Tel Aviv Researcher Finds Potential Therapy for His Son’s Rare Disease - And Beyond
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Research
Jun 26th, 2025
Electric Body Parts: Charged Nanoparticles Can Lead Medications to Specific
Scientists in Dan Peer’s lab found that positively charged mRNA nanoparticles concentrate in the lungs - suggesting new treatments for lung cancer
- ביולוגיה
- ביולוגיה
The mRNA revolution gained speed and worldwide fame thanks to the COVID-19 pandemic. However, antiviral vaccines are just the tip of the iceberg for using mRNA wrapped in microscopic fat bubbles (called lipid nanoparticles - LNPs) to change the function of specific cells and tissues in the body. Yet, realizing this potential requires making sure the LNPs reach the right places in the body.
From Vaccine Vehicles to Precision Medicine
In a new study, published in the scientific journal ACS Nano, researchers in Dan Peer’s lab at Tel Aviv University's Shmunis School of Biomedicine and Cancer Research discovered that tweaking the composition of an LNP can give it a slight positive electric charge, and that these charged particles concentrate in the lungs, unlike other LNPs that tend to reach mainly the liver and spleen. They also showed how such LNPs can be used to carry mRNA that induces toxin production, effectively eliminating lung tumor cells - indicating the discovery can be used to develop new, specific, and effective therapies for hard-to-treat lung cancer and lung metastases.
Dr. Gonna Somu Naidu and Dr. Riccardo Rampado, post-doctoral researchers who led the study in the Peer lab, explain that their research started from practical, mechanistic reasons. "LNPs are made of combinations of different short fat molecules called lipids that self-assemble as a protective bubble around the mRNA molecule as a result of their chemical qualities, such as their hydrophobic (water-averse) nature that pushes them to form shapes that minimize their exposure to water," explains Dr. Rampado.
Selecting the right types and combination of lipids determines whether the mRNA will enter cells and be successfully translated into proteins. "The LNPs need to remain stable in production, in the vials until they are injected into the body, and as they flow through the bloodstream. When they enter the cells, it is usually through the endosome, the cell’s 'digestive organ'," says Dr. Rampado. Then, the mRNA must escape the endosome to the cell’s cytoplasm, where it can be translated into proteins. "To make sure this happens, we design the LNPs with ionizable lipids; as they move from the bloodstream to the endosome, which has a more acidic environment, they become positively charged. This positive charge causes them to interact with the endosomal membranes, disrupt them, and deliver the mRNA to the rest of the cell," adds Dr. Naidu.
Tweaking Chemistry to Target Tumors
The new study began with a large-scale effort to optimize the ionizable lipids needed both to enable this complex cellular process and to remain stable in mass-scale production for clinical use. "We created and screened a lipid library focusing on a less-studied aspect of the lipids - the linker molecules connecting the head and the tail of each lipid," says Dr. Naidu. To their surprise, they discovered that LNPs with ionizable lipids containing amide and urea linkers tended to concentrate in the lungs.
"To understand what drives these specific LNPs to reach the lungs, we conducted sophisticated statistical analyses of particle characteristics such as size and electric charge and realized that the slight positive charge determines the destination of the LNPs in the body," says Dr. Rampado. They then used animal models that enabled them to see which lung cells are transfected by the charged LNPs. "We found that all the different lung cells - epithelial, endothelial and immune cells - took up the nanoparticles and expressed the mRNA they carried. It shows that effective cell transfection is not restricted to receptors on a specific cell type." Finally, by using charged LNPs carrying mRNA encoding a bacterial toxin, they successfully treated mice with melanoma lung metastases, reduced tumor size, and extended survival.
"Our discovery shows how, by making tiny chemical changes, we can alter the properties and behavior of LNPs, opening the way for the development of new therapies for lung tumors. More broadly, our research demonstrates how changes in electric charge can lead LNPs to concentrate in specific tissues. In combination with other techniques for producing cell-type-specific LNPs, this approach opens the door to a new generation of precision mRNA medicine," concludes Prof. Peer, summing up the far-reaching implications of the discovery.
