offers an ideal situation, of sustainable and clean agriculture.
Today, integrated aquaculture is beginning to receive support from governments around the world due to its environmental benefits, which include the reduction of nutrient loads to coastal waters and of the emission of gases and carbon footprints. In this way, it contributes to combatting the climate crisis and global warming.
“Technologies of this type are undoubtedly a model for a better future for humanity, a future where humans live in idyll and in health in their environment,” concludes Ashkenazi.
The research was conducted in collaboration with other leading researchers from around the country, including Guy Paz and Dr. Yael Segal of the Israel Oceanographic and Limnological Research Institute (IOLR) in Haifa, Dr. Shoshana Ben-Valid, an expert in organic chemistry, Dr. Merav Nadav Tsubery of the Department of Chemistry in the Faculty of Exact Sciences at Bar-Ilan University, and Dr. Eitan Salomon from the National Center for Mariculture in Eilat.
Research
Sep 11th, 2022
Covid-19 Antibodies May Eliminate Need for Boosters
Breakthrough TAU discovery can neutralize all known Covid variants
- Medicine
A team of Tel Aviv University researchers has demonstrated that antibodies isolated from the immune system of recovered COVID-19 patients are effective in neutralizing all known strains of the virus, including the Delta and the Omicron variants. The discovery may eliminate the need for repeated booster vaccinations and strengthen the immune system of populations at risk.
The research was led by Dr. Natalia Freund and doctoral students Michael Mor and Ruofan Lee of the Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine and of the TAU Center for Combating Pandemics. The study was conducted in collaboration with Dr. Ben Croker of the University of California San Diego. Prof. Ye Xiang of Tsinghua University in Beijing. Prof. Meital Gal-Tanamy and Dr. Moshe Dessau of Bar-Ilan University also took part in the study. The study was published in the Nature journal Communications Biology.
Highly Effective Against Delta and Omicron
The present study is a continuation of a preliminary study conducted in October 2020, at the height of the COVID-19 crisis. At that time, Dr. Freund and her colleagues sequenced all the B immune system cells from the blood of people who had recovered from the original COVID strain in Israel, and isolated nine antibodies that the patients produced. The researchers now found that some of these antibodies are very effective in neutralizing the new coronavirus variants, Delta and Omicron.
“In the previous study, we showed that the various antibodies that are formed in response to infection with the original virus are directed against different sites of the virus," says Dr. Freund. "The most effective antibodies were those that bound to the virus’s ‘spike’ protein, in the same place where the spike binds the cellular receptor ACE2. Of course, we were not the only ones to isolate these antibodies, and the global health system made extensive use of them until the arrival of the different variants of the coronavirus, which in fact rendered most of those antibodies useless."
“In the current study, we proved that two other antibodies, TAU-1109 and TAU-2310, which bind the viral spike protein in a different area from the region where most of the antibodies were concentrated until now (and were therefore less effective in neutralizing the original strain) are actually very effective in neutralizing the Delta and Omicron variants. According to our findings, the effectiveness of the first antibody, TAU-1109, in neutralizing the Omicron strain is 92%, and in neutralizing the Delta strain, 90%. The second antibody, TAU-2310, neutralizes the Omicron variant with an efficacy of 84%, and the Delta variant with an efficacy of 97%.”
Can Serve as Effective Substitute for Boosters
According to Dr. Freund, the surprising effectiveness of these antibodies might be related to the evolution of the virus: “The infectivity of the virus increased with each variant because each time, it changed the amino acid sequence of the part of the spike protein that binds to the ACE2 receptor, thereby increasing its infectivity and at the same time evading the natural antibodies that were created following vaccinations."
"In contrast, the antibodies TAU-1109 and TAU-2310 don’t bind to the ACE2 receptor binding site, but to another region of the spike protein – an area of the viral spike that for some reason does not undergo many mutations – and they are therefore effective in neutralizing more viral variants. These findings emerged as we tested all the known COVID strains to date.”
"In our view, targeted treatment with antibodies and their delivery to the body in high concentrations can serve as an effective substitute for repeated boosters, especially for at-risk populations and those with weakened immune systems."
