When a pregnant woman is infected with a virus, her immune system’s response to the infection may harm her baby’s brain – even if the fetus is not infected with the virus itself. This finding emerges from a study by researchers at the Weizmann Institute of Science.

It’s been long known that a viral infection during pregnancy may increase the risk of schizophrenia, autism and other neurodevelopmental and neuropsychiatric disorders in her offspring later in life, but the exact mechanism of this effect is unknown. In particular, it’s been unclear whether the baby’s brain is liable to be harmed by the virus itself or by the pregnant woman’s immune response to the virus.

Prof. Michal Schwartz of Neurobiology Department and her team, in collaboration with the team of Prof. Ido Amit of the Immunology Department, explored this question in a study in mice. The researchers had seen in their previous works that within the brain, large amounts of the interferon-beta protein – which, among its other functions, serves as the first line of defense against viral infection in mammals – can harm brain cells called microglia. These cells play an important role in embryonic development, helping to shape neuronal circuits; thus, the scientists designed a study focusing on microglia in the fetus.

They infected pregnant mice with a synthetic RNA molecule that mimics an infection caused by RNA viruses. The latter belong to a large family of viruses that induce diseases such as flu, measles, Ebola and COVID-19. When the mouse pups were born, it turned out that their brain’s immune cells, the microglia, were adversely affected and showed abnormal behavior.

The researchers then set out to check whether this adverse effect on the microglia was caused by the virus-mimicking molecules or by the mother’s immune response to the viral infection – that is, by the antiviral immune system’s protein, interferon-beta, whose levels rise sharply as a result of this infection. They exposed the pregnant mice to the virus-mimicking molecules but at the same time treated them with antibodies that neutralize the interferon-beta. The treatment reduced the adverse effect on the microglia of the pups, suggesting that this effect was due to the interferon-beta.

Next, to double check this conclusion, the scientists – instead of infecting the pregnant mice with the virus-mimicking molecules – injected them with the interferon-beta. In this case, too, the microglia of the newborn pups displayed similar abnormal functioning. Moreover, the pups themselves were later shown to behave abnormally, in a manner similar to the one exhibited in neuropsychiatric disorders, and they were more prone to stress than those born to mothers that had not been exposed to high levels of interferon-beta.

These results show that even when the fetus is not directly exposed to a virus found in the mother’s body, the microglia in the fetal brain might be damaged by the interferon-beta that the mother secretes in large amounts in response to the viral infection.“Further research may find ways of protecting the fetus from the mother’s response to the virus – that is, from the interferon that rises during viral infection,” Schwartz says. “In the meantime, pregnant women would do well to exercise caution, so as to avoid becoming infected with viruses during pregnancy.”

The study was carried out by Dr. Hila Ben-Yehuda with the assistance of several former members of the two teams, including Dr. Alexander Kertser of the Neurobiology Department, and Dr. Orit Matcovitch-Natan and Amit Spinrad of the Neurobiology and Immunology Departments.

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Scientists searching for better diagnostic tests, drugs or vaccines against a virus must all begin by deciphering the structure of that virus. And when the virus in question is highly pathogenic, investigating, testing or developing these can be quite dangerous. Prof. Roy Bar-Ziv, Staff Scientist Dr. Shirley Shulman Daube, Dr. Ohad Vonshak, a former research student in Bar-Ziv’s lab, and current research student Yiftach Divon have an original solution to this obstacle. They demonstrated the production of viral parts within artificial cells.

The cells are micrometer-sized compartments etched into a silicon chip. At the bottom of each compartment, the scientists affixed DNA strands, packing them densely. The edges of the artificial cells were carpeted with receptors that can capture the proteins produced within the cells. To begin with, the scientists flooded their cells with everything needed to make proteins – molecules and enzymes needed to read the DNA information and translate it into proteins. Then, with no further human intervention, the receptor carpet trapped one of the proteins produced in the bottoms of the cells, with the rest of the viral proteins binding to one another, producing structures that the scientists had earlier “programmed” into the system. In this case, they created assorted small parts of a virus that infects bacteria (a bacteriophage).

“We discovered,” says Bar-Ziv, “that we can control the assembly process – both the efficiency and the final products – through the design of the artificial cells. This included the cells’ geometric structure, and the placement and organization of the genes. These all determine which proteins will be produced and, down the line, what will be made from these proteins once they are assembled.”

Dr. Vonshak adds: “Since these are miniaturized artificial cells, we can place a great many of them on a single chip. We can alter the design of various cells, so that diverse tasks are performed at different locations on the same chip.” The features of the system developed at the Weizmann Institute – including the ability to produce different small parts of a single virus at once, could give scientists around the globe a new tool for evaluating tests, drugs and vaccines against that virus. Adds Yiftach Divon: “And because the artificial parts – even if they faithfully reproduced parts of the virus – do not include the use of actual viruses, they would be especially safe from beginning to end.” “Another possible application,” says Dr. Shulman Daube, “might be the development of a chip that could rapidly and efficiently conduct thousands of medical tests all at once.”