Research
May 12th, 2025
How to Make Cancer Cells Go Out with a Bang
A new virus-based therapy targets cancer cells’ ability to die silently, triggering an immune response and enhancing anti-tumor treatments
- ביולוגיה
- ביולוגיה
We all make compromises in life. That is true also for cancer cells. To prosper, they must be able to evade the immune system and internal defenses that prevent cancer from developing. To achieve this, cancer cells must abandon certain internal systems that could otherwise be useful in various situations during cellular life. Prof. Marcelo Ehrlich from Tel Aviv University's Shmunis School of Biomedicine and Cancer Research is studying how to exploit such compromises to fight cancer.
In his latest research, Prof. Ehrlich is working on combining different attacks against cancer cells by leveraging the weaknesses created by these compromises, forcing malignant cells to die a "noisy death"- one that alerts the immune system to the presence of the threat.
A Noisy Death, by Design
One of the systems cancer cells tend to abandon to evade the immune system is the interferon pathway. This system is used by cells to defend themselves against viral infection and communicate with each other, particularly when facing viral threats. When a cell becomes infected by a virus and succumbs to it, one of the functions of the interferon pathway ensures that its death is noisy, and the immune system is alerted to the threat. By disabling this system, cancer cells make sure that even if a specific cell dies, its death remains quiet, failing to alert the body to the malignant danger.
Prof. Ehrlich, in collaboration with his colleague Prof. Eran Bachrach from the Shmunis School, developed a virus that exploits this weakness, specifically attacking cancer cells lacking the interferon pathway, while remaining harmless to healthy cells that retain this functional system. The team engineered the virus to replicate specifically inside cells exhibiting defects in the interferon pathway, causing the targeted cancer cells to die as noisily as possible.
When the Combo Beats the Cancer
However, one of the strengths of tumors is their versatility. Not all cancer cells disable the interferon pathway, and the use of engineered viruses to fight cancer - known as oncolytic viruses - often has limited effects because they fail to infect a sufficient number of tumor cells. To overcome this limitation, Profs. Ehrlich and Bacharach are currently researching combinations of their cancer-killing virus with other treatments to achieve a synergistic effect, where combined therapies enhance each other's effectiveness and lead to increases in both viral infection and cell death.
One approach explored in their latest research involves combining the virus with targeted-therapy compounds. Cancer cells disable the mechanisms that normally limit cell multiplication, allowing them to grow uncontrollably. Targeted therapies may arrest the proliferation of rapidly dividing cells and induce a state of augmented sensitivity to viral infection and virally induced cell death. "In response to anti-cancer treatments, tumor cells attempt to ensure their deaths are as quiet as possible by turning off the interferon pathway," summarizes Prof. Ehrlich. "This exposes their weakness to our virus, allowing it to infect them and transform the quiet cell death into a very noisy one."
Research
Apr 7th, 2025
When the Cell's Production Manager Goes Off Its Rails
The function of our cells and the production of proteins depend on coordination among countless different molecules. In new research, Prof. Orna Elroy-Stein and her colleagues revealed what happens when one of the main orchestrators of protein production malfunctions
- ביולוגיה
- ביולוגיה
The central dogma of biology explains that genetic information is transcribed from DNA into messenger RNA molecules. These molecules are then translated into proteins by the ribosome. The resulting proteins are responsible for most of the cell's functions, interactions with the environment and organisms, and responses to physiological cues.
However, this seemingly simple process depends on breathtaking coordination among numerous different molecules. Prof. Orna Elroy-Stein’s research is dedicated to understanding the last stage of this complex process: what controls and regulates the translation of RNA into proteins.
Decoding a Rare Brain Disease
In a new study published today in NAR Molecular Medicine (Oxford University Press), Prof. Elroy-Stein and researchers from her lab at the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience at Tel Aviv University deciphered what happens when a key regulator of the RNA-to-protein translation process - one of the cell's "production managers" - malfunctions due to a mutation.
The research leading to this discovery focused on understanding a rare neurodegenerative genetic disease called Vanishing White Matter Disease, potentially helping identify new treatment targets. The disease usually appears around the age of three and leads to the patient's death during their teens. Prof. Elroy-Stein's discovery is crucial for understanding basic cell biology and how RNA translation regulation affects multiple cellular functions.
"Vanishing White Matter Disease has been a puzzle for many years. It was known to result from a mutation in a gene called EIF2B, one of the 'master regulators' of the initiation step of RNA translation into proteins by the ribosome - the cell’s protein-producing machine," says Prof. Elroy-Stein. "However, for reasons not yet fully understood, only a few cell types in the body are affected by the mutation, with astrocytes being the most severely impacted. These marvelous star-shaped cells are the primary cell type found in the brain and are responsible for its maintenance."
