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Prof. Rony Seger. Extensions have special functions
 

 

 
 
Like the old-time telephone networks run by switchboard operators, our cells have their very own "switchboard operators" that allow external signals to place a "call" to various cell centers such as the nucleus and other cellular organelles.
 
These "switchboard operators" are receptors – proteins that sit on the outer membrane of the cell wall. When they receive "incoming calls" – in the form of chemical molecules, such as insulin, or physical stimuli, such as heat – they become activated, transferring the message to the nucleus inside the cell. The cell then responds to these external stimuli, initiating cellular functions according to the specific message received. These functions include proliferation, differentiation, survival and even cell death.
 
t was as a postdoctoral fellow working in the laboratory of Nobel laureate Edwin Krebs that Prof. Rony Seger of the Weizmann Institute's Biological Regulation Department first encountered these messages being passed on once the receptor was activated. Signaling pathways – the cells' version of telephone lines – comprise about five to eight proteins each. These proteins, like runners in a relay race, activate the next protein in line until the last one crosses the finish line – in this case, the nuclear membrane.
 
Rather than electrical signals, as in telephones, the proteins use chemical signals, adding a phosphorus molecule to each "runner" in turn.
 
Through the Human Genome Project, it was discovered that cells employ only 100-200 "operators" at a time to receive hundreds of incoming calls. Each call requires an individual response, but just 10-12 main "telephone lines" are available to transfer messages. "How are all these different signals transmitted and responded to with such specificity?" wondered Seger.
 
Over the years, Seger has managed to identify various ways in which specificity is achieved; the most recent findings were published in the Journal of Cell Biology. Together with postdoctoral fellow Dr. Yoav Shaul, he has now shown that the main signaling pathways can branch out and subdivide – something like extension numbers in automated answering systems that prompt "Please press 1 for…, 2 for..."
 
This discovery came about when they were studying one of the main signaling pathways, called ERK, and noticed that it had various "extension numbers" – namely, ERK1, ERK1b, ERK1c and ERK1d. "The question was whether these extensions are redundant, dealing with the same 'queries' as the main ERK pathway, or whether they handle different messages of their own," explains Seger.
 
It turns out that the extensions do indeed have very specific functions. One role of the ERK signaling pathway is the regulation of cell division. During cell division, one of the cell's components – the Golgi apparatus – splits into thousands of tiny fragments that are doled out among the daughter cells for later reassembly. Seger found that only one of the ERK branch lines, ERK1c, was capable of transmitting the message to carry out this process.
 
Because breakdown in communication can lead to malfunction in cellular processes, discovering how specific messages are delivered may prove to be of major importance. For example, ERK signaling inhibitors are currently used to try to modulate the excessive cell growth of cancer, but because ERK is a main pathway involved in many cellular functions, jamming the signal may interfere with some necessary ones as well. The ability to target a specific pathway could lead to a more effective treatment and cause fewer side effects in the process.
 
Prof. Rony Seger's research is supported by the M.D. Moross Institute for Cancer Research; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and La Fondation Raphael et Regina Levy. Prof. Seger is the incumbent of the Yale S. Lewine and Ella Miller Lewine Professorial Chair for Cancer Research.
 

Cell to Cell

A surprising discovery in the lab of Prof. Rony Seger has shown that the body's cells appear to be able to "answer" calls made by cell phones. Our cells apparently pick up the radiation signals transmitted from cell phones and respond to the messages they are receiving.
 
Seger and Dr. Joseph Friedman, working part-time in Seger's lab, exposed living cells grown in lab dishes to cell phone radiation emissions in the range of frequencies and intensities used by cell phone networks for up to 45 minutes – well within the range of the average teenage phone conversation.
 
The researchers found that the "calls" placed by cell phone radiation were transmitted to the human cells via the ERK line – one of the more prominent intracellular telephone lines described here. Once the ERK line was activated, the cells were able to respond, providing various "answers" – adjusting cellular activity depending on the radiation frequency and intensity they were exposed to.
 
Do these findings suggest that cell phones "connect" to the central ERK line directly? Seger and Friedman suspect that cell phone radiation emissions first "call up" another set of molecules, known as free radicals. Free radicals are highly reactive molecules that are created in cells and may, under specific conditions, participate in the regulation of normal cellular processes such as proliferation, or pathological processes such as cancer. These, in turn, might activate the ERK telephone line.
 
The implications for human health are unknown at this point. To investigate further, Seger and Friedman intend to move their research up a step, from living cells to living organisms. This may lead to a better understanding of the effects of cellular phone radiation on living cells and help in assessing its effects on the human body.
 