Participating in this research were Stefanie Förste, Dr. Sophia Rudorf and Prof. Reinhard Lipowsky from the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, and David Garenne and Prof. Vincent Noireaux from the University of Minnesota. The research was published in Nature Nanotechnology. Prof. Roy Bar Ziv’s research is supported by the Clore Center for Biological Physics; and the Harry Perlman Family.

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Choosing the right drug for each cancer patient is key to successful treatment, but currently physicians have few reliable pointers to guide them in designing treatment protocols. Researchers at the Weizmann Institute of Science in collaboration with Broad Institute of MIT and Harvard have now developed a new method for selecting the best drug therapy for a given tumor based on assigning scores to the cells’ internal messaging activities. In addition to helping physicians choose from a list of existing treatments, the method can help identify new molecular targets for the development of future drugs. In fact, the researchers have already used it to single out a gene that can be targeted for effectively treating breast cancers with a BRCA mutation. The study was recently published in Nature Communications.

The most common molecular way of matching drugs to a tumor is to look for particular mutations in the tumor’s cells. Unfortunately, the presence of such mutations is no guarantee a drug will work, and, in any event, many drugs are not aimed at mutations to begin with. Two labs – one headed by Dr. RavidStraussman of Weizmann’s Molecular Cell Biology Department, the other by Prof. Gad Getz of the Broad Institute of MIT and Harvard – joined forces to develop a more effective approach, basing their study on the enormous datasets on cancer that have become available in the past few years. This approach does not rely on mutations or on individual genes, but rather on signaling pathways: chains of biochemical signals that convey crucial cellular messages, for example, whether a cell should divide or grow, or in what way its metabolism should be altered. Numerous genes are expressed in the cell in order to transmit the message in each pathway, so sophisticated methods are needed to uncover the activity in these chains.

Postdoctoral fellow at the Weizmann Institute of Science, Dr. Rotem Ben-Hamo analyzed vast international datasets containing information on the expression of all genes in ~ 460 cancer cell lines – that is, different models of cancer – from ten different cancer types. Using an advanced bioinformatics tool,‘PathOlogist’, developed by Prof. Sol Efroni of Bar Ilan University, the researchers assigned to each pathway an activity score, which takes into account not only gene expression levels but also prior knowledge about the structure of each pathway, the interactions of the genes within it, and whether a given gene blocks or stimulates the pathway’s message. The scientists then correlated these scores with datasets containing information on the sensitivity of different cancer cells to nearly 500 different anti-cancer drugs.

They found that the activity scores of some of the pathways enabled them to predict whether a specific cancer would be sensitive to a particular drug. In other words, the researchers created a profile for the cancerous tissue that could direct clinicians to the best drugs for eradicating the tumor. Overall, they were able to make such predictions for more than 30 existing drugs. For example, when certain lung cancer cells had a high score for a pathway triggering apoptosis, a form of cell suicide, these cells were likely to be killed by a class of drugs known as micro tubule inhibitors.

Next, the scientists showed that they could use the pathway knowledge not only to predict but to alter the cells’ response to a drug. They obtained from one patient lung cancer tissue in which, according to their analysis, the apoptosis-triggering pathway was not particularly active. In test tube experiments this lung cancer tissue, as expected, was resistant to micro tubule inhibitor drugs. But when, in addition to micro tubule inhibitors, the researchers simultaneously applied a substance that increased the activity in the apoptosis pathway, these drugs effectively killed the cancer cells.

In further analysis of the datasets, the researchers correlated the activity scores of signaling pathways with yet another type of information: which genes play such an essential role in various tumors that silencing, or blocking these genes can kill the tumor. They found that here too, the pathway scores helped them identify such “sensitive” genes in a variety of tumors. For example, they found that breast tumors with specific activity in the BRCA pathway – which correlated with the presence of a BRCA mutation – were extremely dependent on the activity of a gene called MAD2L1. The bioinformatics analysis predicted that silencing this gene can result in the death of tumor cells in patients with a BRCA mutation. This prediction can serve as a starting point in the search for new or existing drugs to treat this devastating breast cancer.

Overall, the study’s findings suggest that signaling pathways can serve as predictive biological markers in personalized medicine of the future, helping physicians tell in advance which patients will best respond to which drug. Moreover, the pathways can help researchers identify the Achilles heel of various tumors to which drug development can be directed.

