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Science Feature Articles</p>

Cellular Senior Moments

English

 

(l-r) Dr. Zohar Mukamel, Zohar Shipony and Prof. Amos Tanay
 
Aged cells, just like aged humans, have memory issues, according to a new study at the Weizmann Institute of Science. Insights gained by the study of a particular form of cellular memory may shed new light on the development of cancer and on the use of stem cells in therapy.

Our cells have a great deal to remember. Their genetic memory has long been known to be remarkably accurate: The rate of mistakes, or mutations, in the DNA during cell division is as low as one in millions or even billions of genetic letters, so that all the cells in our body – which have originated from a single cell, the fertilized egg – have the same genes. But as reported recently in Nature, Weizmann Institute scientists have now found that the cells’ epigenetic memory, the one not encoded in their DNA, is fraught with a surprisingly high rate of mistakes.


The scientists have focused on a particular epigenetic mechanism in which a chemical tag, a methyl group, is attached to the DNA. The activity of the cell’s genes is in part dictated by the distribution of these tags, the DNA methylation pattern. The methyl tags help regulate the turning of genes on and off, which, among other things, determines the cell’s identity – whether it will become part of the skin, the kidneys, the brain or some other tissue.
 

Selection of cells by CellCelector, a technology used in the research on cellular epigenetic memory: The machine identifies a single cell (circled in red) in a cell culture and removes it for study
 
Using innovative techniques they developed for mapping memory patterns, which combine massive DNA sequencing with mathematical algorithms, the scientists found that when the methylation pattern is passed on to daughter cells in the same organism during cell division, mistakes occur in as often as one in 200 - 1000 tags. The mistakes accumulate with each division, so that the methylation of an old cell – one that has been produced by a large number of divisions – can be completely garbled. In this sense, the passing on of epigenetic memory resembles the game of Chinese whispers, or broken telephone.
 
This revelation suggests that mistakes in epigenetic memory may make older cells more liable to undergo malignant transformation. Just as the build-up of minerals prevents older people from making full use of their joints, so the accumulation of epigenetic mistakes can prevent an older cell from responding properly to various signals, among them the signal to self-destruct when the cell is about to lose its normal growth control and turn cancerous.
 
A colony of human skin cells (circled in red) is picked out by the CellCelector
 
The “Chinese whispers” discovery may prove useful in fighting cancer. By studying the pattern of epigenetic mistakes in tumor cells, it might be possible to chart their “family trees,” that is, to trace their origins to a particular site in the body. This, in turn, can affect treatment decisions. In addition, epigenetic mistakes may serve as markers helping to distinguish cancerous cells – which undergo so many divisions they accumulate these mistakes in huge numbers – from cells that are old but healthy.

Moreover, the study suggests that even in the same tissue, individual cells – for example, certain cells of the spleen or liver – differ from one another in their methylation patterns. Such findings need to be taken into consideration in the development of diagnostic assays or drugs, because this variability may affect the effectiveness of a medication.

The Weizmann researchers have also found that in contrast to mature cells, embryonic stem cells have an excellent epigenetic memory. For instance, when stem cells are maintained in their immature cell state for a while, they preserve a stable methylation pattern despite numerous divisions. How do these cells remember so well who they are?

The surprising answer is that they do not listen to their ancestors: The researchers have shown that unlike what happens in mature cells, epigenetic memory in embryonic stem cells is not maintained through the transmission of stored information to the newly divided cells. Rather, the pattern of methyl tags is erased and created anew continuously during and between cell divisions. Thanks to this dynamic mechanism, an accumulation of epigenetic mistakes is avoided.

This discovery explains what happens when mature cells are genetically reprogrammed into stem cells. Scientists who discovered the possibility of such cellular reprogramming – which promises to ensure an unlimited supply of stem cells for therapy – were awarded the 2012 Nobel Prize in medicine; but until now it was unclear how a mature cell could be suddenly induced to “remember” the methylation pattern it had as a stem cell. The Weizmann study has resolved the mystery: When a mature cell is reprogrammed, machinery capable of erasing and rewriting methyl tags is turned on, so that the epigenetic memory state of an embryonic stem cell is rapidly reconstituted.

The study was performed by Prof. Amos Tanay of the Computer Science and Applied Mathematics, and Biological Regulation Departments and his research team, including lead authors Zohar Shipony and Dr. Zohar Mukamel; together with Netta Mendelson Cohen, Gilad Landan and Elad Chomsky; Weizmann researcher Dr. Nir Friedman and Dr. Shlomit Reich-Zeliger from his group in the Immunology Department; and Drs. Yael Chagit Fried and Elena Ainbinder of the Department of Biological Services.
 
Prof. Amos Tanay’s research is supported by the Helen and Martin Kimmel Award for Innovative Investigation; Pascal and Ilana Mantoux, Israel/France; the Wolfson Family Charitable Trust; the Rachel and Shaul Peles Fund for Hormone Research; Moise and Carol-Ann Emquies, Santa Monica, CA; and the estate of Evelyn Wellner.
 
Dr. Nir Friedman’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Clore Center for Biological Physics; the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Victor Pastor Fund for Cellular Disease Research; the Abraham and Sonia Rochlin Foundation; the Adelis Foundation; the Norman E. Alexander Family Foundation; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Crown Endowment Fund for Immunological Research; the estate of John Hunter; and the estate of Suzy Knoll. Dr. Friedman is the incumbent of the Pauline Recanati Career Development Chair.

 
(l-r) Dr. Zohar Mukamel, Zohar Shipony and Prof. Amos Tanay
Math & Computer Science
English
  • Aging
  • Algorithm
  • Amos Tanay
  • Biological Regulation
  • Cancer
  • Computer Science and Applied Mathematics
  • Epigenetics
  • Human stem cells
  • Immunology
  • Nir Friedman

Master Key

English
Dr. Elik Chapnik, Natali Rivkin and Dr. Eran Hornstein
 
It takes only a tiny key to open a door wide or set large machinery in motion. Dr. Eran Hornstein of the Weizmann Institute’s Molecular Genetics Department and his team recently discovered such a key – one that unlocks the cellular machinery for producing mature blood cells. That key is a minuscule, hairpin-shaped RNA belonging to a class of RNA strands so small they had long been ignored. Even now, these so-called microRNAs are too often thought to be secondary to the cell’s major processes. The new findings suggest that microRNAs can also be master keys, putting several vital processes into motion at once.