Breakthrough in Studying Astrocytes
In previous research, Prof. Elroy-Stein and her lab members established the first mouse model to study this disease. Their next challenge was determining how to study the translation process in astrocytes. "The most popular method of studying RNA translation regulation involves isolating ribosomes, especially polysomes - multiple ribosomes connected to the same RNA molecule, indicating active translation. By focusing on polysomes and sequencing the RNA molecules they connect to, we can determine which genetic sequences are actively translated into proteins. Comparing healthy and diseased cells allows us to identify RNA molecules not correctly translated due to mutations.”
However, for a long time, extracting ribosomes from astrocytes was unsuccessful. In significant research published by Prof. Elroy-Stein and her doctoral student, Shir Mandelboum, two years ago, they overcame this challenge. "Once we realized most ribosomes in astrocytes attach to membranes inside the cells, we developed an effective procedure to release them and extract the translated RNA for sequencing."
In the current research, this method enabled Prof. Elroy-Stein, for the first time, to identify genes in diseased astrocytes not effectively translated into proteins in response to cytokines. "We discovered that a mild mutation in a single gene can disrupt the translation regulation of about 30% of genes expressed in astrocytes, many related to cell metabolism and energy production. This provides directions for possible therapeutic targets and hints at why astrocytes, with high energy demands crucial for maintaining brain homeostasis, are primarily affected by the mutation."
Research
Mar 13th, 2025
Same but Different: How Viruses Mimic Human Proteins to Hijack Our Cells'
Dr. Tzachi Hagai explores the ensuing evolutionary arms race between our proteins and their viral copycats
- ביולוגיה
- ביולוגיה
Viruses are masters of efficiency. With a short genome encoding a small set of proteins, they can infiltrate our much more complex cells and take control of multiple mechanisms inside them. Some of the viral proteins are meant to neutralize the cells' defense systems, but many others are used to interact with the cells' proteins and hijack them for the virus’s purposes - primarily the multiple steps needed for the virus to replicate its genome and multiply. The genetic material encoding these viral proteins was stolen from ancient hosts, and their similarity to the cell's proteins enables them to hack into the protein network and manipulate it.
Dr. Tzachi Hagai from Tel Aviv University's Shmunis School for Biomedicine and Cancer Research studies these interactions between human and viral proteins and how they co-evolve. "This co-evolution is classically presented as an arms race, where one side tries to outmaneuver the other, and the other counters to contradict the change. Kind of like the Queen of Hearts' run in Alice in Wonderland," explains Dr. Hagai. "However, when taking an in-depth look into the known interactions between viral and host proteins, we discover that the interacting host proteins tend to change less than other host proteins not affected by viruses."
To better understand when a protein interaction can evolve and when it cannot, Dr. Hagai's lab is studying how host cells are evolutionarily responding to viruses using proteins crucial for the cell's function in some way. "For example, we are trying to understand why a protein cannot change in the location the viral protein is targeting."
Mapping Viral Proteins
To do that, as part of the newly ERC-funded project, the first step for Dr. Hagai and his colleagues is to map viral proteins "stolen" from hosts to hijack the host networks. "We use recent advancements in predicting protein folding using AI to compare the structures of viral proteins and identify similarities to human proteins, indicating that they can be used to mimic their function in the cell."
The next step is to understand how the identified viral proteins function in a similar manner to that of human proteins. "We want to understand how much the mimicking proteins can serve the same roles as the ‘original’ host proteins in the human cell. Analyzing the similarities and differences allows us to identify points of diversification - when the virus is using the human 'building block' for a new function - and better understand why other viral mimicking proteins remained unchanged."
Dr. Hagai's research is a classic example of basic science: the use of advanced technologies to answer fundamental questions about how biology functions. However, the successful completion of this project could also contribute significantly to our future health. "Identifying conserved viral proteins could help us pinpoint viral weaknesses we can use to design new antiviral therapies," explains Dr. Hagai. "And mapping the viral protein pathways that remain flexible for change can help us better predict which viruses are more or less likely to jump from one species to the next - and through which mechanisms this change could happen."
Research
Jan 21st, 2024
Designing Smart Liquids
Dr. Ayala Lampel is developing microscopic droplets of liquid that have the unique ability to respond to specific conditions in the environment. Her latest study was the first to demonstrate how to design a smart liquid that can serve as a sensitive biosensor.