Prof. Rony Seger.
Life Sciences
English
  • Biological Regulation
  • Cell division
  • Rony Seger
  • Signaling

Muscling In

English
 
Prof. Ben-Zion Shilo and research team. Merging muscle cells

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Some people say a man is made out of mud
A poor man’s made out of muscle and blood 
     – Merle Travis, Sixteen Tons

 

Muscle fibers are unique, massive cells that contain many nuclei. They begin, like all animal cells, as naive embryonic cells. These cells then differentiate, producing intermediate cells called myoblasts, which, while not yet muscle, are already stamped with their future destiny. New myoblasts seek out other myoblasts, and when they find each other, they stick together like best friends. In the final stage of muscle fiber development, the cell membranes of the attached myoblasts open up and fuse together, forming one large, unified cell. The new muscle fiber is now complete, capable of contracting, stretching and working.

 
How myoblasts identify other myoblasts and how they cling together had been established, but the way that cell membranes fuse into one remained a mystery. A recent study by Weizmann Institute scientists has now shed light on this mystery. The study was carried out by research student Rada Massarwa and lab technician Shari Carmon under the guidance of Dr. Eyal Schejter and Prof. Ben-Zion Shilo of the Institute’s Molecular Genetics Department, with help from Dr. Vera Shinder of the Electronic Microscopy Unit.
 
The cells’ system for identifying other myoblasts and sticking to them consists of protein molecules that poke through the outer cell membrane – one end pointing out and the other extending into the body of the cell. Both ID scanner and anchor, these protein molecules are capable of recognizing each other and holding the cells in position next to each other. But the research team wondered what happens in the next stage, when the myoblasts open their doors to each other and merge into one cell.
 
The scientists discovered that a protein called WIP, which attaches to the internal part of the myoblast recognition protein, plays a key role in muscle cell fusion. WIP communicates between the identification molecule and the cell’s internal skeleton, which is made of tough, elastic fibers composed of a protein called actin. The skeletal actin applies force to the abutting cell membranes, tearing them open and enlarging those holes so that the cells can merge. The Weizmann Institute team found that the WIP protein is turned on by an external signal telling it that another myoblast has been identified and is now snuggled up close. Only when it receives this signal does WIP hook up the actin fibers in the skeleton to the myoblast recognition protein, enabling cell fusion to proceed.
 
The WIP protein has been conserved evolutionarily. In other words, versions of it exist in all animals, from microorganisms such as yeast, through worms and flies, and up to humans. Not only does this mean that the protein fulfills an important function necessary for life but also, say the scientists, because of this conservation, studies conducted on this protein in fruit flies can teach us quite a bit about how it works in humans.
 
To further examine the role of WIP, the scientists used sophisticated genetic research techniques to knock out the gene responsible for producing it in fruit flies. In flies that did not make the protein, normal muscle fibers failed to take shape. WIP-deficient myoblasts continued to identify and cozy up to one another, but fusion between cell membranes didn’t take place, and multi-nucleated muscle fibers failed to form. A scientific paper describing these findings appeared in the journal Developmental Cell.
 
This study, which improves our understanding of the process of muscle formation, may in the future assist in devising new and advanced methods for healing muscle. These might include, in particular, ways of fusing stem cells with injured or degenerated muscle fibers. 
 
Fusion between cell membranes also plays a key role in the development of different kinds of bone cells, placental cells and immune system cells, as well as in fertilization and in the penetration of viruses into living cells. Understanding how membrane fusion takes place may one day lead to the development of ways to encourage the process when it’s needed or hinder it when it’s likely to cause harm.  
   
Prof. Ben-Zion Shilo’s research is supported by the M. D. Moross Institute for Cancer Research; the Y. Leon Benoziyo Institute for Molecular Medicine; the Clore Center for Biological Physics; the Dr. Josef Cohn Minerva Center for Biomembrane Research; the J & R Center for Scientific Research; and the Jeanne and Joseph Nissim Foundation for Life Sciences Research. Prof. Shilo is the incumbent of the Hilda and Cecil Lewis Professorial Chair in Molecular Genetics.
 

Fruit fly muscle fibers:

 

The normal fibers consist of large multinucleated cells, while the mutant mucles are thin and disorganized, due to failure of muscle cells to fuse with the founder muscle cells.