In collaboration with Prof. Steffen Jung of the Immunology Department and his coworkers Dr. Elik Chapnik, Natali Rivkin and Dr. Alexander Mildner, Hornstein discovered that a microRNA called miR-142 was involved in the process by which the immature cells in the bone marrow give rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells. In fact, an early hint for the importance of this microRNA had been documented years earlier, in 1989, as it plays a role in a type of B-cell leukemia. But back then, before the era of genomics and before the microRNA revolution, it was thought to be a protein-coding gene.

 

Wild type megakaryocyte
 
The Weizmann researchers looked at a broad lineage of myeloid cells – a group that includes the red blood cells and the platelets that make our blood clot. They were looking for cells in which miR-142 is instrumental, and that could provide a clear insight into its function. Their initial analysis pointed to megakaryocytes as the ideal experimental model.  

Megakaryocytes are very large cells in the bone marrow that generate platelets by budding off bits of their internal cytoplasm. The development of megakaryocytes and their ability to function as they mature depends on a strong, malleable internal structure – the cytoskeleton. In a series of experiments on mouse megakaryocytes, the researchers found that miR-142 is essential to the proper formation of the primary building material of the cytoskeleton – actin fibers. When miR-142 activity was halted, the production of actin was deregulated, and the megakaryocytes were not able to mature and produce platelets.
 
Megakaryocyte in which the microRNA mir-142 has been knocked out
 
Using a large array of techniques in their labs, the researchers were able to reveal the precise activities of miR-142. Their findings, which were recently published in eLife, show that miR-142 is, indeed, a master key that turns on and off a number of different cellular processes; these are crucial to actin production and regulation. To put it another way, microRNA-142 is a “hub” in the cellular network of pathways that keeps the cell growing, dividing, developing and functioning.  
 
According to Hornstein, the impact of microRNA-142 and its mechanism may even go all the way back to the first blood cells in the embryo. In addition, miR-142 malfunctions are likely to show up in certain clotting disorders; but the findings hint that the same miRNA gene may be involved in any number of other blood diseases. Hornstein: “This model for blood cell development is very informative and fruitful. Together with Jung we have already characterized four different cell types in which this miRNA is influential, which is very exciting.” 
 
The implications are clear for microRNA research, says Hornstein, helping cast microRNA in a new light: they can no longer be seen as mere helper molecules that “fine-tune” the cellular pathways; they are also key players with the power to direct the development of the cell.
 
 
 
 
Dr. Eran Hornstein’s research is supported by the Kekst Family Institute for Medical Genetics; the David and Fela Shapell Family Center for Genetic Disorders Research; the Crown Human Genome Center; the Yeda Sela Center; the Nella and Leon Benoziyo Center for Neurological Diseases; the Y. Leon Benoziyo Institute for Molecular Medicine; the Helen and Martin Kimmel Institute for Stem Cell Research; the Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; the Julius and Ray Charlestein Foundation; the Celia Benattar Memorial Fund for Juvenile Diabetes; the Wolfson Family Charitable Trust; the Legacy Heritage Fund; the Adelis Foundation; the Minna-James-Heineman Stiftung; Dr. Sidney Brenner and Friends; Maria Halphen, France; and the estate of Fannie Sherr. Dr. Hornstein is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair.

Prof. Steffen Jung’s research is supported by the Leir Charitable Foundations; the Leona M. and Harry B. Helmsley Charitable Trust; the Maurice and Vivienne Wohl Biology Endowment; the Adelis Foundation; Lord David Alliance, CBE; the Wolfson Family Charitable Trust; the estate of Olga Klein Astrachan; and the European Research Council.
 
Wild type megakaryocyte
Life Sciences
English
  • Actin
  • Eran Hornstein
  • Immunology
  • MicroRNA
  • Molecular Genetics
  • Steffen Jung

Protein Reporters Go on Location

English
 
 
Dr. Emmanuel Levy
 
 
 
 
 
 
 
 
 
 
Each cell in your body is an entire world: Hundreds of millions, or even billions, of protein molecules are crowded into its microscopic confines. Some have permanent “jobs” in particular locations in the cell while others move around. Some form parts of long-lasting structures while others are produced for particular tasks and degraded soon after. To get an overall picture of this world, we need to know the rules that underlie its “social structure.” For example: Are certain kinds of proteins more populous than others? Where do the various proteins “go to work”? Which other proteins do they meet up with – either casually or in longer-term partnerships?
 


Dr. Emmanuel Levy of the Structural Biology Department is working on clarifying the answers to these questions. To do so, he is using a technique he helped develop during his postdoctoral research in the lab of Prof. Stephen Michnick at the University of Montreal. Now, using this technique, Levy, together with Michnick, has observed the comings and goings of the proteins in some 4,000 strains of yeast cells. Their results paint a picture of the cell’s world in which “social networks” and chance meetings seem to play a much larger role than previously thought. The results of their study appeared recently in Cell Reports.

The new technique involves splitting a protein that is vital for the cell’s survival into two halves and attaching each half to another protein. One of those proteins is the reporter, the other the target. If the target protein approaches the reporter, the two halves of the split protein will reunite and the yeast strain will survive and grow. The more abundant the target protein is in the vicinity of the reporter, the healthier the growth of the yeast. The method is so good at measuring protein levels and their localization that the researchers obtained an accurate “census” of nearly all the proteins probed. This, says Levy, means that, for the first time, we can measure with great accuracy the protein concentration in a particular region of a living cell. Measuring local protein concentration is indeed hard-to-impossible to accomplish by other methods – for example, mass spectrometry, which involves killing the cell, or microscopy, which would be a very tedious undertaking on such a scale.

 
Reporters Illustration

“If we think of the campus of the Weizmann Institute as a cell and the people who work here as the proteins, the reporters we use can record how much time each individual spends in which building,” he says. Their findings show that proteins are highly varied in their habits. Indeed, the scientists were surprised at the wide range they measured: Unlike your average human workers, whose hours on the job don’t vary too much from one to the other, some proteins were thousands of times more industrious – that is, abundant – than others. “It’s as if some go to work for just a minute, while others spend a whole week straight in their workplace,” says Levy. The most abundant proteins were also likely to be seen outside of their regular workplace. Going back to the Weizmann Institute metaphor, a person who works in the cafeteria, if he is there for just a minute a week, will not make an impression. In contrast, someone who actually works in a chemistry lab but also spends a few hours a week in the cafeteria could create more personal ties with the serving staff. This has profound consequences for the incidence of protein interactions. An analysis of the data revealed that, in fact, the chances of any two proteins meeting were first and foremost a product of their numbers in the cell.

