The study was led by Tel Aviv University’s Dr. Edo Kon and Prof. Dan Peer, VP for R&D and Head of the Laboratory of Precision Nano-Medicine at The Shmunis School of Biomedicine and Cancer Research at The George S. Wise Faculty of Life Sciences, in collaboration with researchers from the Israel Institute for Biological Research: Dr. Yinon Levy, Uri Elia, Dr. Emanuelle Mamroud, and Dr. Ofer Cohen. The results of the study were published in the journal Science Advances.

"So far, mRNA vaccines, such as the COVID-19 vaccines which are familiar to all of us, were assumed to be effective against viruses but not against bacteria," explains Dr. Edo Kon. "The great advantage of these vaccines, in addition to their effectiveness, is the ability to develop them very quickly: once the genetic sequence of the virus SARS-CoV2 (COVID-19) was published, it took only 63 days to begin the first clinical trial. However, until now scientists believed that mRNA vaccines against bacteria were biologically unattainable. In our study we proved that it is, in fact, possible to develop mRNA vaccines that are 100% effective against deadly bacteria."

Running RNA gel

Combining Breakthrough Strategies

The researchers explain that viruses depend on external (host) cells for their reproduction. Inserting its own mRNA molecule into a human cell, a virus uses our cells as a factory for producing viral proteins based on its own genetic material, namely replicates of itself.

In mRNA vaccines this same molecule is synthesized in a lab, then wrapped in lipid nanoparticles resembling the membrane of human cells. When the vaccine is injected into our body, the lipids stick to our cells, and consequently the cells produce viral proteins. The immune system, becoming familiar with these proteins, learns how to protect our body in the event of exposure to the real virus.

Since viruses produce their proteins inside our cells, the proteins translated from the viral genetic sequence resemble those translated from the lab-synthesized mRNA.

"If tomorrow we face some kind of bacterial pandemic, our study will provide a pathway for quickly developing safe and effective mRNA vaccines." Prof. Dan Peer

Bacteria, however, are a whole different story: They don't need our cells to produce their own proteins. And since the evolutions of humans and bacteria are quite different from one another, proteins produced in bacteria can be different from those produced in human cells, even when based on the same genetic sequence.

"Researchers have tried to synthesize bacterial proteins in human cells, but exposure to these proteins resulted in low antibodies and a general lack of protective immune effect, in our bodies," explains Dr. Kon. "This is because, even though the proteins produced in the bacteria are essentially identical to those synthesized in the lab, being based on the same 'manufacturing instructions', those produced in human cells undergo significant changes, like the addition of sugars, when secreted from the human cell."

"To address this problem, we developed methods to secrete the bacterial proteins while bypassing the classical secretion pathways, which are problematic for this application. The result was a significant immune response, with the immune system identifying the proteins in the vaccine as immunogenic bacterial proteins. To enhance the bacterial protein's stability and make sure that it does not disintegrate too quickly inside the body, we buttressed it with a section of human protein. By combining the two breakthrough strategies we obtained a full immune response."

WATCH: Prof. Dan Peer and Dr. Edo Kon on the world's first mRNA vaccine for deadly bacteria

Solution to Antibiotic-resistant Bacteria?

"There are many pathogenic bacteria for which we have no vaccines," adds Prof. Peer. "Moreover, due to excessive use of antibiotics over the last few decades, many bacteria have developed resistance to antibiotics, reducing the effectiveness of these important drugs. Consequently, antibiotic-resistant bacteria already pose a real threat to human health worldwide. Developing a new type of vaccine may provide an answer to this global problem."

"In our study, we tested our novel mRNA vaccine in animals infected with a deadly bacterium. Within a week, all unvaccinated animals died, while those vaccinated with our vaccine remained alive and well. Moreover, in one of our vaccination methods, one dose provided full protection just two weeks after it was administered. The ability to provide full protection with just one dose is crucial for protection against future outbreaks of fast-spreading bacterial pandemics. It is important to note that the COVID-19 vaccine was developed so quickly because it relied on years of research on mRNA vaccines for similar viruses. If tomorrow we face some kind of bacterial pandemic, our study will provide a pathway for quickly developing safe and effective mRNA vaccines."

