Research suggests: extinct animals explain Israel’s lack of cave art.
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Research
Dec 31st, 2024
Can Foreign DNA Outsmart Bacterial Defenses?
A step toward combating resistance and manipulating bacteria
- Life Sciences
A new study by Tel Aviv University reveals how bacterial defense mechanisms can be neutralized, enabling the efficient transfer of genetic material between bacteria. The researchers believe this discovery could pave the way for developing tools to address the antibiotic resistance crisis and promote more effective genetic manipulation methods for medical, industrial, and environmental purposes. The study was led by PhD student Bruria Samuel from the lab of Prof. David Burstein at the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University’s Wise Faculty of Life Sciences. Other contributors to the research include Dr. Karin Mittelman, Shirly Croitoru, and Maya Ben-Haim from Prof. Burstein's lab. The findings were published in the prestigious journal Nature.
The researchers explain that genetic diversity is essential for the survival and adaptation of different species in response to environmental changes. For humans and many other organisms, sexual reproduction is the primary driver of the genetic diversity required for survival. However, bacteria and other microorganisms lack such a reproduction mechanism. Nevertheless, as demonstrated by the alarming speed at which antibiotic resistance spreads among bacterial populations, bacteria have alternative mechanisms to maintain the genetic diversity necessary for survival, including the direct DNA transfer between bacteria.
DNA transfer between bacteria plays a crucial role in their survival. Yet, a key aspect of this process has remained underexplored: how is the exchange of genetic material so prevalent despite bacteria having a wide range of defense mechanisms designed to destroy any foreign genetic material entering their cells? The new research focuses on “conjugation”, one of the main mechanisms for transferring DNA from one bacterium to another. During conjugation, one bacterial cell connects directly to another through a tiny tube that allows the transfer of genetic material fragments known as plasmids. Prof. Burstein explains: “Plasmids are small, circular, double-stranded DNA molecules classified as ‘mobile genetic elements.’ Like viruses, plasmids move from one cell to another, but unlike viruses, they do not need to kill the host bacterium to complete the transfer”.
Plasmids That Outsmart Bacterial Defenses
As part of the natural exchange, plasmids often give recipient bacteria genetic advantages. For example, many antibiotic-resistance genes spread through plasmid transfer between bacteria. However, bacteria also have numerous defense mechanisms aimed at eliminating any foreign DNA entering their cells. “Conjugation is a well-known process that scientists also use in the lab to transfer genes between bacteria. It’s also known that bacteria possess mechanisms to destroy foreign DNA, including plasmid DNA, and some of these mechanisms are even used for various research purposes. However, until now, no one has fully explored how plasmids overcome these defense mechanisms”, says Prof. Burstein. Samuel explains that she began the research by conducting a computational analysis of 33,000 plasmids and identifying genes associated with ‘anti-defense’ systems that help plasmids bypass bacterial defense mechanisms. What was even more interesting was the location of these genes. As mentioned, plasmids are double-stranded circular DNA segments. To pass through the thin tube that connects the bacteria, one of those circular strands is cut at a certain point by a protein, which then binds to the cleaved strand and initiates its transfer to the recipient cell. “The genes for the anti-defense systems that I identified were found to be concentrated near that cutting point, and organized in such a manner that they would be the first genes to enter the new cell. This strategic positioning allows the genes to be activated immediately upon transfer, giving the plasmid the advantage needed to neutralize the recipient bacteria’s defense systems”.
Left to right: Prof. David Burstein & PhD student Bruria Samuel.
Prof. Burstein recounts how, when Samuel first showed him her results, he found it hard to believe that such a phenomenon had not been identified before. “Bruria conducted an extensive literature review and found that no one had previously made this connection,” he says. Since the discovery was made by analyzing existing databases with computational tools, the next step was to demonstrate in the lab that this phenomenon indeed occurs during plasmid transfer between bacteria. Samuel explains, “To do this, we used plasmids that confer antibiotic resistance and introduced them into bacteria equipped with CRISPR, the well-known bacterial defense system that can target and destroy DNA, including that of plasmids. This method allowed us to easily test the conditions under which the plasmid could overcome the defense system — if it succeeds in overcoming the CRISPR system, the recipient bacteria become resistant to antibiotics. If it fails, the bacteria die”. Using this method, Samuel demonstrated that if the anti-defense genes are positioned near the DNA entry point, the plasmid successfully overcomes the CRISPR system. However, if these genes are located elsewhere on the plasmid, the CRISPR system destroys the plasmid, and the bacteria die upon exposure to antibiotics.