That, along with their other findings, raises some very basic questions about how the cell truly functions. Randomness – a basic principle of evolution – appears to be built into our cells’ constitution. Nature is an opportunistic tinkerer, Levy says, that is just as likely to repurpose a tool that’s at hand as to evolve a new one. So rather than working on the assumption that the world of the cell is a highly organized realm in which every protein has a place in the overall structure, this research implies that scientists might begin to view the world of the cell as a fuzzy, “social network” type of organization in which chance meetings around the cell may determine how it functions.
 

Setting up an Experimental Lab

Dr. Emmanuel Levy
 
Dr. Emmanuel Levy joined the Weizmann Institute in 2012, where he soon began setting up a robotic lab for proteome analysis. Here, hundreds of yeast colonies are grown on a single plate, and hundreds of plates can be incubated at once, their results photographed and analyzed by computer. He first started working experimentally with proteins in his postdoctoral research with Prof. Stephen Michnick at the University of Montreal; in his undergraduate and graduate studies in his native Paris, and then at Cambridge University, UK, Levy had focused on the theoretical side of proteins, studying their structure and their evolution.
 
Levy, whose previous experience in Israel had been a one-month vacation on a kibbutz, says he was persuaded to join the Institute after he had been invited to give a lecture to the department. “I chose to come here because it is the best place to do this type of science,” he says. He is married to Melanie, whom he met at Cambridge, and they are expecting their first child. Melanie is pursuing postdoctoral research in health law and bioethics. When he has spare time, Levy enjoys cooking and composing electronic music.   
 
Dr. Emmanuel Levy's research is supported by the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Louis and Fannie Tolz Collaborative Research Project; Anne-Marie Boucher, Canada; the Samuel and Helene Soref Foundation; and the estate of William Weingarten. Dr. Levy is the incumbent of the Recanati Career Development Chair of Cancer Research in Perpetuity.
 
 
Dr. Emmanuel Levy
Chemistry
English
  • Emmanuel Levy
  • Protein
  • Protein-protein interaction
  • Robot›Robotic lab
  • Structural Biology

Completing the Metabolite Picture

English

 

Prof. Lucio Frydman
 
When you run, your body is undergoing all sorts of metabolic changes: A slew of substances produced from head to toe increase circulation and breathing rates, cause muscles to take up and burn sugars, open the pores in the skin and induce fatigue. Yet the changes that can presently be measured during exercise – for example, one’s heart rate – are few. If the levels of these substances could be tracked as they are released and go to work, a much more complete picture of an individual’s metabolic processes could be obtained. Since metabolic malfunctions are involved in many diseases – from circulatory and cardiac diseases to diabetes and many cancers – such a method could be a highly useful diagnostic tool to understand health and disease. Prof. Lucio Frydman and his coworkers in the Chemical Physics Department recently developed a new method based on MRI scanning that can find these substances (metabolites) and track their levels in real time – for instance, as muscles are stimulated.

This method is related to widely used functional MRI technologies such as those used in brain research, but it entails a significant departure from them. Standard MRI, explains Frydman, relies on basic physical properties of the nuclei of the water molecules in the body. At the heart of an MRI exam is the scanner’s strong magnet, which polarizes the water’s protons. These nuclei behave as tiny compass needles aligning with the MRI magnet, enabling the subsequent detection of their collective “nuclear symphony.” Yet at room temperatures, only around one in 100,000 water molecules is actually aligned – or polarized – by the scanner, while the rest basically stay “silent” throughout the “symphony.”  This tiny proportion of polarized protons is adequate for reporting on water, since it is present in very high concentrations in tissues. But it cannot capture the low concentrations of metabolites as they are produced in real time – that is, when tissues or organs become involved in a particular task.
 
 
Running muscles may be predominantly fast- or slow-twitch
 
The new method that Frydman, together with Drs. Avigdor Leftin and Tangi Roussel in his lab, developed, is based on a technique that they and others have been working on over the past several years, called nuclear hyperpolarization. Using new physics-based concepts and experiments to transform a natural alignment of only one in 100,000 molecules into that of around one in every five molecules, hyperpolarization creates a phenomenal increase in the “symphony’s volume.”
 
The method involves taking the wanted metabolite, cooling it to near absolute zero – a temperature at which magnetism is strongest – and using free electrons to further align the compass-like nuclei of interest. Combined, these procedures lead to intense metabolic signals, but under conditions that are incompatible with MRI investigations in living organisms. To get around this incompatibility, the hyperpolarization procedure is carried out in a special device positioned right next to the MRI scanner. When the substance to be analyzed has been sufficiently magnetized, the compound is rapidly heated to room temperature and injected into the organism. The nuclei retain their alignment long enough to produce a single, but highly intense, image in the MRI.   

Though involved, the method could lead to a highly sensitive tool for detecting the functional MRI response of individual metabolites. To demonstrate, the team focused on muscle stimulation. The skeletal muscles – those you use to run, for example – can be broadly divided into two classes, depending on whether they are rich in fast-twitch or slow-twitch fibers. Fast-twitch muscles – the kind that help you sprint – produce lactate as a byproduct; while slow-twitch muscles – the kind your body uses for endurance running – make much less of this metabolite. Athletes who excel at either short races or marathons often have more of one kind of muscle fiber than the other.
As the muscular stimulus is changed, hyperpolarized functional MRI reveals how injected pyruvate is metabolized by the exercising leg into varying levels of lactate
 
To image the rate of lactate production, Frydman and his coworkers focused on pyruvate: a harmless tracer that the body would naturally use – particularly under certain exercise conditions – to create lactate. Using nuclear hyperpolarization together with custom-made MRI sequences that could collect multiple rapid, simultaneous images of individual metabolites in the muscles, they followed the processes taking place in the exercising thigh of a living mouse. The hyperpolarized tracer was injected via the mouse’s tail and, as the rate of exertion changed (controlled by mild electrical stimulation), the researchers looked at the signature of the pyruvate tracer, which was metabolized into lactate and other byproducts. Sure enough, the team identified peaks associated with lactate production as the muscles were stimulated; the imaging techniques revealed more rapid rates of lactate production in the fast-twitch than in the slow-twitch fibers.

This study, which appeared in PLoS ONE, is a clear demonstration that the combination of advanced hyperpolarization methods and customized magnetic resonance techniques can extend the technology far beyond today’s functional MRI, to one based on metabolic signatures. This technique might open many doors to diagnosis, enabling clinicians or researchers, for example, to observe what happens in the body after glucose enters the bloodstream, how a tumor takes in nutrients or what happens to our bodies when we are frightened.
 