Study participants included Dr. Adi Jacob Berger, Dr. Nancy Gavert and Dr. YaaraZwang of the Straussman lab in Weizmann’s Molecular Cell Biology Department; Dr. Mendy Miller of the Getz lab at the Broad Institute; Dr. Guy Pines of Kaplan Medical Center; Dr. Roni Oren of Weizmann’s Veterinary Resources Department; Prof. Eli Pikarsky and Dr. TzahiNeuman of the Hebrew University of Jerusalem; and Prof. Cyril H. Benes of Massachusetts General Hospital.

Dr. RavidStraussman’s research is supported by the Moross Integrated Cancer Center; the Knell Family Center for Microbiology; the Maurice and Vivienne Wohl Biology Endowment; the Fabricant-Morse Families Research Fund for Humanity; the Dr. Chantal d’Adesky Scheinberg Research Fund; the Rising Tide Foundation; and the European Research Council. Dr. Straussman is the incumbent of the Roel C. Buck Career Development Chair.

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When the heart recovers from injury, the blood flowing through its vessels is essential. But lymph – the colorless fluid that circulates in a parallel network – and the lymphatic vessels in which it moves are just as crucial, according to researchers at the Weizmann Institute of Science. They showed that without an adequate network of lymphatic vessels, the hearts of zebra fish – which can completely regenerate following injury – fail to heal, even in the presence of blood vessels. The researchers also identified two distinct types of lymphatic vessels in the fish heart, which form by different mechanisms and perform different tasks.These findings may help develop new ways for promoting heart repair and facilitating the growth of organs for transplant.

The body’s network of lymphatic vessels serves as a conduit for immune cells and drains fluid, as well as providing individual services to various organs. Prof. Karina Yaniv of Biological Regulation Department and her team wanted to learn what role the lymphatic vessels play in the heart, particularly following injury. Zebrafish are perfect for exploring this question because unlike mammals, they have a remarkable capacity for heart regeneration: Within approximately two months after being injured, up to one-third of their heart tissue can regrow without scarring. An injured mammalian heart, in contrast, does not naturally regenerate at all, instead forming scar tissue at the injury site.

In earlier research, Prof. Yaniv and colleagues had shown that in the zebra fish embryo, lymphatic vessels form by two separate mechanisms: either by sprouting and growing from pre-existing vessels, or by differentiating from progenitor cells called angioblasts. In the new study, the researchers found that in adult zebra fish, these two mechanisms are recapitulated. Moreover, each set of lymphatic vessels features its own genetic markers and responds to its own molecular signals. The scientists found that both distinct types of lymphatic vessels are also found in the hearts of mice, indicating that the disparate mechanisms by which they develop have been conserved in the course of evolution.

The researchers then asked whether either or both types play a role in regeneration. After injuring the hearts of zebra fish, Yaniv and her group discovered that the hearts’ regenerating area contained lymphatic vessels of just one type – those derived from isolated lymphatic cells, rather than vessels. These cells then merged together into vessels. Although these vessels eventually connected with the larger lymphatic vessels that belong to the other type, they remained distinct. Thus, the experiments revealed that the two types of lymphatic vessels perform different functions in the heart: It is evidently mainly the progenitor cell-derived ones that contribute to heart regeneration after injury.

Research may in the future help to grow heart tissue :

The researchers then showed that, in fact, these lymphatic cells do more than facilitate heart regeneration – the process cannot take place without them. When the scientists studied mutant zebra fish with no lymphatic vessels at all, the hearts of these mutants failed to regenerate after injury even though their blood vessels were entirely normal. “We’ve shown that the lymphatic system plays a crucial role in heart regeneration in the zebrafish,” says Prof. Yaniv. “By clarifying this role further, we may learn what the fish heart ‘knows’ about regeneration that the mammalian one doesn’t, and use this knowledge to heal human hearts.”

A more detailed understanding of this role may indeed help develop new ways of preventing scarring and promoting healing after heart attacks or other types of injury to the heart muscle. In addition, knowing exactly how the lymphatic system contributes to heart muscle growth may in the future help to grow heart tissue in laboratory conditions for the purposes of transplantation.

Study authors included Dr. Dana Gancz, Gal Perlmoter, Dr. Jonathan Semo, Hila Raviv and Noga Moshe of Biological Regulation Department; Brian C Raftrey and Prof. Kristy Red-Horse of Stanford University; Dr. Rubén Marín-Juez, Prof. Ryota L. Matsuoka and Prof. Didier Y. R. Stainier of the Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Dr. Ravi Karra and Prof. Kenneth D. Poss of Duke University; and Dr. Yoseph Addadi and Ofra Golani of Weizmann’s Life Sciences Cored Facilities Department.