How Can Gene Transfers Be Improved?
Prof. Burstein notes that understanding the positioning of anti-defense systems on plasmids could enable the identification of new anti-defense genes, a subject currently under highly active research. "Moreover, our study can contribute to designing more efficient plasmids for genetic manipulation of bacteria in industrial processes. While plasmids are already widely used for these purposes, the efficiency of plasmid-based genetic transfer in lab conditions is significantly lower than that of natural plasmids,” he says. “Another potential application could involve designing effective plasmids for genetic manipulation of natural bacterial populations. This could help block antibiotic resistance genes in hospital bacterial populations, teach bacteria in soil and water to break down pollutants or fix carbon dioxide, and even manipulate gut bacteria to improve human health”.
Ramot, Tel Aviv University’s technology transfer company, regards this discovery as a significant biotechnological breakthrough with broad applications. Dr. Ronen Kreizman, CEO of Ramot, states: “First, I want to congratulate Prof. David Burstein and his lab team on this fascinating scientific discovery. The new research opens revolutionary possibilities in areas such as developing drugs against resistant bacteria, synthetic biology, agritech and foodtech. The ability to control and fine-tune genetic material transfer between bacteria could become a powerful tool for addressing environmental, agricultural, and medical challenges. We are currently working on commercializing this technology to realize its full potential”.
Research
Dec 31st, 2024
Mystery in the Stones: The Truth About Rujm el-Hiri
Geodynamic shifts challenge Rujm el-Hiri’s role as an ancient observatory.
- Medicine
A new study by Tel Aviv University and Ben-Gurion University of the Negev reveals groundbreaking findings about the famous Rujm el-Hiri site (known as the "Wheel of Ghosts") in the Golan Heights. Based on geomagnetic analysis and tectonic reconstruction, the researchers determined that geodynamic movement over 150 million years, at an average rate of 8–15 mm per year, caused significant shifts in the ground, rotating and reorienting it over millennia. This finding challenges the widely held theory that the structure was used as an astronomical observatory, as the original alignment of the walls and entrances does not correspond to celestial observations, as previously hypothesized.
The study was led by a research team headed by Dr. Olga Khabarova and Prof. Lev Eppelbaum of the Department of Geophysics at the Porter School of the Environment and Earth Sciences, Tel Aviv University, in collaboration with Dr. Michal Birkenfeld of the Department of Archaeology at Ben-Gurion University. The article was published in the prestigious journal Remote Sensing.
Left to right: Dr. Olga Khabarova & Prof. Lev Eppelbaum.
The researchers employed geophysical methods and remote sensing techniques to demonstrate that Rujm el-Hiri’s current orientation differs from its original position due to thousands of years of geodynamic shifts. This discovery raises new questions regarding the site’s possible identification as an observatory. The team conducted initial mapping and documentation of the archaeological landscape within 30 kilometers around the Sea of Galilee. It visually analyzed the region to identify typical landscape features associated with historical human activity and the reconstruction of archaeological objects.
According to the research team, "The study was based on calculations of the sky map and aligning the directions of the solstices, equinoxes, and other celestial bodies as they appeared between 2500–3500 BCE, coordinated with the symmetry and entrances of Rujm el-Hiri in its current position. The findings show that the entrances and radial walls during that historical period were entirely different, reopening the question of the site's purpose".
The study also provides the first comprehensive mapping of the archaeological landscape surrounding Rujm El-Hiri, using advanced satellite technology. Unique landscape features were identified, including circular structures with 40–90 meters diameters, thick walls, and round enclosures approximately 20 meters in diameter, which appeared to serve agricultural or herding purposes. Dozens of burial mounds (tumuli) were documented in the area, some of which were likely used as storage facilities, shelters, or dwellings, in addition to their traditional role as burial sites.
The researchers conclude: "This new study not only opens a window to understanding Rujm el-Hiri but also enriches our knowledge of ancient life in the Golan Heights and the connections between various archaeological findings in the area".