 

Multi-nucleated muscle cells

 

Mutated fruit fly muscle cells are unfused

 

  

 

(l-r) Shari Carmon, Dr. Vera Shinder, Prof. Ben-Zion Shilo, Rada Massarwa and Dr. Eyal Schejter. Unraveling cell fusion
Life Sciences
English
  • Ben-Zion Shilo
  • Embryonic development
  • Molecular Genetics
  • Muscle tissue

Eaten Up Inside

English
(l-r) Sharon Reef and Prof. Adi Kimchi. One gene, two methods

 

 
 
 
 
 
 
 
 
 
 
 
 
 
In an emotionally difficult situation, it’s easy to feel as though we are “eating ourselves up from the inside.” In humans, this is no more than a psychological feeling, but for cells in our body, getting eaten from the inside can really happen. Every one of our cells is uploaded with a special “program” that instructs the cell to abort if it becomes a threat to the body – if it begins to turn cancerous, for example. This phenomenon of cellular suicide can occur in two different ways. The most commonly known is named “apoptosis” (in Greek: “falling off,” like leaves from a deciduous tree). In apoptosis, the cell produces toxic proteins that cause it to break apart. Cells that kill themselves in this way are “eaten” by neighboring cells. The second cellular suicide method, called autophagy, occurs when the cell literally eats itself from within. Malfunctions in these self-destruct programs may result in diseases such as cancer.
 
Prof. Adi Kimchi, Head of the Molecular Genetics Department, and research student Sharon Reef recently identified a novel protein that tells the cancerous cell to choose the self-eating method of suicide. In research that was published in the journal Molecular Cell, Kimchi and Reef discovered that this new protein is actually a shortened version of a previously known protein that usually causes apoptosis. These two proteins are in fact encoded by the same gene, even though each instructs the cancerous cell to commit suicide in a different way. The scientists proved that the shorter version of the protein, due to the missing segment, carries out its activity in an area of the cell completely different from that used by the longer protein. Consequently, autophagy is
triggered instead of apoptosis. 
 
The process of autophagy is based on the concept of “recycling bins”: double-membraned sac-like structures that actively develop in the cells. Especially during times of starvation, when food is lacking, these bins are able to recycle some of the cell’s contents, providing it with extra food and energy. But under certain circumstances, the recycling bins work in overdrive mode, resulting in self-eating to the point of death. The question arose: Is the observed autophagy – that triggered by the novel protein – a survival mechanism or its opposite, an agent of self-destruction? 
 
To answer the question, Kimchi and Reef, together with Einat Zalckvar and Shani Bialik of the Molecular Genetics Department and Prof. Moshe Oren and Ohad Shifman of the Molecular Cell Biology Department, silenced two genes that are known to be necessary for assembling the sac-like autophagic “recycling bins.” They discovered that reducing the occurrence of autophagy via gene silencing increased the survival of cells and thus concluded that the formation of the membrane-bound sacs in this case spells total degradation for the cells’ contents. 
 
But why have two different suicide mechanisms developed in cells? Kimchi suggests that the autophagy track is a sort of back-up plan, in case the cancer cell fails – for a variety of possible reasons – to sacrifice itself by apoptosis. By employing a back-up plan, the cell continues to ensure the prevention of the spread of cancer. Now the scientists plan to check if their understanding is correct, or whether autophagy is an independent process, unrelated to the cell's  earlier failed attempts to commit apoptosis.    
  
Prof. Adi Kimchi’s research is supported by the Clore Center for Biological Physics; the Leo and Julia Forchheimer Center for Molecular  Genetics; the Levine Institute of Applied Science; the Jeans-Jacques Brunschwig Fund for the Molecular Genetics of Cancer; the Joseph and Bessie Feinberg Foundation; the Flight Attendant Medical Research Institute; the Anne P. Lederer Research Institute; the Lombroso Prize for Cancer Research; the Ruth and Samuel Rosenwasser Charitable Fund; and the Jacqueline Seroussi Foundation Israel. Prof. Kimchi is the incumbent of the Helena Rubinstein Professorial Chair in Cancer Research.
 
 
 

Eating Machines

 
Prof. Zvulun Elazar. Protein plugs
 
 
 
 
 
 
 
Anyone who’s had the experience of putting machinery back together and having a part left over knows that some parts are more essential than others. Prof. Zvulun Elazar of the Biological Chemistry Department has used this principle to identify, for the first time, two sites on a particular yeast protein that are indispensable for protein recognition. Without these recognition sites, the process of assembling the “recycling bins” needed for cellular self-eating can’t take place. 
 
For the protein to carry out its activity, a specific, complementary protein needs to recognize and “plug” into one of its “sockets” – an action that initiates a cascade of events. By removing various socket-like structures one at a time from the protein and seeing how this affected the overall working of the autophagic machine, Elazar and his research team were able to isolate the specific site the second protein must recognize and hook up to. When this site was missing, that protein remained unplugged, leaving the cellular recycling machinery idle. They also found a second site on the protein that appears to be necessary for autophagic activity, although how it works needs to be studied further. 
 
Autophagy in mammalian cells has significant associations with neurodegenerative diseases, heart disease, cancer, program-med cell death, and bacterial and viral infections. Because the autophagic recycling system found in yeast is similar to that in mammals, this research could provide crucial insight for further studies into the malfunctioning of cellular machinery and its consequences.
 