Prof. Karina Yaniv’s research is supported by the Maurice and Vivienne Wohl Biology Endowment; the estate of Emile Mimran; and the European Research Council. Prof. Yaniv is the incumbent of the Enid Barden and Aharon J. Jade Professorial Chair in Memory of Canter John Y. Jade. http://wis-wander.weizmann.ac.il/

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Cancer cells are comfy havens for bacteria. That conclusion arises from a rigorous study of over 1,000 tumor samples of different human cancers. The study, headed by researchers at the Weizmann Institute of Science, found bacteria living inside the cells of all the cancer types – from brain to bone to breast cancer – and even identified unique populations of bacteria residing in each type of cancer. The research suggests that understanding the relationship between a cancer cell and its “mini-microbiome” may help predict the potential effectiveness of certain treatments or may point, in the future, to ways of manipulating those bacteria to enhance the actions of anticancer treatments. The findings of this study were published in Science.

Dr. Ravid Straussman of the institute’s molecular cell biology department had, several years ago, discovered bacteria lurking within human pancreatic tumor cells; these bacteria were shown to protect cancer cells from chemotherapy drugs by “digesting” and inactivating these drugs. When other studies also found bacteria in tumor cells, Straussman and his team wondered whether such hosting might be the rule, rather than the exception. To find out, Drs. Deborah Nejman and Ilana Livyatan in Straussman’s group and Dr. Garold Fuks of the Physics of Complex systems department worked together with a team of oncologists and researchers around the world. The work was also led by Dr. Noam Shental of the mathematics and computer science department of the Open University of Israel.

Ultimately, the team  produced a detailed study describing, in high resolution, the bacteria living in these cancers – brain, bone, breast, lung, ovary, pancreas, colorectal and melanoma. They discovered that every single cancer type, from brain to bone, harbored bacteria and that different cancer types harbor different bacteria species. It was the breast cancers, however, that had the largest number and diversity of bacteria. The team demonstrated that many more bacteria can be found in breast tumors compared to the normal breast tissue surrounding these tumors, and that some bacteria were preferentially found in the tumor tissue rather than in the normal tissue surrounding it.

To arrive at these results, the team had to overcome several challenges. For one, the mass of bacteria in a tumor sample is relatively small, and the researchers had to find ways to focus on these tiny cells-within-cells. They also had to eliminate any possible outside contamination. To this end they used hundreds of negative controls and created a series of computational filters to remove the traces of any bacteria that could have come from outside the tumor samples.

The team was able to grow bacteria directly from human breast tumors, and their results proved that the bacteria found in these tumors are alive. Electron microscopy visualization of these bacteria demonstrated that they prefer to nestle up in a specific location inside the cancer cells – close to the cell nucleus. The team also reported that bacteria can be found not only in cancer cells, but also in immune cells that reside inside tumors. “Some of these bacteria could be enhancing the anticancer immune response, while others could be suppressing it – a finding that may be especially relevant to understanding the effectiveness of certain immuno therapies,” says Straussman. Indeed, when the team compared the bacteria from groups of melanoma samples, they found that different bacteria were enriched in those melanoma tumors that responded to immuno therapy as compared to those that had a poor response.

Straussman thinks that the study can also begin to explain why some bacteria like cancer cells and why each cancer has its own typical microbiome: The differences apparently come down to the choice of amenities offered in each kind of tumor-cell environment. That is, the bacteria may live off certain metabolites that are overproduced by or stored within the specific tumor types. For example, when the team compared the bacteria found in lung tumors from smokers with those from patients who had never smoked, they found variances. These differences stood out more clearly when the researchers compared the genes of these two groups of bacteria: Those from the smokers’ lung cancer cells had many more genes for metabolizing nicotine, toluene, phenol and other chemicals that are found in cigarette smoke.

In addition to showing that some of the most common cancers shelter unique populations of bacteria within their cells, the researchers believe that the methods they have developed to identify signature microbiomes with each cancer type can now be used to answer some crucial questions about the roles these bacteria play: Are the bacteria freeloaders on the cancer cell’s surplus metabolites, or do they provide a service to the cell? At what stage do they take up residence? How do they promote or hinder the cancer’s growth? What are the effects that they have on response to a wide variety of anticancer treatments?

“Tumors are complex ecosystems that are known to contain, in addition to cancer cells, immune cells, stromal cells, blood vessels, nerves, and many more components, all part of what we refer to as the tumor micro environment. Our studies, as well as studies by other labs, clearly demonstrate that bacteria are also an integral part of the tumor micro environment. We hope that by finding out how exactly they fit into the general tumor ecology, we can figure out novel ways of treating cancer,” Straussman says.

http://wis-wander.weizmann.ac.il/

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