Research
Dec 29th, 2024
What Happens When the Brain Learns Two Behaviors at Once?
TAU researchers reveal the brain resolves conflict by blocking dual learning.
- Biology
- Medicine
A new study from Tel Aviv University could reshape our scientific understanding of how humans learn and form memories, particularly through classical and operant conditioning. The research team found that our brain engages in fierce competition between these two learning systems and that only one can prevail at any given time. If we try to learn two conflicting actions for the same situation simultaneously, the result will be confusion, making it difficult to perform either action when re-encountering the situation. In their study, the researchers demonstrated this phenomenon in fruit flies. When the flies were trained to associate a smell with a randomly delivered electric shock (classical conditioning) and also to connect their actions to the smell and shock (operant conditioning), the flies became confused and failed to exhibit a clear response to the shock.
The intriguing research was led by Prof. Moshe Parnas and PhD student Eyal Rozenfeld from the Laboratory for Neural Circuits and Olfactory Perception at Tel Aviv University's Faculty of Medical and Health Sciences. The findings were published in the prestigious journal Science Advances.
The researchers explain that humans learn in a variety of ways. A well-known example of learning is Ivan Pavlov’s famous experiment, where a dog learns to associate the sound of a bell with food. This type of learning is called classical conditioning and involves passive associations between two stimuli. On the other hand, humans can also learn from their own actions: if a specific action produces a positive outcome, we learn to repeat it, and if it harms us, we learn to avoid it. This type of learning is called operant conditioning and involves active behavior.
Freeze or flee? Cracking the brain’s decision code
For many years, scientists believed that these types of memory work together in the brain. But what happens if the two memories dictate conflicting actions? For instance, mice can be trained to fear a certain smell using both conditioning methods, but their responses will differ depending on which method is employed. Under classical conditioning, the mice will freeze in place, while under operant conditioning, they will flee. What happens if both memories are present simultaneously? Will the mice freeze, flee, or simply continue behaving as if nothing happened?
In a unique study conducted on fruit flies (Drosophila), researchers at Tel Aviv University discovered that the brain cannot learn using both classical and operant conditioning simultaneously. The brain actively suppresses the formation of both types of memories at the same time, using this strategy to determine which behavior to execute. During the experiment, the researchers taught the flies to associate a smell with an electric shock. When classical conditioning was used flies learned to freeze when they smelled the conditioned odor. In contrast, when operant conditioning was used, flies learned to flee from the smell to avoid the electric shock. They demonstrated that the flies could not learn both lessons together and that attempts to teach both types of learning simultaneously led to no learning at all. Furthermore, they identified the brain mechanisms that prioritize one type of learning over the other.
"Our research completely changes the way we have thought for decades about how our brain learns," explains Prof. Parnas. "You can think of the brain as engaging in a 'mental tug-of-war': if you focus on learning through your actions, the brain blocks the formation of automatic associations. This helps avoid confusion but also means you can't learn two things simultaneously".
Why multitasking makes you forget
Prof. Parnas adds: "Fruit flies have simple brains, which makes them easy to study, but their brains are surprisingly similar to those of mammals—and thus to our own. Using powerful genetic tools, the researchers gained a deep understanding of how different learning systems compete for 'space in the brain.' They found that the brain's 'navigation center' intervenes to ensure that only one type of memory is active at any given moment, preventing clashes between the two systems. This discovery can help us understand why multitasking sometimes leads to forgetting important details".
Eyal Rozenfeld concludes: "Not only does this discovery reshape what we know about human learning, but it could also lead to the development of new strategies for treating learning disorders. By better understanding how memories are formed in individuals with conditions like ADHD or Alzheimer’s, we might be able to create new treatments. It’s fascinating that our brain selects between different learning systems to avoid confusion—all without us even being aware of it".
Research
Dec 25th, 2024
Rewriting the Narrative of King Solomon’s Mines
TAU research overturns myths about ancient copper pollution.
- Archeology
A new study from Tel Aviv University overturns prevailing scientific beliefs that King Solomon’s Mines not only harmed workers' health in the ancient copper industry but also posed risks to the health of modern residents living near the site.