The two antibodies, cloned in Dr. Freund’s laboratory at Tel Aviv University, were sent for tests to check their effectiveness against live viruses in laboratory cultures at the University of California San Diego, and against pseudo viruses in the laboratories of the Faculty of Medicine of Bar-Ilan University in the Galilee; the results were identical and equally encouraging in both tests.
Dr. Freund believes that the antibodies can bring about a real revolution in the fight against COVID-19: “We need to look at the COVID-19 pandemic in the context of previous disease outbreaks that humankind has witnessed. People who were vaccinated against smallpox at birth and who today are 50 years old still have antibodies, so they are probably protected, at least partially, from the monkeypox virus that we have recently been hearing about. Unfortunately, this is not the case with the coronavirus. For reasons we still don’t yet fully understand, the level of antibodies against COVID-19 declines significantly after three months, which is why we see people getting infected again and again, even after being vaccinated three times."
"In our view, targeted treatment with antibodies and their delivery to the body in high concentrations can serve as an effective substitute for repeated boosters, especially for at-risk populations and those with weakened immune systems. COVID-19 infection can cause serious illness, and we know that providing antibodies in the first days following infection can stop the spread of the virus. It is therefore possible that by using effective antibody treatment, we will not have to provide booster doses to the entire population every time there is a new variant.”
Research
Sep 5th, 2022
Stop Blaming the Bats for Covid-19
Researchers conclude there's insufficient proof of correlation between bats and the outbreak of the epidemic
- Life Sciences
Shortly after outbreak of the Corona epidemic, accusations were voiced among the public, as well as within the scientific community, claiming that the bats are considered a health threat, as reservoirs of viruses', including the Covid-19 virus. A new Tel Aviv University study rejects this correlation between the Covid-19 outbreak and bats, which the researchers say was not based on sufficient compelling scientific proof. Bats have a highly effective immune system that enables them to deal relatively easily with viruses that are considered lethal for other mammals.
Bats with a Bad Rap
The study was led by Dr. Maya Weinberg from the laboratory of Prof. Yossi Yovel, Head of the Sagol School of Neuroscience and faculty member of the School of Zoology and the Steinhardt Museum of Natural History at Tel Aviv University. The research team reviewed dozens of leading articles and studies in this field, and their conclusions were published in writing in the prestigious iScience Journal.
The researchers explain that the infamous reputation of the bats is well known among both the scientific community and the public at large, namely that they are often accused of being reservoirs of viruses including Covid-19, thus posing a threat to public health. While there is indeed evidence that the origin of the "ancient potential" Covid-19 was in bats, the researchers note that two years after the pandemic first broke out, we still do not know for sure what the exact origin of the COVID-19 variant is.
"Bats have a highly effective immune system that enables them to deal relatively easily with viruses considered lethal for other mammals."
Dr. Weinberg: “In general, bats are mistakenly conceived of as reservoirs of many contagious disease, only due to their being positive serologically positive; in other words, in possession of antibodies, which means that bats have survived the disease and developed an immune response. After that, they overcame the virus altogether and disengaged from it; hence, they are no longer its carriers. Nevertheless, in many cases, a virus similar to a human pathogen is liable to be found in bats; however, it is not pathogenic to humans, and is not sufficient to use bats as a reservoir.”
Dr. Weinberg with a friend
Capable of Coping with Different Viruses
To examine the overall situation, the researchers conducted a meta-analysis of literature on over 100 viruses for which bats are considered potential reservoirs, including Ebola, SARS, and COVID. "We found that in a considerable number of cases (48%) this claim was based on the incidence of antibodies or PCR tests, rather than actual isolation of identical viruses. Moreover, many of the reported findings are not convincing," says Dr. Weinberg.
"The mere isolation of a virus is not enough to see an animal as a reservoir, since a minimum number of index cases is required in which the virus is isolated in order to be considered a reservoir animal, as well as the existence of an established path of transmission. Furthermore, the very detection of a particular virus in bats does not necessarily ensure further infection. Additional biological, ecological, and anthropogenic conditions must exist for such an event to occur.”
According to the researchers, simultaneously, in recent years evidence is accumulating of the fact that bats are capable of coping with different viruses, including lethal ones, better than humans and most other mammals. After over 100 years of focus on viruses carried by bats, it appears that bats' immune system is characterized by a restrained response during inflammatory processes. As we see it, bats have developed an excellent balance between resistance and tolerance: an increased defense response of the host, and immune tolerance through a number of different mechanisms. Moderate inflammatory pathways contribute to immune tolerance with bats, and a well-balanced response that prevents the virus from developing.