The study was funded by research grants from the European Union (ERC; EXPERT) and the Shmunis Family (for Prof. Peer).

The research was led by Prof. Neta Erez, head of the laboratory for the biology of tumors from the Department of Pathology at the Sackler Faculty of Medicine, and members of her team: Omer Adler, Yael Zeit, and Noam Cohen, in collaboration with Prof. Shlomit Yust Katz from Rabin Medical Center (Beilinson Hospital) and Prof. Tobias Pukrop from Regensburg Hospital, Germany. The study was supported by the Melanoma Research Alliance (MRA), the Cancer Biology Research Center at Tel Aviv University, the Personalized Medicine Program of the Israel Science Foundation (ISF IPMP) and the German Cancer Research Foundation (DFG), and was published in the journal Nature Cancer.

In this new study, the researchers show that Lipocalin-2 (LCN2) [a protein which in humans is encoded by the LCN2 gene] is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival.

LCN2 is a secreted protein that functions in the innate immune system and was originally discovered due to its ability to bind iron molecules and as part of the inflammatory process in fighting bacterial infection. LCN2 is produced by a large variety of cells and was shown to be involved in multiple cancer-related processes.

"Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target," says Prof. Neta Erez.

"In blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases." Prof. Neta Erez

LCN2 as a Predictive Marker for Brain Metastases

The researchers used models of melanoma and breast cancer brain metastases to reveal the mechanism by which neuroinflammation is activated in the metastatic niche in the brain.

"We show that signals secreted into the blood from the primary tumor stimulate pro-inflammatory activation of astrocytes in the brain. The astrocytes promote the recruitment of inflammatory cells from the bone marrow (granulocytes) into the brain, and they in turn become a main source of signaling by LCN2," explains Prof. Erez.

"We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases."

Prof. Erez adds: "We analyzed the LCN2 protein levels in the blood and cerebrospinal fluid (CSF) of mice with brain metastases and found that LCN2 levels increased greatly in mice with melanoma and breast cancer metastases compared to healthy mice. Importantly - an increase in blood LCN2 preceded the detection of brain metastases by MRI. Furthermore, the mice in which LCN2 levels were very high developed brain metastases later, further establishing LCN2 as a predictive marker for brain metastases.”

The researchers also examined whether LCN2 is elevated in the blood of melanoma patients at the time of initial diagnosis, and whether it can be a prognostic factor. The findings indicated that patients with melanoma had significantly higher levels of LCN2 in their blood compared to samples from healthy individuals. Strikingly, patients who developed brain metastases displayed significantly higher levels of LCN2 even before the diagnosis of the metastases, and high levels of LCN2 in the blood correlated with worse survival.

"We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance. The functional and prognostic aspects of LCN2 that we have identified in brain metastases in mouse models as well as in cancer patients suggest that targeting LCN2 may be an effective therapeutic strategy to delay or prevent the recurrence of brain metastases," summarizes Prof. Erez.

A new study from Tel Aviv University's School of Zoology tested the impact of prolonged low-intensity light pollution on two species of desert rodents: the diurnal golden spiny mouse, and the nocturnal common spiny mouse. The findings were highly disturbing: on two different occasions, entire colonies exposed to ALAN (Artificial Light At Night) died within days, and reproduction also decreased significantly compared to control groups. According to the researchers, the results show clearly for the first time that light pollution can be extremely harmful to these species, and suggest they may be harmful to ecosystems, biodiversity, and even human health.

"According to latest studies, about 80% of the world's human population is exposed to ALAN, and the area affected by light pollution grows annually by 2-6%. In a small and overcrowded state like Israel, very few places remain free of light pollution." Hagar Vardi-Naim

Humans Changed the Rules

The study was led by Prof. Noga Kronfeld-Schor, Chief Scientist of Israel's Ministry of Environmental Protection, and PhD student Hagar Vardi-Naim, both from TAU's School of Zoology and the Steinhardt Museum of Natural History.  The paper was published in Scientific Reports.