- ביולוגיה
- ביולוגיה
If you are interested in groundbreaking developments and technologies, you’ve probably heard of the term smart materials - materials that "sense" their environment. These materials are designed to have at least one property capable of significantly changing in a controlled way as a result of external stimuli. Dr. Ayala Lampel is one of the few researchers in the world working to bring this smart material revolution to the next stage: instead of smart solid materials, she and her colleagues are developing smart liquids, liquids that are purposely designed to react to their environment in specific ways.
Like droplets of balsamic vinegar floating in olive oil, the researchers at Lampel’s lab at the Tel Aviv University Shmunis School of Biomedicine and Cancer Research are working with liquids that remain separated from each other and form these distinct droplets, or condensates, as a result of their chemical properties. The specific design and composition of the molecules inside these condensates is what gives the liquids their smart properties.
In the latest breakthrough in the field, a study published by Lampel and her colleagues two weeks after the war in Israel erupted, they were able to show for the first time how they can design these condensates to serve as optical sensors: that they change their color and fluorescence intensity in response to the presence and activity of a specific enzyme. The paper appeared in the October issue of the Proceedings of the National Academy of Sciences (PNAS) journal.
Bio-inspired study
Even though her lab is working solely with synthetic materials, without any living organisms involved in the research, the study in Lampel’s lab is bio-inspired: it is based on processes happening in nature, and specifically in her case, inside living cells. "Our cells contain multiple compartments, or organelles, used for different purposes, such as mini-factories for the production of molecules the cell needs. Some of these organelles are separated from the rest of the cell by membranes, but others are created by a process called 'liquid-liquid phase separation' - which relies on multiple weak interactions between the molecules inside the organelle that collectively results in separation from the rest of the environment and formation of condensate with distinct microenvironment," Dr. Lampel explains.
In cells, these condensates are made up of a mixture of proteins and nucleic acids, the cell's genetic material. "Long proteins, composed of hundreds of amino acids, are challenging to work with. So, in the lab, we use peptides - 'mini-proteins' made from short amino acid chains - instead of whole proteins. Because of their short length, the peptides are completely disordered, and lack stable structures and their flexibility is what promotes them to interact and undergo phase separation with nucleic acids into condensates".
By studying the sequences of amino acids in proteins in naturally-occurring condensates, Lampel and other researchers in the field have identified sequences that are involved in the formation of various cellular condensates. "This allows us to use the different sequences like Lego blocks in designing our peptides to control the specific functions we want them to have," she says.
Designing condensates to serve as liquid biosensors
In previous research, Lampel showed how she can design the condensates to release the molecules they contain in response to light - a development that can be used for a controlled release of medications in the body or other functions. In her most recent research, she explored a different approach.
"We wanted to see if we can design condensates that will serve as sensors. Melanin, the pigment that determines our skin color, is produced by an enzyme called tyrosinase which oxidizes a certain amino acid called tyrosine. Elevated levels of this enzyme are involved in several dermal disorders including hyperpigmentation and melanoma. So we designed the peptide that forms the condensate to contain tyrosine. This way, when we added the enzyme to the condensates, it oxidized the peptides within the condensates and changed their optical properties - turning them fluorescent. This study demonstrated the ability to design condensates to serve as liquid biosensors". This work was led by M.Sc. student Amit Netzer with the help other lab members, including Itai Katzir and Dr. Avigail Baruch Leshem, and in collaboration with Dr. Michal Weitman from Bar Ilan University.
Today, Lampel and her colleagues are working on giving the condensates many other new properties. She emphasizes that her interest is also focused on basic science - on discovering and expanding the uses and capabilities of the smart materials.
For example, in addition to advanced and sensitive biosensors, the ability to accurately control the phase separation can also be used to design smart liquids for the effective production of therapeutic biomolecules that today requires costly and complicated conditions to produce. Lampel also envisions how the condensates could be used as vessels to deliver medication into the body and even to serve as "mini-factories" producing medications inside us, and they can be designed to react to specific environments and this way control where exactly this production is happening.
"This is a brand new field. It still doesn’t know what it is, and what it is good for, but it is expanding rapidly, with many new papers and patents published every month," Lampel summarizes.
Read full article - "Emergent properties of melanin-inspired peptide/RNA condensates" >>