In the new study, researchers conducted geochemical surveys at copper production sites in the Timna Valley, dating back to the 10th century BCE and the era of the Biblical Kings David and Solomon. They found that the environmental pollution from copper production was minimal and spatially restricted, posing no danger to the region's inhabitants in the past or today. Additionally, TAU's archaeologists reviewed previous studies and found no evidence that the ancient copper industry polluted the planet.
The study was led by Prof. Erez Ben-Yosef, Dr. Omri Yagel, Willy Ondricek, and Dr. Aaron Greener from the Department of Archaeology and Ancient Near Eastern Cultures from The Lester & Sally Entin Faculty of Humanities at Tel Aviv University. The paper was published in the prestigious journal Scientific Reports by Nature.
Prof. Erez Ben-Yosef.
Did Ancient Copper Mines Really Cause Pollution?
“We inspected two major copper production sites in the Timna Valley, one from the Iron Age and King Solomon’s era and another nearby that is about 1,500 years older”, says Prof. Erez Ben-Yosef. “Our study was extensive. We took hundreds of soil samples from both sites for chemical analyses, creating high-resolution maps of heavy metal presence in the region. We found that pollution levels at the Timna copper mining sites are extremely low and confined to the locations of the ancient smelting furnaces. For instance, the concentration of lead — the primary pollutant in metal industries — drops to less than 200 parts per million just a few meters from the furnace. By comparison, the U.S. Environmental Protection Agency defines industrial areas as safe for workers at 1,200 parts per million and residential areas as safe for children at 200 parts per million”.
The new study contradicts a series of papers published since the 1990s about pollution caused allegedly by the ancient copper industry. “We demonstrate that this is not true. Pollution in Timna is very restricted spatially, and only those working directly at the furnace likely suffered from inhaling toxic fumes, while just a short distance away, the soil is entirely safe. Moreover, the match we found between the spatial distribution of copper and lead concentrations in the soil further indicates that the metals are ‘trapped’ in slag and other industrial waste - which keeps them from leaching into the soil and affecting plants or humans. Our findings align with several recent studies from the Wadi Faynan region in Jordan, which also point to very low levels of pollution. Timna and Faynan are ideal sites for this type of research because they have not been disturbed by modern mining, as happened in Cyprus for example, and thanks to their dry climates the metals in the soil are not washed away. In Faynan, a team led by Prof. Yigal Erel of the Hebrew University examined 36 skeletons of people who lived at the mining site during the Iron Age, and only three showed any trace of pollution in their teeth. The rest were completely clean. We now present a similar picture for Timna”. In addition to the geochemical survey, the TAU archaeologists also conducted a comprehensive review of existing literature, pointing out that hypotheses about global pollution during the pre-Roman period lack solid evidence.
Dr. Omri Yagel recording the precise sampling location.
Clearing the Record: Not What We Thought
“There was a trend in the 1990s, which presented ancient copper production as the first instance of industrial pollution”, explains Dr. Omri Yagel, a leading researcher in the current study. “Such statements grab headlines and attract research grants, but they unnecessarily project modern pollution problems onto the past. Moreover, the research literature tends to use the term ‘pollution’ to describe any trace of ancient metallurgical activity, and this has led to the mistaken assumption that metal industries were harmful to humans from their earliest beginnings — which is patently untrue. Even when metal production was large-scale, becoming integral to human civilization, it was the toxic lead industry that caused global pollution, not necessarily other metals. A 1990s study argued that traces of copper found in Greenland ice cores had traveled through the atmosphere from sites like Timna. This claim, however, has not been corroborated by any subsequent study. As modern researchers grappling with the consequences of climate change, we have an inherent tendency to seek similar shifts in the past, but we must be careful. We may call a few pieces of slag lying on the ground ‘pollution’, but we should not confuse this local waste with regional or global environmental pollution”.
Research
Dec 23rd, 2024
GPS for Cancer: Directing Drugs to the Tumor
A breakthrough method delivers two drugs straight to the cancer site.
- Medicine
Researchers at Tel Aviv University have developed a new platform using polymeric nanoparticles to deliver drug pairs to specific cancer types, including skin and breast cancer. The researchers explain that having both drugs arrive at the tumor site significantly amplifies their therapeutic effects and safety profiles.