"We have been studying these closely related rodent species for years.  They both live in Israel's rocky deserts: the golden spiny mouse (Acomys russatus) is diurnal [active during the day], and the common spiny mouse (A. cahirinus) in nocturnal [active during the night]," explains Prof. Kronfeld-Schor. "The two species share the same natural habitat but use it at different times to avoid competition. By comparing closely related species that differ in activity times, we gain new insights into the biological clock and its importance to the health of both animals and humans."

Hagar Vardi-Naim notes that, "in most species studied to date, including humans, the biological clock is synchronized by light. This mechanism evolved over millions of years in response to the daily and annual cycles of sunlight – day and night and their varying lengths that correspond to the change of seasons. Different species developed activity patterns that correspond to these changes in light intensity and daylength and developed anatomical, physiological and behavioral adaptations suitable for day or night activity and seasonality."

"However, over the last decades, humans have changed the rules by inventing and extensively using artificial light, which generates light pollution. According to latest studies, about 80% of the world's human population is exposed to ALAN, and the area affected by light pollution grows annually by 2-6%. In a small and overcrowded state like Israel, very few places remain free of light pollution. In our study, we closely monitored the long-term effects of ALAN on individuals and populations under semi-natural conditions."

"We had seen no preliminary signs (…) We assume that exposure to ALAN had impaired the animals' immune response, leaving them with no protection against some unidentified pathogen [organism causing disease to its host]." Prof. Noga Kronfeld-Schor

Prof. Noga Kronfeld-Schor

Dramatic Turn of Events

In the study, the researchers placed 96 spiny mice, males and females in equal numbers, in eight spacious outdoor enclosures at TAU's Zoological Research Garden. The enclosures simulated living conditions in the wild: all animals were exposed to natural environmental conditions, including the natural light/dark cycle, ambient temperatures, humidity, and precipitation. Each enclosure contained shelters, nesting materials and access to sufficient amounts of food. The experimental enclosures were exposed to low-intensity ALAN (like a streetlamp in urban areas) of different wavelengths (colors) for 10 months: two enclosures were exposed to cold white light, two to warm white (yellowish) light, and two to blue light, while two of the enclosures remained dark at night and served as controls. All animals were marked to enable accurate monitoring of changes in behavior and physical condition. The experiment was conducted twice in two successive years.

"The average life expectancy of spiny mice is 4-5 years, and our original plan was to monitor the effects of ALAN on the same colonies, measuring the effects on reproductive output, wellbeing and longevity," says Prof. Kronfeld-Schor. "But the dramatic results thwarted our plans: on two unrelated occasions, in two different enclosures exposed to white light, all animals died within several days. We had seen no preliminary signs, and autopsies at TAU's Faculty of Medicine and the Kimron Veterinary Institute in Beit Dagan revealed no abnormal findings in the dead spiny mice. We assume that exposure to ALAN had impaired the animals' immune response, leaving them with no protection against some unidentified pathogen. No abnormal mortality was recorded in any of the other enclosures, and as far as we are aware, no similar event has ever been documented by researchers before."

"Our findings show that light pollution, especially cold white and blue light, increases mortality and disrupts reproduction, and thus may be detrimental to the fitness and survival of species in the wild. This adverse effect can have far-reaching consequences at the current wide distribution of light pollution." Prof. Noga Kronfeld-Schor

Disrupted Reproduction

Other findings also indicated that exposure to ALAN disrupts the reproductive success of spiny mice: "In the wild both species of spiny mice breed mainly during summer, when temperatures are high, and the newborn pups are most likely to survive," shares Hagar Vardi-Naim. "Artificial light, however, seemed to confuse the animals. The common spiny mice began to breed year-round but produced a lower number of pups per year. Pups born during winter are not expected to survive in nature, which would further reduce the species' reproductive success in the wild."