Prof. Lucio Frydman’s research is supported by the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research; the Helen and Martin Kimmel Award for Innovative Investigation; the Helen and Martin Kimmel Institute for Magnetic Resonance Research, which he heads; the Adelis Foundation; the Mary Ralph Designated Philanthropic Fund of the Jewish Community Endowment Fund; Gary and Katy Leff, Calabasas, CA; Paul and Tina Gardner, Austin TX; and the European Research Council.
 


 

 
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Running muscles may be predominantly fast- or slow-twitch
Chemistry
English
  • Chemical Physics
  • Lucio Frydman
  • MRI
  • Metabolite
  • Muscle tissue
  • NMR

When the Reshaping Tool Reshapes Itself

English

Cells move inside our bodies all the time: to heal wounds, fight infection, perform maintenance of tissues. This may sound routine, but even the simplest move is a marvel of cellular engineering. It requires the cell to continuously reshape its inner scaffolding – the cytoskeleton – to create the protruding “foot” that propels it forward, all the while pulling up the rear. A new Weizmann Institute study published in Nature Communications has produced surprising revelations about the tools responsible for the reshaping.

Cytoskeletal fibers (green) and adhesion sites (orange) grow when the Arp2/3 complex is present in its hybrid version (right) compared with the regular, seven-subunit version (left). When Arp2/3 is absent altogether, the fibers and the adhesion sites deteriorate (center)
 

 

 
 
 
 
 
 
 
 
 
 
 
Playing a central role in the reshaping process is a large molecular complex called Arp2/3 that attaches itself to the filaments in the cytoskeleton, causing them to branch out and thereby helping to create the protrusion the cells need for movement. Known for more than two decades and investigated in dozens of laboratories around the world, Arp2/3 has been widely thought to be consistent: the same seven subunits always arranged in the same manner.
 
(l-r) Dror Chorev, Prof. Benjamin Geiger and Dr. Michal Sharon
 
Now Weizmann Institute scientists have shown that this complex is modular, and that it can perform different functions by assuming different shapes and attaching itself to different sites in the cytoskeleton. In fact, instead of helping the cell move, it can help it stay in place. In the latter case, the complex contains only three or four core components rather than its classic set of seven, as well as one or two proteins that play a role in cellular adhesion. This hybrid complex attaches to those sites in the cytoskeleton that promote the adhesion. As a result, these sites multiply and increase in size, causing the cell to remain anchored.
 
Much as the finding was unexpected, the modular mechanism makes evolutionary sense: It’s more economical for the cell to have a single versatile tool that can be adjusted to different uses than to harbor a separate tool for each. The study was performed by graduate student Dror Chorev in the laboratories of Dr. Michal Sharon of the Biological Chemistry Department and Prof. Benjamin Geiger of the Molecular Cell Biology Department.
 
The scientists determined the properties of several Arp2/3 protein complexes, using mass spectrometry. After identifying the presence of hybrid complexes, they confirmed their anchoring effect by manipulating their levels in human cells and comparing the behavior of these cells with the ones containing the better-known seven-unit complex.
 
The findings open up a new avenue of research by suggesting that in addition to Arp2/3, other important protein complexes might be modular and versatile. They may also one day help control cellular migration on a molecular level, enhancing it or, conversely, blocking it on demand – for example, to prevent the spread of cancer cells throughout the body.  
 
 
 
Prof. Benjamin Geiger’s research is supported by the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; the Fondazione Henry Krenter; Paul and Tina Gardner, Austin, TX; David and Molly Bloom, Canada; the estate of Anne S. Lubliner; the estate of Raymond Lapon; the estate of Alice Schwarz-Gardos; and the European Research Council. Prof. Geiger is the incumbent of the Professor Erwin Neter Professorial Chair of Cell and Tumor Biology.
 
Dr. Michal Sharon’s research is supported by the Abramson Family Center for Young Scientists; the European Research Council; and the Sergio Lombroso Award for Cancer Research. Dr. Sharon is the incumbent of the Elaine Blond Career Development Chair in Perpetuity.


 
 
Cytoskeletal fibers (green) and adhesion sites (orange) grow when the Arp2/3 complex is present in its hybrid version (right) compared with the regular, seven-subunit version (left). When Arp2/3 is absent altogether, the fibers and the adhesion sites deteriorate (center)
Life Sciences
English
  • Benjamin Geiger
  • Biological Chemistry
  • Cell adhesion
  • Cell migration
  • Michal Sharon
  • Molecular Cell Biology

Gaining Potential

English
 
 
(l-r) Prof. Dov Zipori, Drs. Dena Leshkowitz, Orly Ravid and Meirav Pevsner-Fischer. (Insets,l-r) Hassan Massalha and Dr. Ofer Shoshani

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
Stem cells, we know, are highly variable. In the embryo, these cells are capable of giving rise to all the types of mature functional cells in the body; the more limited types of adult stem cell each give rise to a variety of specialized, mature cells belonging to specific tissues. But for all these stem cells the common view is somewhat uniform: It is generally believed that differentiation – the process by which the cells gain their specialization – is strictly a one-way street with signposts at every intersection. Weizmann Institute Prof. Dov Zipori has been challenging that dogma, and his recent research suggests that much of what scientists believe about stem cell activity could be mistaken.

In his lab in the Molecular Cell Biology Department, Zipori researches cells known as mesenchymal stem cells. As opposed to other types of adult stem cell, which are found in such specific locations as the bone marrow, mesenchymal cells are scattered throughout the body. Mesenchymal stem cells are usually defined by their capacity to give rise to three types of cell: bone, cartilage and fat – a sort of "golden triangle." In the basic one-way scenario, a mesenchymal stem cell divides either symmetrically, giving rise to two identical stem cells, or asymmetrically, when one daughter cell remains a stem cell and the other begins the process of differentiation. Over several rounds of division, subsequent generations of cells continue to differentiate until the specialized adult cells appear. The intermediate cells progress by shedding their differentiation potential: In each round they are increasingly limited in the kinds of tissue their progeny can become.  
 