“The comprehensive study we've conducted raises serious doubts regarding the possibility of bats being the origin of the Covid19 outbreak. The findings give rise to the opposite perspective, according to which we must study in-depth the immunological anti-viral capabilities of bats, and thus obtain new and effective means of coping in humanity's struggle against contagious disease, aging, and cancer,” concludes Dr. Weinberg.
Research
Sep 1st, 2022
Eradicating Deadly Brain Tumors by 'Starvation'
Inhibiting energy supply to glioblastoma cells, resulted in tumor regression within days
- Life Sciences
A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma, a highly lethal type of brain cancer. The researchers achieved the dramatic outcome using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other supplies the energy required for rapid tumor growth. The researchers found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.
The study was led by Ph.D. student Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH) in the USA. The paper was published in the scientific journal Brain and was highlighted with special commentary.
Focusing on Tumor Environment
The researchers explain: "Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors."
"We tackled the challenge of glioblastoma from a new angle," explains Dr. Mayo. "Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells."
"In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse - indicating that the astrocytes are essential to tumor progression and survival."
"Specifically, we studied astrocytes – a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth."
Using a lab model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all lab models with glioblastoma tumors within 4-5 weeks. Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated lab models survived. Moreover, even after discontinuing treatment, most of the lab models survived.
WATCH: Dr. Lior Mayo explains the dramatic breakthrough in addressing glioblastoma, a deadly brain cancer
Exposing Mechanisms of Double Agents
"In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse - indicating that the astrocytes are essential to tumor progression and survival," notes Dr. Mayo. "Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?"
To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors. They found two main differences – thereby identifying the changes that astrocytes undergo when exposed to glioblastoma:
- The first change was in the immune response to glioblastoma. Dr. Mayo clarifies, "The tumor mass includes up to 40% immune cells – mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes 'persuade' them to 'change sides' and support the tumor instead of attacking it. Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly – thereby protecting the tumor and facilitating its growth."
- The second change through which astrocytes support glioblastoma is by modulating their access to energy - via the production and transfer of cholesterol to the tumor cells. The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself – namely in the astrocytes' 'cholesterol factory', which usually supplies energy to neurons and other brain cells. "We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells," explains Dr. Mayo. "Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor."
The Tumor's Vulnerability, a Therapeutic Opportunity
Next, the researchers engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially 'starved' to death in just a few days. These remarkable results were obtained in both lab models and glioblastoma samples taken from human patients and are consistent with the researchers' starvation hypothesis.
"The challenge now, is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study."
Dr. Mayo notes: "This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability – the tumor's dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity."
The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above. The researchers explain: "For each patient, we examined the expression levels of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients."
"Currently, tools to eliminate the astrocytes surrounding the tumor are available in lab models, but not in humans," notes Dr. Mayo. "The challenge now, is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors," he concludes.
Research
Sep 1st, 2022
Can Music Help Prevent Severe Cognitive Decline?
TAU researchers developed musical tests to detect mental deterioration in old age
- Arts
- Social Sciences
- Exact Sciences
Modern technology contributes to increased longevity and thus to the growth of the elderly population. It is therefore important to take steps to ensure their quality of life, including inventing tools for accessible and quick diagnosis of age-related conditions. While preventative tests are commonly accepted for a variety of physiological problems such as diabetes, high blood pressure or breast cancer, no method has yet been developed to enable routine, accessible monitoring of the brain for cognitive issues.
Researchers at Tel Aviv University have developed a method that employs musical tests and a portable instrument for measuring brain activity to detect cognitive decline in old age. The method entails measuring 15 minutes of electrical activity in the subject's brain while he or she performs simple musical tasks and can be easily implemented by any staff member in any clinic, without requiring special training. The researchers believe the method could pave the way towards early detection of cognitive decline when treatment and prevention of severe decline are possible, improving the quality of life of millions around the world
Many Powers of Music
The study was led at Tel Aviv University by PhD student Neta Maimon from the School of Psychological Sciences and the Buchmann-Mehta School of Music, and Lior Molcho from Neurosteer Ltd, headed by Prof. Nathan Intrator from the Blavatnik School of Computer Science and the Sagol School of Neuroscience. Other participants included: Adi Sasson, Sarit Rabinowitz, and Noa Regev-Plotnick from the Dorot-Netanya Geriatric Medical Center. The article was published in the journal Frontiers in Aging Neuroscience.