"The reproduction of golden spiny mice was affected in a different way: colonies exposed to ALAN continued to breed in the summer, but the number of young was reduced by half compared to the control group, which continued to thrive and breed normally. These findings are in accordance with the fact that in seasonal long day breeders the cue for reproduction is day length."

Additional tests revealed that exposure to ALAN caused physiological and hormonal changes – most significantly in the level of cortisol, an important stress hormone involved in the regulation and operation of many physiological pathways, including the regulation of the immune system. Lab tests indicated that exposure to blue light increased cortisol levels of golden spiny mice, while white light reduced cortisol levels of golden spiny mice males in winter.

"Our findings show that light pollution, especially cold white and blue light, increases mortality and disrupts reproduction, and thus may be detrimental to the fitness and survival of species in the wild. This adverse effect can have far-reaching consequences at the current wide distribution of light pollution. Our clear results are an important step toward understanding the impact of light pollution on biodiversity and will help us promote science-based policies, specifically with regard to the use of artificial light in both built and open areas. In future studies we plan to investigate what caused the extensive deaths in the enclosures exposed to ALAN, focusing on the effect of light pollution exposure on the immune system," concludes Prof. Kronfeld Schor.

The study was led by Noa Katabi, a research student in the lab of Dr. Yaara Yeshurun in The School of Psychological Sciences and the Sagol School of Neuroscience. The study was published in the Journal of Neuroscience.

During the study, participants watched video-clips, including a neutral (in terms of political characteristics) video-clip and different political campaign-ads and political speeches by politicians from both blocs, Right and Left. The researchers were surprised to discover widespread partisanship-dependent brain activation and synchronization when Right-wing individuals watched the videos of their political bloc, or when Left-wing individuals watched the videos of left-wing politician.

Interestingly, the researchers found that such partisanship-dependent differences in brain synchronization was not limited to "higher" areas of the brain, associated with interpretation and abstract thinking, as was previously found. Rather, these differences occurred already in regions responsible for sight, hearing and even touch.

"This is the first study to show political-dependent brain activity in early sensory and motor areas, and it can be said that at the most basic brain level, rightists and leftists in Israel literally (and not just metaphorically) don't see and hear the same things." Dr. Yaara Yeshurun

Dr. Yaara Yeshurun

Rightists and Leftists Experience Things Differently

"The research clearly showed that the more the subjects were politically aligned with a certain group, the more their brain response was synchronized, including in motor and somatosensory areas, that is, those areas of the brain that are active when we move or feel things with our senses," explains Dr. Yeshurun. "In fact, just by the brain’s response in these primary sensory areas we could tell if a certain individual was left or wight wing. Intriguingly, it was not necessary to examine the activity in 'higher' brain areas - areas that are involved in understanding why a certain character did something, or what that character thinks and feels - to predict participants' political views, it could even be done by examining an area of the brain that is responsible for seeing or hearing.”

The researchers think that this surprising finding is due to the fact that the participants they chose were politically involved, and also due to the timing of the experiment - a few weeks before the elections, when the political atmosphere in Israel was very present and emotional.

"This is the first study to show political-dependent brain activity in early sensory and motor areas, and it can be said that at the most basic brain level, rightists and leftists in Israel literally (and not just metaphorically) don't see and hear the same things. I think that if we try to understand how people who hold opposite political views to ours experience the world, we might be able to conduct a slightly more effective public discussion that can hopefully attenuate the current political polarization,” adds Dr. Yeshurun.

Right or left? "If we try to understand how people who hold opposite political views to ours experience the world, we might be able to conduct a slightly more effective public discussion (…)"

The research was led by Dr. Boaz Barak from the School of Psychological Sciences and the Sagol School of Neuroscience at Tel Aviv University and Dr. Asaf Marco from the Faculty of Agriculture, Food and Environment of the Hebrew University. Also participating in the research were Dr. Sari Trangle, Mr. Gilad Levy and Ms. Ela Bar from Dr. Barak's laboratory, and Dr. Tali Rosenberg and Ms. Hadar Parnas from Dr. Marco's laboratory. The research findings were published in the prestigious journal Molecular Psychiatry from the Nature publishing group.