 
Sequential appearance and disappearance of differentiation potencies, absent in the parent cell population due to single cell cloning. Left hand side is a schematic representation of the actual images of adipogenic differentiation potential seen, on the right, in reddish cells stained for fat accumulation

 
This model – including the "golden triangle" – was mostly set in stone by a scientific paper published in 1999. Mesenchymal stem cells were placed atop the triangle, as they could give rise to any of the three tissue types. Much subsequent research into these cells – and stem cells in general – has relied on this scenario. But Zipori, even then, wondered if these findings truly reflected what happens in the body. For one thing, even though it had not been shown in mammals, fruit fly experiments had found evidence that certain maturing cells in the reproductive system can revert to a stem cell state. And his own experiments with these cells suggested that mesenchymal cells were a bit more unruly than the rigid, one-way model would suggest. He had already noted in the mid-1980s that when the conditions in the cells' environment were slightly changed, some differentiated cells readily lost their mature cell properties and returned to a seemingly undifferentiated state.

By 2004, in an article he published in Nature Reviews Genetics, Zipori suggested that researchers begin to think in terms of a "stem state" – a state of the cell – rather than stem cells – an either-or category. Stemness thus implies a fluid condition that a cell might pass into or out of. He also raised the notion that this activity might happen spontaneously in the body. In fact, he wrote, the production of new stem cells could result from maturing cells gaining stem cell potential, rather than from symmetrical stem cell division.
 
stem state infographic
 
Just two years later, in 2006, the idea of the “stem state” or “stemness” was vindicated when researchers in Japan took mature cells and endowed them with stemness by reverting them back to the very first cell type – embryonic-like stem cells. This was done by artificially imposing specific gene expression in the cells. Nevertheless, few were ready to believe that cells could revert spontaneously in the body from maturity to stemness.

In the present study, which appeared recently in Stem Cell, Zipori and his team, set out to test the true rigidity of the mesenchymal differentiation pathways: Did the commonly accepted paths, with their inflexible chain of events, reflect reality? Following the procedure used in the earlier experiments, the team isolated single mesenchymal cells from mice, cloned them and grew them in lab dishes. But, using modern methods of single cell tracking and analysis, they were able to dig deeper. The study had been initiated five years earlier by Dr. Ofer Shoshani, then a Ph.D. student, who was later joined by additional members of the team, including Dr. Orly Ravid, Hassan Massalha, Alla Aharonov and Yossi Ovadya, and Drs. Meirav Pevsner-Fischer and Dena Leshkowitz of the Institute’s Bioinformatics Unit.
 
 
The researchers managed to capture mesenchymal cells in the intermediate stages of differentiation. If the original model was correct, each generation should show a progressive loss of differentiation potential. But what they found was very different: Some cells, indeed, lost a particular sort of differentiation potential – say, the ability to turn into cartilage; but others of their siblings and cousins at each stage regained it. Rather than a linear, one-way street, they now had a more jumbled picture in which cells could go back and forth from  one state to another. Although the team was looking at the potential to turn into one of the golden triangle tissues – fat, bone or cartilage – they also saw signs that the mesenchymal cells could give rise to other kinds, for example, endothelial-like or epithelial-like cells.
Mesenchymal stem cells (MSCs) seeded densely and sparsely. Left column: phase contrast images; right column: staining with antibodies to either epithelial (E-cahedrin) or endothelial (vWF) markers. (Top) Dense seeding: The cells exhibit random morphology and are negative for the two markers. (Middle) Cells grown from isolated colonies: These develop “cuboidal” shapes typical of epithelial cells and are positive for E-cahedrin. (Bottom) Other sparsely-seeded cells take on elongated shapes and are positive for vWF, the endothelial marker
 
According to Zipori, these mesenchymal cells may have easily acquired and discarded various states of stemness because they were under stress – in this case the stress of the cell being removed from the surroundings in which it normally functions and placed in a lab dish. This fits in with another observation the team had made: The cells tended to revert much less often when they were grown in low oxygen conditions. Within the body, low oxygen is the default situation for stem cells; high oxygen, in the case of injury, for example, signals stress. To Zipori, these findings hint that the body’s mesenchymal cells may jump back to higher-potential states in such situations as tissue damage, in which many types of new cells may be quickly needed.
 
Zipori: "Our findings imply that the single-cell cloning used in the past to define mesenchymal stemness may not have discovered true mesenchymal stem cells that give rise to all the differentiated types. Rather, they most likely observed intermediate mesenchymal cells that, because they were removed from their normal environment and thus grown in stressful conditions, had simply jumped back to a higher differentiation potential. Much research has relied on this model over the past 15 years; but our findings suggest that we need to rethink even our most basic assumptions about the ways that cells are renewed in our bodies."
 
Prof. Dov Zipori’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research, which he heads; the J & R Center for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; David and Molly Bloom, Canada; and Roberto and Renata Ruhman, Brazil. Prof. Zipori is the incumbent of the Joe and Celia Weinstein Professorial Chair.

 

 
 
stem state infographic
Life Sciences
English
  • Cell
  • Cell differentiation
  • Dov Zipori
  • Human stem cells
  • Molecular Cell Biology

Drift against the Tide

English
 
 
Diatom cells expressing ROS-sensitive proteins in the nucleus (green) and chlorophyll (red)
 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
They are the foundation of the entire marine food chain – without them there would be no life in the ocean. They are also responsible for half the photosynthetic activity on the planet – rivaling rainforests in carbon dioxide absorbed and oxygen released. These are impressive feats for phytoplankton – microscopic single-celled organisms that range in size from 1 to 100 microns (smaller than the width of a human hair) and make up less than one percent of Earth’s biomass.

The name phytoplankton means “plant drifters” in Greek.  But are they really just passive wanderers at the mercy of the ocean currents, or is there more to them than meets the eye? Dr. Assaf Vardi of the Weizmann Institute’s Plant Sciences Department is looking to overturn this common paradigm by revealing the molecular mechanisms underpinning their ecological success. In new research published in Proceedings of the National Academy of Sciences (PNAS), Vardi, and Dr. Shilo Rosenwasser and their team have discovered that phytoplankton have developed an active stress surveillance system to help them cope with their ever-changing environment.
 
Dr. Assaf Vardi
 
Vardi: “Phytoplankton blooms are amazing biological phenomena, forming communities that span thousands of kilometers across the ocean and depths of up to 100 meters. But such environmental stresses as lack of carbon dioxide, sunlight or nutrients, or virus attacks, among other factors, can cause a bloom’s rapid demise. To be ecologically successful, an organism needs to be alert and on guard in order to respond and adapt to its environment.”

The research team found that phytoplankton’s stress surveillance system begins at home. When organisms carry out metabolic processes such as photosynthesis and respiration, they produce a toxic byproduct called ROS (reactive oxygen species). At low levels, this is usually no cause for concern – in fact, it has recently been recognized that ROS may function as signals to promote cell proliferation and survival. When phytoplankton cells are exposed to environmental stress, however, as in many pathophysiological conditions, ROS are overproduced; and this can lead to disease and ultimately to cell death.
 
