After developing an innovative technology that enables the growth of seaweed enriched with proteins and minerals such as zinc, iron, iodine, magnesium, and calcium for humans and animals, researchers from Tel Aviv University's School of Zoology at The George S. Wise Faculty of Life Sciences and the Israel Oceanographic and Limnological Research Institute (IOLR) have made a new advancement: They succeeded in significantly increasing the ability of seaweed to produce healthy natural substances, focusing on enhancing the production of bio-active compounds that offer medical benefits to humans, such as antioxidants - the concentration of which was doubled in the seaweed; natural sunscreens - its concentration tripled; and unique protective pigments of great medical value, the concentration of which increased by ten-fold.

The study was carried out with the innovative and sustainable approach of integrated aquaculture, which combines seaweed with fish cultivation, upgrading the seaweed while at the same time helping to purify the seawater and minimizing negative environmental impacts. According to the researchers, these findings may serve the pharmaceutical, cosmetics, food, and nutritional supplement industries.  

Manufacturers of Valuable Compounds

The new development was led by Ph.D. student Doron Ashkenazi of Tel Aviv University and the Israel Oceanographic and Limnological Research Institute, under the guidance of Prof. Avigdor Abelson of Tel Aviv University’s School of Zoology and Prof. Alvaro Israel of the IOLR in Haifa, in collaboration with other leading researchers from Israel and around the world, including Guy Paz from IOLR; organic chemistry expert Dr. Shoshana Ben-Valid; Dr. Eitan Salomon from the National Center for Mariculture in Eilat; and Prof. Félix López Figueroa, Julia Vega, Nathalie Korbee, and Marta García-Sánchez from Malaga University in Spain. The article was published in the scientific journal Marine Drugs.

Ph.D. student Doron Ashkenazi (left) and Prof. Avigdor Abelson (right)

Doron Ashkenazi explains that “seaweed, also known as macroalgae, are marine plants that form the basis of the coastal marine ecosystem. The seaweed absorb carbon dioxide and release oxygen into the environment. They purify the water, provide food, habitat, and shelter for numerous species of fish and invertebrates. Not many know that seaweed also produce a wide variety of distinct bio-active compounds that are beneficial to humans. The seaweed living in the intertidal zone face extreme stress conditions, which include changes in salinity, temperature, desiccation [loss of moisture] conditions, changes in the availability of nutrients and high exposure to solar radiation, especially in the ultraviolet (UV) range."

"Not many know that seaweed also produce a wide variety of distinct bio-active compounds that are beneficial to humans." Doron Ashkenazi

To survive, the seaweed has developed a unique set of chemical defense mechanisms – natural chemicals that help them cope with these harsh environments. They are highly efficient natural factories that produce valuable substances that may offer significant benefits to humans.

In the current study, they sought to examine whether and how it is possible to increase and maximize the seaweed’ production of bio-active compounds, and secondary metabolites, that offer significant health benefits. These substances include antioxidants, protective pigments, and natural UV radiation filters.

A dedicated aquaculture system where the researchers grew three local species of algae

Future Looking Greener Than Ever?

To this end, the researchers developed an original and practical cultivation approach, whereby three local seaweed - Ulva, Gracilaria and Hypnea - were initially grown alongside fish effluents, and subsequently exposed to stressors including high irradiance, nutrient starvation, and high salt content.

They investigated how these changes affected the concentration of specific valuable biomaterials in the seaweed, to enhance their production. The results were impressive: antioxidant levels had doubled, seaweed natural sunscreen molecules tripled, and protective pigments were increased by ten-fold. “We developed optimal cultivation conditions and invented a new and clean way to increase the levels of healthy natural bio-active compounds in seaweed to an unprecedented level,” says Ashkenazi. “We in fact produced ‘super seaweed’ tailor designed to be utilized by the emerging health industries for food and health applications.”

“In the future, humanity will focus on creating science-based environmental solutions (...) technologies that promote recycling and the sound use of natural resources without overexploiting them.” Doron Ashkenazi  

The researchers believe that in the future it will be possible to use their cultivation approach to elevate in seaweed additional natural materials with important medical properties, such as anti-cancer, anti-diabetic, anti-inflammatory, anti-viral, and ant-biotic substances.

They also emphasize that seaweed aquaculture is environmentally friendly, preserving the ecological balance, and reducing environmental risks by minimizing excessive amounts of pollutants caused by humans, reducing the emission of greenhouse gases, and lowering the carbon footprint. In this way, seaweed aquaculture can help cope with global environmental challenges such as pollution, habitat loss, and the climate crisis.

“In the future, humanity will focus on creating science-based environmental solutions, like the one we offer in this study - technologies that promote recycling and the sound use of natural resources without overexploiting them. Our study demonstrates how we can enjoy nature without harming it,” concludes Ashkenazi.

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 (…)"