"We wanted to examine whether the Williams Syndrome is also characterized by defects in the genomes contained in brain cells which prevent the proper expression of essential genes." Dr. Boaz Barak

Dr. Barak: “Williams syndrome is a rare, multisystem genetic syndrome that includes disorders in brain development that lead to heightened social interactions, mental retardation, and other characteristic features. Past research has revealed that twenty-five genes are missing from the DNA on chromosome number seven of people with Williams syndrome, and the study of the syndrome to date has mainly focused on those missing genes and their functions."

"We wanted to examine whether the syndrome is also characterized by defects in the genomes contained in brain cells which prevent the proper expression of essential genes. Specifically, we asked: ‘Is it possible that certain genes are not expressed properly in the brains of people with Williams syndrome due to the phenomenon of methylation - when a molecule known as a 'methyl group' is located on a certain gene that is present in the genome, preventing it from expressing itself properly?".

To illustrate the phenomenon of the missing genes, Dr. Barak took an instruction book in which some of the pages were torn out. As a result of the missing pages, anyone following the instructions would make mistakes. Similarly, hiding some of the letters in the pages left in the book with a black marker would result in instructions being corrupted, just like methylation on an existing gene disrupts its expression.

Methylation is in many cases a normal mechanism in the cells of the body, as its role is to prevent expression of certain genes when appropriate. However, when there are disruptions in the correct application of methylation, the abnormal expression of the genes may lead to impairments in cell function, and subsequently cause damage to various organs, including to normal brain development.

Dr. Boaz Barak  from the School of Psychological Sciences and the Sagol School of Neuroscience at Tel Aviv University

Uncovering New Factors

The researchers examined human brain tissues taken from adults with and without Williams syndrome who died of causes unrelated to the syndrome and donated their brains to science.

“We focused on samples from the frontal lobe, the area of the brain that is responsible for brain functions such as cognition and decision-making," Dr. Barak explained. "In a previous study, we located in this area damage to the characteristics of the nerve cells and the cells that support nerve cell activity in people with Williams syndrome. In this study, we examined all the genes in all the cells of the frontal lobe to determine whether there are genes in people with Williams syndrome that have undergone abnormal methylation processes, i.e., increased or decreased gene silencing compared to a brain with typical development.”

"We uncovered significant information about the defective expression of genes in people with Williams syndrome. While these genes are fully present in the genome of the brain cells, until now it was not known that these abnormally regulated genes are involved in the syndrome." Dr. Asaf Marco.

The researchers found that indeed in people with Williams syndrome abnormal methylation does exist in this area of the brain, resulting in disruption of the normal expression of many genes related to the normal development of the brain's neural functions, such as regulation of social behavior (people with Williams syndrome are known to be overly friendly), cognition, plasticity of the brain, and cell survival.

“We uncovered significant information about the defective expression of genes in people with Williams syndrome. While these genes are fully present in the genome of the brain cells, until now it was not known that these abnormally regulated genes are involved in the syndrome," says Dr. Marco.

"Building on our findings, it will be possible to focus future efforts on the development of targeted treatments that will reach the disrupted sites that we identified in the study in order to 'correct' the defective expressions." Dr. Boaz Barak

Next Step: Target Disrupted Sites

"In addition, one of our main findings is that the disruptions in methylation do not have to appear near the gene whose function is impaired, and sometimes the disruptions are located far away from it. This information is critical because it allows us to better understand the spatial organization of DNA and its effect on gene control."

He adds that, "since we know of enzymes that are able to remove or add methyl molecules, the next challenge will be to precisely direct those enzymes to the disrupted sites identified in our research, with the aim of allowing the genes to be properly expressed.”

Dr. Barak concludes: "Our research revealed new factors related to the disabilities that characterize Williams syndrome. Instead of focusing on the effects of the missing gene, as has been done until now, we shed light on many more genes that are expressed in a defective manner. Building on our findings, it will be possible to focus future efforts on the development of targeted treatments that will reach the disrupted sites that we identified in the study in order to 'correct' the defective expressions.”