Using a unique proteomics approach, which was developed by Vardi’s team in collaboration with Dr. Yishai Levin of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, the scientists discovered that phytoplankton have a large network of hundreds of ROS-sensitive proteins. This protein network can respond rapidly to changes in ROS levels produced under various stress conditions and transmit signals aimed at activating specific biological pathways. The information they perceive is then used to determine the cell’s fate: If ROS levels are relatively low, the cell can “rescue” itself by adapting its metabolic activity so that less ROS are produced; antioxidants are also produced to “scavenge” the extra ROS and reduce their toxic effects. If ROS reach levels beyond repair, however, a type of programmed cell suicide is activated.

By coupling the proteomics approach to live measurements of ROS levels in different subcellular locations under stress conditions, the scientists can now predict which sub-network of proteins will be activated under a given stress condition and the specific metabolic pathways they will trigger to achieve stress acclimation. They have also shown that the surveillance system works in a rapid and reversible manner – an important factor in enabling it to continually detect new stress.
 
Diagram of ROS-sensitive proteins in key metabolic pathways and their intracellular locations in diatoms. Identified ROS-sensitive proteins are highlighted in red, showing the difference in degree of oxidation when the cell is under stress. ROS-sensitive reactions participating in nitrogen metabolism are highlighted in bold
 

 

 
To corroborate these findings, the scientists conducted a more specific investigation into what happens to cells under conditions of nitrogen starvation – nitrogen being an essential component for the formation of blooms. They revealed that different locations within the cell respond differently to fluctuations in nitrogen availability, suggesting that this may serve as a signaling mechanism allowing cross-talk between intracellular organelles. These organelles can then mount an appropriate response, triggering specific biological pathways according to the cell’s needs.

“The beauty of these findings is that phytoplankton ‘invented’ photosynthesis more than 2.3 billion years ago, which helped to drive evolution. But the downside is that with the production of oxygen came toxic ROS. We believe that they co-evolved this sensor protein network to help them adapt to environmental stress,” says Vardi. “At the same time, the suggestion that single-celled organisms have a program to activate cell death raises controversial questions: How do single-celled organisms carry genes that cause death in the first place? And since cellular suicide is an evolutionary dead end for the single cell, what are the consequences of such cell fate decisions for the population of cells?”
 
Understanding the ecology and evolution of these ancient microorganisms has wide-ranging implications, which may, among other things, help reveal how highly conserved metabolic pathways across kingdoms adapt to high ROS levels or gauge the effect of a bloom’s demise on global warming. Those adaptations may also have implications for the understanding of human cellular metabolism, in which ROS play a crucial role in health and disease, as well as advancing the use of phytoplankton and other microorganisms in the biotech industry for biofuel development.  
 
Dr. Assaf Vardi's research is supported by Charles Rothschild, Brazil; Roberto and Renata Ruhman, Brazil; Luis Stuhlberger, Brazil; the Lord Sieff of Brimpton Memorial Fund; the European Research Council; and the estate of Samuel and Alwyn J. Weber. Dr. Vardi is the incumbent of the Edith and Nathan Goldenberg Career Development Chair.
 
 
 
Diatom cells expressing ROS-sensitive proteins in the nucleus (green) and chlorophyll (red)
Life Sciences
English
  • Assaf Vardi
  • Cell suicide
  • Ocean
  • Phytoplankton
  • Plant Sciences
  • Proteomics
  • Signaling

A Break in the Signal

English

Our nerves respond to a range of stimuli

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The story of the boy who cried “wolf” is more than just a fairy tale. In the story, the more he cried out, the less attention the villagers paid to his cries. That phenomenon, we now know, reflects a deeper biological reality: The nervous system cannot sustain attention at high levels of stimulation. Our sensory systems contain mechanisms for adapting, so that a few seconds after entering a crowded room we can carry on a conversation; we barely pause in our reading when someone turns on a light; and we cease to feel the clothing on our bodies seconds after we get dressed.  

Scientists think that this downward adjustment of the nerves’ responses helps them cope with the gap between the huge physical range of stimuli they must take in and their limited abilities when it comes to processing them. For example, a loud sound can be thousands of times the intensity of a weak one, whereas the nerve cells can vary the rate of their firing only on a scale of hundreds. By adapting to persistent environmental stimuli, the nerve cells are freed to function at their optimal activity range, both when responding to strong stimuli – such as the din of a train – or to much weaker inputs – say, a whisper.

This phenomenon has been demonstrated in the lab, with exposure to a stimulus that repeats periodically. After a short while, the nerve cells adapt and the signals they fire in response to the stimulus gradually diminish in strength. Research in the lab of Prof. Ilan Lampl of the Neurobiology Department, which recently appeared in the Journal of Neuroscience, takes the subject of adaptation one step further. Dr. Keti Cohen-Kashi, a postdoctoral fellow in his group, asked what happens when one interrupts the regular periodicity of the stimulus, even by a little.
 
(l-r) Dr. Keti Cohen-Kashi, Prof. Ilan Lampl and Boaz Mohar
 
She designed an experiment in which the activity of nerve cells in a part of the rats’ brains – the cortex – was monitored as their whiskers were exposed to a periodic stimulus. The repeating stimulus was then stopped and, after a short rest, a single stimulus – identical to those in the previous series – was given again. As expected, the firing of the nerve cells steadily faded – some three- to four-fold – as the periodic stimulus continued. The researchers’ surprise was in the response to the “unexpected” stimulus that followed: About a third of the monitored cells responded with a bang – three times the intensity of their maximal response to the original stimulus.
 
Lampl explains that the single, sudden stimulus “breaks” the adaptation. This mechanism may arise from our survival instincts: Adaptation leaves the sensory systems free to pick up on the unfamiliar, sudden surprises in our surroundings while ignoring the familiar background stimuli.
 
Although the research was done on rats, Lampl says that the findings may explain the results of certain experiments done with human volunteers. In one experiment conducted in Italy, the subjects experienced the stimuli on a finger. Like the rats in Lampl’s lab, these subjects received an additional, surprise stimulus, but this one was in a slightly different frequency and was sometimes applied to the corresponding finger of the other hand. The volunteers were then asked to guess whether the additional stimulus was identical to the previous set. It turns out that their answers were more accurate if the second stimulus was given on the same hand. The new study suggests that this is because some of the nerve cells in the brain that are connected to this hand may have had a stronger response to the second stimulus.
 

