Researchers offer possible reason why neutral sequences in the genome of living creatures continue to exist millions of years later
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Research
Mar 14th, 2023
Do We Need 'Junk DNA'?
- Life Sciences
A new model developed at Tel Aviv University offers a possible solution to the scientific question of why neutral sequences, sometimes referred to as "junk DNA", are not eliminated from the genome of living creatures in nature and continue to exist within it even millions of years later.
According to the researchers, the explanation is that junk DNA is often located in the vicinity of functional DNA. Deletion events around the borders between junk and functional DNA are likely to damage the functional regions and so evolution rejects them. The model contributes to the understanding of the huge variety of genome sizes observed in nature.
Border Induced Selection
The model describes a phenomenon which the team of researchers refer to as "border induced selection," and was developed under the leadership of PhD student Gil Loewenthal in the laboratory of Prof. Tal Pupko from the Shmunis School of Biomedicine and Cancer Research at the The George S. Wise Faculty of Life Sciences and in collaboration with Prof. Itay Mayrose, also from TAU's Faculty of Life Sciences. The study was published in the journal Open Biology.
Throughout evolution, the size of the genome in living creatures in nature changes. For example, some salamander species have a genome ten times larger than the human genome. "The rate of deletions and short insertions, dubbed 'indels', is usually measured by examining pseudogenes," explains Prof. Pupko. "Pseudogenes are genes that have lost their function, and in which there are frequent mutations, including deletions and insertions of DNA segments."
In previous studies that characterized the indels, it was found that the rate of deletions is greater than the rate of additions in a variety of creatures including bacteria, insects, and even mammals such as humans.
Prof. Tal Pupko
Reverse Bias for Short Segments
The question the researchers sought to answer is how the genomes are not deleted when the probability of DNA deletion events is significantly greater than DNA addition events: "We have provided a different view to the dynamics of evolution at the DNA level," says Loewenthal. "When measuring the rate of indels there will be more deletions, but the measurements are carried out in pseudogenes which are quite long sequences. We assert that in shorter neutral segments, deletions would likely remove adjacent functional segments which are essential for the functioning of the organism, and they will therefore be rejected [through 'border-induced selection']. Accordingly, we assert that when the segment is short, there will be a reverse bias – there will be more insertions than deletions - and therefore short neutral segments are usually retained."
"In our study, we simulated the dynamics of indels, while taking into account the effect of 'border-induced selection,' and compared the simulation results to the distribution of human intron lengths (introns are DNA segments in the middle of a protein-coding gene, which themselves do not code for a protein). A good match was obtained between the results of the simulations and the distribution of lengths observed in nature, and we were able to explain peculiar phenomena in the length distribution of introns, such as the large variation in intron lengths, as well as the complex shape of the distribution which does not look like a standard bell curve."
Research
Mar 13th, 2023
World's First mRNA Vaccine Against Deadly Bacteria
Israeli researchers develop vaccine that is 100% effective against bacteria lethal to humans
- Life Sciences
For the first time worldwide, a team of researchers from Tel Aviv University and the Israel Institute for Biological Research have developed an mRNA-based vaccine that is 100% effective against a type of bacteria that is lethal to humans. The study, conducted in a lab model, demonstrated that all treated models were fully protected against the bacteria. The researchers believe their new technology can enable rapid development of effective vaccines for bacterial diseases, including diseases caused by antibiotic-resistant bacteria, for example in case of a new fast-spreading pandemic.
"In our study we proved that it is, in fact, possible to develop mRNA vaccines that are 100% effective against deadly bacteria." Dr. Edo Kon
Quickly Developed
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).
Research
Mar 2nd, 2023
New Snake Family Identified
As far as researchers are aware the Micrelapidae family includes only three species, one in Israel and neighboring countries, and two in East Africa.
- Life Sciences
An extensive international study identified a new family of snakes: Micrelapidae. According to the researchers, Micrelaps, small snakes usually with black and yellow rings, diverged from the rest of the evolutionary tree of snakes about 50 million years ago. As far as they know, the new family includes only three species, one in Israel and neighboring countries, and two in East Africa.
"Today we tend to assume that most large groups of animals, such as families, are already known to science, but sometimes we still encounter surprises, and this is what happened with Micrelapid snakes." Prof. Shai Meiri
Exploring the Micrelaps' Family Tree
The study was conducted by Prof. Shai Meiri of TAU's School of Zoology, The George S. Wise Faculty of Life Sciences, and of The Steinhardt Museum of Natural History Museum, as well as researchers from Finland, the USA, Belgium, Madagascar, Hong Kong, and Israel. The paper was published in Molecular Phylogenetics and Evolution.
"Today we tend to assume that most large groups of animals, such as families, are already known to science, but sometimes we still encounter surprises, and this is what happened with Micrelapid snakes," explains Prof Meiri.
"For years, they were considered members of the largest snake family, the Colubridae, but multiple DNA tests conducted over the last decade contradicted this classification. Since then, snake researchers around the world have tried to discover which family these snakes belong to – to no avail. In this study we joined the scientific effort."
The researchers used micro-CT technology – high-resolution magnetic imaging, to examine the snake's morphology, focusing specifically on the skull. In addition, they applied methods of deep genomic sequencing – examining about 4,500 ultra-conserved elements, namely regions in the genome that take millions of years to exhibit any change.
Prof. Meiri explains that "in addition to the DNA of Micrelaps, we sampled DNA from various snake groups to which they might have belonged. This way, we discovered some unique genomic elements in Micrelaps, which were not found in any of the other groups."
Prof. Shai Meiri
"Even through these snakes have been known for decades, they were mistakenly included in other families for many years." Prof. Shai Meiri
Family Relocation
According to the researchers their findings indicate that Micrelaps diverged from the rest of the evolutionary tree of snakes about 50 million years ago. Since then, these snakes have evolved independently, as a distinct and separate family.
Apparently, this is a very small family, including only three species: two in Kenya and Tanzania in East Africa, and one in Israel and nearby regions (northern Jordan and the Palestinian Authority, southern Syria, and southern Lebanon). The geographic dispersion suggests that these snakes probably originated in Africa, and then, at some point in their history, some of them made their way north through the Great Rift Valley.
"In this study we were able to associate a new snake family – the Micrelapidae. Even through these snakes have been known for decades, they were mistakenly included in other families for many years. Since most animals have already been classified into well-defined families, such a discovery of a new family is quite a rare occurrence in modern science," concludes Prof. Meiri.
Research
Feb 26th, 2023
Researchers Discover Mechanism that Facilitates Formation of Brain Metastases
Findings could help predict metastatic recurrence in the brain and a worse prognosis
- Medicine
Brain metastases are one of the deadliest forms of cancer metastasis, with grave survival rates of less than one year in many cases. The incidence of brain metastases has been increasing in recent years and developing better therapeutic strategies for brain metastasis is an urgent need. In a new study from Tel Aviv University, researchers identified and characterized a new mechanism that facilitates the formation of brain metastases and found that impairing this mechanism significantly reduced the development of brain metastases in lab models.
"The findings establish LCN2 as a new prognostic marker and a potential therapeutic target." Prof. Neta Erez
On the Radar: LCN2
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.