The study was led by Prof. Ronit Satchi-Fainaro and doctoral student Shani Koshrovski-Michael from the Department of Physiology and Pharmacology at Tel Aviv University's School of Medicine, in collaboration with other members of Prof. Satchi-Fainaro's lab: Daniel Rodriguez Ajamil, Dr. Pradip Dey, Ron Kleiner, Dr. Yana Epshtein, Dr. Marina Green Buzhor, Rami Khoury, Dr. Sabina Pozzi, Gal Shenbach-Koltin, Dr. Eilam Yeini, and Dr. Rachel Blau. They were joined by Prof. Iris Barshack from the Department of Pathology at Tel Aviv University's School of Medicine, Prof. Roey Amir and Shahar Tevet from the School of Chemistry at Tel Aviv University, and researchers from the Israel Institute of Biological Research, Italy, Portugal, and the Netherlands. The study was published in the prestigious journal Science Advances.
Bringing Precision to Drug Partnerships
Prof. Satchi-Fainaro explains: "Currently, cancer treatment often involves a combination of multiple drugs that work synergistically to enhance their anti-cancer effect. However, these drugs differ in their chemical and physical properties – such as their rate of degradation, their circulation time in the bloodstream, and their ability to penetrate and accumulate in the tumor. Therefore, even if multiple drugs are administered simultaneously, they don't arrive together at the tumor, and their combined effects are not fully realized. To ensure maximal efficacy and minimal toxicity, we sought a way to deliver two drugs simultaneously and selectively to the tumor site without harming healthy organs".
The researchers developed biodegradable polymeric nanoparticles (which break down into water and carbon dioxide within one month) capable of encapsulating two different drugs that enhance each other's activity. These nanoparticles are selectively guided to the cancer site by attaching them to sulfate groups that bind to P-selectin, a protein expressed at high levels in cancer cells as well as on new blood vessels formed by cancer cells to supply them with nutrients and oxygen.
The researchers loaded the platform with two pairs of drugs approved by the FDA: BRAF and MEK inhibitors used to treat melanoma (skin cancer) with a BRAF gene mutation (present in 50% of melanoma cases), and PARP and PD-L1 inhibitors intended for breast cancer with a BRCA gene mutation or deficiency. The novel drug delivery system was tested in two environments: in 3D cancer cell models in the lab and in animal models representing both primary tumor types (melanoma and breast cancer) and their brain metastases.
The findings showed that the nanoparticles, targeted toward P-selectin, accumulated selectively in primary tumors and did not harm healthy tissues. Furthermore, the nanoparticles successfully penetrated the blood-brain barrier, reaching metastases in the brain with precision without harming healthy brain tissue.
Additionally, the combination of two drugs delivered simultaneously was far more effective than administering the drugs separately, even at 30 times lower doses than prior preclinical studies. The nanoparticle treatment significantly reduced tumor size, prolonging time to progression by 2.5 times than standard treatments, and extended the lifespan of mice treated with the nanoparticle platform. Mice had a 2-fold higher median survival compared to those receiving the free drugs and a 3-fold longer survival compared to the untreated control group.
A New Approach to Cancer Treatment
Prof. Satchi-Fainaro summarized: "In our study, we developed an innovative platform using biodegradable polymeric nanoparticles to deliver pairs of drugs to primary tumors and metastases. We found that drug pairs delivered this way significantly enhanced their therapeutic effect in BRAF-mutated skin cancers and BRCA-mutated breast cancers and their brain metastases. Since our platform is versatile by design, it can transport many different drug pairs that enhance each other’s effects, thereby improving treatment for a variety of primary tumors and metastases expressing the P-selectin protein, such as glioblastoma (brain cancer), pancreatic ductal adenocarcinoma, and renal cell carcinoma".
The project received competitive research grants from Fundación “La Caixa”, the Melanoma Research Alliance (MRA), the Israel Science Foundation (ISF), and the Israel Cancer Research Fund (ICRF). It is also part of a broader research effort in Prof. Satchi-Fainaro’s lab supported by an Advanced Grant from the European Research Council (ERC), ERC Proof of Concept (PoC), EU Innovative Training Networks (ITN), and the Kahn Foundation.