How is adaptation broken? To further understand the phenomenon, the scientists used a special recording method that enabled them to distinguish between two types of signal sent between cortical cells – one that excites a response and one that inhibits it. They found that it is actually the inhibitory signals that are responsible for the increased strength of the response the second time around. While the signals that excite the response have had a chance to return to their former levels over the rest period, the inhibitory signals, which have also dropped in magnitude with the repeated stimulus, are still only at partial strength. So it was the absence of inhibition that caused a stronger signal in some of the nerve cells.

 

neuron
 

Parallel paths


In an additional study in Lampl’s lab, which appeared in the Journal of Neuroscience, he and his team uncovered some clues to a long-standing question: If adaptation involves a drop in the nerves’ response to a periodic stimulus, how does the brain distinguish between signals that lessen in intensity due to internal adaptation and those that lessen because the signal from the external stimulus falls off (for example a receding train whistle)?

Research student Boaz Mohar used a new technique to insert electrodes deep into the brain – in the rats’ brainstem – to measure the electrical activity of a group of cells involved in the first stage of processing information from the whisker. These experiments showed that when the intensity of the stimulus is higher, the corresponding adaptation is slower and weaker. But then Mohar discovered a second group of cells responding to the stimuli. Surprisingly, in these cells, higher stimulus was tied to stronger and faster adaptation.   

Each group of cells represents the starting point of a different information-processing pathway, both of them leading to the higher levels of the brain, in the cortex. The existence of two, parallel paths for transferring sensory information may help the brain decide, by monitoring how fast the nerves’ responses fade, which of the two kinds of stimulus – adapation or ebbing – is being experienced.

According to Lampl, the mechanism of the first group of cells goes against conventional thinking. It has been supposed that at higher intensities the response of the nerve cells should fall off faster, as they would deplete their reserves more quickly; but the research findings show that this is not always the case. In his present research, Lampl is looking to see if the explanation might lie in interactions between the two pathways, as well as investigating how these pathways are involved in processing more complex, natural stimuli.
 
Prof. Ilan Lampl's research is supported by the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Marianne Manoville Beck Laboratory for Research in Neurobiology in Honor of her Parents; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Adelis Foundation; the estate of Dorothy Geller; and the estate of Florence and Charles Cuevas.


 
 
Our nerves respond to a range of stimuli
Life Sciences
English
  • Ilan Lampl
  • Nerve cell
  • Neurobiology
  • Sensory nerves
  • Sensory stimulus

Backup

English
 
 
(l-r) Idan Frumkin, Zohar Bloom-Ackerman, Prof. Tzachi Pilpel, Dr. Orna Dahan and Avihu Yona
 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Every cell has an entire legion of translators providing their crucial service. The work of these highly specialized molecules must be efficient yet accurate; research shows that they accomplish this partially through teamwork. When one is hurt or needs help, others provide backup. Research at the Weizmann Institute, which was recently reported in eLife, explains how the backup mechanism works, as well as revealing how evolution enables the cell to cope with change. That change may be an alteration in the cell’s environment that necessitates adaptation, or it could be a change in the cell, itself, that turns it cancerous and then induces further modifications in the protein manufacturing process so as to support the cancer growth.

Translation – the second step in the process of transforming the DNA code to protein – involves a conversation between two different chemical languages: the encoded nucleotide argot of the messenger RNA and the amino-acid vernacular of the proteins. The Rosetta Stone of cellular translation is a two-headed molecule called transfer RNA (tRNA). The side that “speaks” nucleotide is called an anticodon; it identifies a single triple-nucleotide sequence in the messenger RNA, called a codon, which encodes a specific amino acid. The other head on the molecule identifies that amino acid. Simple enough, but the translation team works with added layers of complexity. For example, each of the 20 amino acids can be encoded in a number a different codons, each with its own tRNA. And not all tRNA molecules are equal: Some are encoded in a single gene, and are thus rare in the tRNA legions, while others are found in multiple copies.
 
 
Yeast tRNA. Blue and gray are the anticodon end, purple translates to amino acid. Image: Yikrazuul via Wikimedia Commons
 
Prof. Tzachi Pilpel of the Molecular Genetics Department researches the translation system.  Several years ago, Zohar Bloom, then a research student in Pilpel’s group, created a “library” of mutated yeast cells, each containing a different mistake in one of the cell’s 274 tRNA genes (as well as some with multiple mutations). In particular, they wanted to see how the cell copes with these potentially damaging mutations, and whether it employs a good backup system.

Their research showed that such a backup does, indeed, exist – one that could be called tinkering. The cell patches together a chemical alteration on a similar tRNA molecule so that it can substitute for the missing one. This quick (and reversible) mechanism keeps the cell alive, but it is imperfect: The growth efficiency of yeast cells with a tRNA mutation was about 90% that of a normal cell.

As a quick fix, the chemical modification could be seen as a relative success, but over time, such yeast cells would lose out in the evolutionary fitness race. Can evolution provide a better, more permanent solution to the loss of a tRNA? Pilpel and his lab group, including research students Avihu Yona, Zohar Bloom-Ackerman, Idan Frumkin, Yoav Charpak-Amikam and research fellow Dr. Orna Dahan had a method to test this question in the lab: test-tube evolution. Yeast cells from the library's collection were grown in a robotic system over a period of weeks or months, allowing them to divide and accumulate further mutations. Continuous analysis of the yeast in this system enabled the researchers to track their evolution in real time.

After a month, one of their strains of yeast gave them a surprise: Its development had improved, and now rivaled that of normal yeast. As to why, the team members had two competing theories, and they began to place bets on the eventual outcome. The first theory stated that the solution to the missing tRNA was in another mutation. The second group thought that the recovery was too quick for a mutation of this sort to have taken effect, and the cell must have better tinkering skills to adapt on the similar molecule.
 

 

amino end
 

 

Common genes and rare ones

To settle the issue, the team sequenced all of the genes that coded for relevant tRNA molecules. The result: Those claiming a genetic mutation won the bet. The mutation was in the anticodon of the gene for a different tRNA that binds to the same amino acid, but with a different codon. This mutation was successful because it was in a gene for a common tRNA – there are normally 11 copies of it in the yeast cell. To exclude the possibility that another backup mechanism was at work, the scientists created yeast cells with two mutations – intentionally creating the mutation they had seen and removing the original tRNA. These yeast grew normally.
 