As part of the study, the researchers developed a groundbreaking method combining a portable device for the measurement and innovative analysis of electroencephalography (EEG), developed by Neurosteer, and a short musical test of about 12-15 minutes, developed by Maimon.
"We have actually succeeded in illustrating that music is indeed an effective tool for measuring brain activity."
Maimon, who specializes in musical cognition, explains that music has great influence on different centers in the brain. On the one hand, music is known to be a quick mood stimulant, particularly of positive emotion. On the other hand, in different situations, music can be cognitively challenging, activating the frontal parts of the brain, especially if we try to concentrate on different aspects of the music, and at the same time perform a particular task. According to Maimon, if we combine these two capabilities, we can create cognitive tests that are quite complex, yet also pleasant and easy to perform.
Neta Maimon specializes in musical cognition
Furthermore, music that is positive and reasonably rhythmic will enhance concentration and performance of the task. Thus, for example, the famous “Mozart effect,” whereby subjects perform better on intelligence tests after listening to Mozart’s music, has nothing to do with Mozart’s music, but rather the fact that music creates a positive mood and stimulates us to a state that is optimal for performing intelligence and creativity tests.
Accordingly, the researchers hypothesized that with musical tools, it would also be possible to challenge the subjects to an extent that would enable testing of the brain’s frontal activity as well as raising their spirits, thus enhancing their performance on the test while the overall experience is pleasant.
Enabling Early Detection of Cognitive Decline
The study included an experiment testing 50 elderly people hospitalized at the Dorot-Netanya Geriatric Medical Center. “Anyone hospitalized at Dorot, or any other geriatric rehabilitation institution, undergoes a standard test called 'mini-mental,' designed to evaluate their cognitive condition as a routine part of the intake process," explains Maimon.
During the test, the subject is connected to the portable EEG device by means of an adhesive band with three electrodes attached to the forehead. The test includes a variety of tasks, including enumerating the days of the week or months of the year backwards. The subject performs a series of musical-cognitive tasks according to audible instructions given automatically through earphones. Short melodies are played by different instruments, and the subjects are instructed to perform various tasks on them at varying levels of difficulty. For example, pressing a button each time any melody is played or pressing it only when the violin plays. In addition, the test includes several minutes of musically guided meditation designed to bring the brain to a resting state, as this state is known to indicate cerebral functioning in various situations. Up to 30 points can be accrued, a high score indicating normal cognition.
"Our method enables the monitoring of cognitive capability and detection of cognitive decline already in the early stages, all by simple and accessible means."
"The participants scored 18-30 on the mini-mental test, indicating various levels of cognitive functioning," explains Maimon. "The EEG device registered the electrical activity in the brain during the activity, and the results were analyzed using machine learning technology. This allowed mathematical indices to be identified that were precisely correlated with the mini-mental test scores; in other words, we obtained new neuro-markers [brain markers] that may stand alone as indices of the subject’s cognitive status."
Maimon adds: “We have actually succeeded in illustrating that music is indeed an effective tool for measuring brain activity. The brain activity and response times to tasks correlated to the subjects’ cerebral conditions (correlating to the mini-mental score assigned to them). More importantly, all those who underwent the experiment reported that, on the one hand, it challenged the brain, but on the other it was very pleasant to perform”.
The researchers conclude: “Our method enables the monitoring of cognitive capability and detection of cognitive decline already in the early stages, all by simple and accessible means, with a quick and easy test that can be conducted in any clinic. This method is of special importance today due to the increase in longevity and accelerated population growth, particularly among the elderly. Today, millions of people around the world already suffer or are liable to suffer soon from cognitive decline and its dire consequences, and their number will only increase in the coming decades. Our method could pave the way towards efficient cognitive monitoring of the general population, and thus detect cognitive decline in its early stages, when treatment and prevention of severe decline are possible. It is therefore expected to improve the quality of life of millions around the world.”