That the evolutionary change in these yeast was so rapid as to seem impossible, but a mathematical analysis showed it was actually not too fast to have occurred in a month of evolution. A likely explanation, says Pilpel, is that for these particular cells there is a large selection of available genes – 11. A mutation in any one of them would be sufficient to solve the problem. When the potential backup tRNA molecules are rare, there would be fewer opportunities for beneficial changes to occur.
 
This raises another question: Why are some tRNAs common and others rare? “Essentially, the question comes down to what the cell profits from having these rare tRNA molecules,” says Pilpel. “The answer we have proposed is that rareness functions as ‘punctuation’ – like a period at the end of a sentence that creates a pause in the flow.”  Such pauses are necessary because of protein folding – a process that takes place as translation proceeds. Slowing down translation at various points gives the tricky task of proper folding a chance to catch up. To demonstrate, the scientists added extra copies of these tRNAS to the yeast cells, so they were no longer rare. The result was a complete collapse of the protein folding process.  In other words, to work as a team, tRNA molecules need to be available to back up their friends, but also need to know when to make themselves scarce.
 
Prof. Yitzhak Pilpel's research is supported by the Sharon Zuckerman Laboratory for Research in Systems Biology; the Braginsky Center for the Interface between Science and Humanities; and the European Research Council. Prof. Pilpel is the incumbent of the Ben May Professorial Chair.
 
 
 
 

 

 
Yeast tRNA. Blue and gray are the anticodon end, purple translates to amino acid. Image: Yikrazuul via Wikimedia Commons
Life Sciences
English
  • Gene code
  • Molecular Genetics
  • Protein
  • RNA
  • Yitzhak Pilpel

Goblet Cells Get Their Germs

English
 
Inside our digestive system, a thin layer of cells forms one of the body’s most important lines of defense. These cells – the epithelial cells – stand between a population of gut bacteria, the microbiota, which form one of the densest microbial ecosystems on the planet, and our sterile inner body. These cells not only prevent the microbes – friendly and disease-causing alike – from crossing into the tissue, they also help maintain the balance of bacteria in the gut. Among these front-line cells are the goblet cells, named for their unique shape, which secrete various substances to repel invaders.
Tunneling electron microscope image captures two goblet cells secreting their contents into the intestine
 

 

Conventional scientific wisdom has pretty much viewed goblet cells as simple cups that spilled their antibacterial substances into the gut with little plan or design. But recent research led by Weizmann Institute researchers, in collaboration with scientists from the University of British Columbia and Yale University, has revealed for the first time a sophisticated feedback mechanism in the these cells for controlling the secretion of their bacteria-repelling substances. Their findings, which appeared in Cell, show that this mechanism is key to deciphering the complex relationship between the gut bacteria and the body of their host.
 
It has been known for many decades that goblet cells are important for preventing disease. Comprising between one twentieth and one fifth of the gut epithelial cells, the goblet cells secrete both antibiotic proteins and mucus – a highly effective antibacterial gel that coats the gut lining and prevents microbial penetration. These vital substances are produced within the cell and transported to the cell membrane for release into the gut inside little bubbles known as vesicles. What has not been known, until now, is how the cells know which substance to pack off in the vesicles, and when.
Scanning electron microscope image of the inside of the gut lining. Note the vesicles protruding from the surface of the goblet cells, prior to release. In inflammasome-free mice, these vesicles are not released
 
In the present study, research students Christoph Thaiss, Maayan Levy and Meirav Katz in the group of Dr. Eran Elinav of the Weizmann Institute’s Immunology Department, the group of Prof. Bert Finley of the University of British Columbia and the group of Prof. Richard Flavell of Yale University investigated this process in the goblet cells in mice. At the core of the control mechanism they discovered a unique protein cluster called an inflammasome. This cluster monitors the bacterial population: It is created when a precise series of signals is sent around the cell, and it activates the cell’s response to infection. Elinav had, in previous research, discovered the first inflammasome expressed in an epithelial cell, and the present study showed that it is mainly produced in goblet cells. The researchers found that its function is to direct the vesicles: When they created goblet cells lacking inflammasomes, the various antibacterial substances continued to be produced and even packed for shipping in the vesicles; but those vesicles did not release their contents into the gut, and thus the defensive layer did not form. 

 

n the gut of a normal mouse (left) there is a thick, internal layer of mucus (wide green stripe), while an inflammasome-free mouse (right) does not produce this layer
I
 
 
Without the antibacterial proteins and mucus secreted by these cells, the intestinal tissue was vulnerable to disease-causing bacteria, which gain entrance by first attaching themselves to the gut lining. But the disruption also affects the overall balance in the population of gut bacteria – the ones that normally do not cause problems. When the body’s defense is weakened, these can reproduce rapidly; and when they, too, come into direct contact with the body’s tissue, they can increase its susceptibility to everything from intestinal inflammation to obesity, diabetes and cancer.

How exactly does the inflammasome affect the vesicle secretion process in the goblet cells? Further investigation revealed that a well-known cellular mechanism called autophagy was at work. Autophagy – literally “self-eating” – is mostly known as a survival mechanism that enables cells to repurpose their non-essential substances in times of starvation or stress. The researchers found that in the goblet cells, the autophagy mechanism directs a sort of “ripening” process the vesicles must undergo before making their way to the cell membrane. In short, autophagy, a cellular survival mechanism, is employed by the inflammasome to regulate the goblet cells’ secretion of various antibacterial substances into the gut.
 
(l-r) Meirav Katz, Christoph Thaiss, Dr. Eran Elinav and Maayan Levy
 

 

 
 
This study is the first to make the connection between a crucial regulatory mechanism and the body’s plan for managing its relationship with its bacterial population, and it has clarified how disrupting the mechanism can lead to all sorts of ailments. Elinav: “The epithelial cells, particularly the goblet cells, interact directly with the external environment within the gut. The research shows that these cells are an integral part of the innate immune system, an insight that expands our view of biological immunity. As we improve our understanding of the molecular mechanisms our bodies use to control the bacterial population inside us, we will be better able to develop new treatments against some of the more common human multi-factorial diseases.”      
 
Dr. Eran Elinav’s research is supported by the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; Yael and Rami Ungar, Israel; the Crown Endowment Fund for Immunological Research; John L. and Vera Schwartz, Pacific Palisades, CA; Alan Markovitz, Canada; Cynthia Adelson, Canada; the estate of Jack Gitlitz; the estate of Lydia Hershkovich; and the European Research Council.
 
 
 
 
Tunneling electron microscope image captures two goblet cells secreting their contents into the intestine
Life Sciences
English
  • Bacteria
  • Eran Elinav
  • Immune system
  • Immunology
  • Intestine
  • Microbiota

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