This research, which was published in EMBO Reports, was conducted with Ph.D. students Nira Amar of the Biological Chemistry Department and Gila Lustig of the Biological Regulation Department, in collaboration with Dr. Yoshinobu Ichimura and Prof.Yoshinori Ohsumi of the National Institute for Basic Biology, Japan.
  
Prof. Zvulun Elazar’s research is supported by the Philip M. Klutznick Fund for Research; Mr. and Mrs. Stanley Chais, Beverly Hills, CA; and Mr. and Mrs. Mitchell Caplan, Bethesda, MD.
 
(l-r) Sharon Reef and Prof. Adi Kimchi. One gene, two methods
Life Sciences
English
  • Adi Kimchi
  • Apoptosis
  • Biological Chemistry
  • Cancer
  • Cell suicide
  • Molecular Genetics
  • Zvulun Elazar

Beyond the Parts List

English
Prof. Benjamin Geiger. Cell repair manual

 

 

 

Even the most inveterate tinkerer must occasionally consult the instruction manual. Unfortunately, for some important machines we rely on every day - the assortment of microscopic machinery that makes up our body's cells - no such manual exists. While the parts list - genes, proteins and biological molecules - grows longer by the day, scientists are just beginning to understand how these components all work together to make up the complex machinery of cells, and how breakdowns in this equipment, the cause of many diseases, might be fixed.

A new international research project aims to improve this situation by setting out to write a "Cell Operations Manual" and a "Cell Repair Manual." This project is part of an ambitious initiative of the National Institutes of Health (NIH) in the U.S. called the "Roadmap for Medical Research." The brainchild of NIH director Elias Zerhouni, the Roadmap was set up to fund innovative biomedical research in a number of areas, with no less a goal than that of transforming medical science. In the futuristic area of nanomedicine, four groups were awarded grants totaling $43 million over five years. Prof. Benjamin Geiger, Dean of Biology and researcher in the Molecular Cell Biology Department at the Weizmann Institute of Science, is a member of one of these four groups, the NanoMedicine Center for Mechanical Biology. Each member of the group, which includes biologists, materials scientists, physicists and theoreticians from the U.S., Israel and Switzerland, will bring his or her own research experience to bear on fundamental questions concerning the mechanics of life on the incredibly tiny scales of cells and molecules.

Scale, in fact, is one of the more tangled puzzles the scientists plan to address. How do cells, around 40 microns across (a micron is a millionth of a meter), self-organize to become organisms that are meters in size? At the other end of the scale, single molecules, the information-bearing units of the cell, are in the nanometer range - just thousandths of the cell's size. If cells were the size of people, their sense organs would be little bigger than grains of sand. How does communication between a cell and its parts take place across this range?

Communication is another subject the scientists will tackle. Cells are continually subjected to mechanical forces, whether the pumping force of blood or the structural force of bones, tissues and neighboring cells. Endowed with sophisticated means of sensing these forces, they are able to convert their "readout" on the nature of the force into biochemical signals that then inform the cell's actions. But how exactly does this happen? Many diseases - including metastasis, in which cancer cells stop clinging to their neighbors and move away - might be tied to the cells' failure to properly sense and interpret forces. In addition, bioengineers attempting to grow tissues from various stem cells have found that cells need the proper mechanical cues in their environment to know how to develop into specific cell types.

From nanomaterials and nanoelectronics to molecular biology, the world of the ultra-small has its own physical laws, which very often differ from those of the everyday world. By incorporating knowledge from varied fields, the research group intends to develop new approaches to understanding the mechanics of the cell. As their work progresses, the scientists hope to gain insight into many of the major health issues facing us today: wound healing, hypertension and cardiovascular diseases, osteoporosis, nerve regeneration,immune responses and cancer. The "instruction manuals" they're planning will then become works-in-progress that can be applied to maintaining the machinery of life in good working order.

Prof. Benjamin Geiger's research is supported by the Clore Center for Biological Physics; the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research; the Levine Institute of Applied Science; the Women's Health Research Center; the Edith C. Blum Foundation; the Samuel R. Dweck Family Foundation; Mr. and Mrs. James Adler, Chevy Chase, MD; the estate of Evelyn Blum, Switzerland; the estate of Ernst and Anni Deutsch, Liechtenstein; and Ms. Ruth Browns Gundelfinger, San Rafael, CA. Prof Geiger is the incumbent of the Professor Erwin Neter Professorial Chair of Cell and Tumor Biology.
 

Surface Patterns

For a number of years Prof. Geiger, a molecular cell biologist, and Prof. Joachim Spatz of the University of Heidelberg, a materials scientist, have been working together to try to figure out how the cell "reads" and responds to the information in its environment. Spatz and his group in Heidelberg create materials with surfaces that mimic collagen, one of the body's support materials. They simulate different conditions by controlling various properties of these materials, such as their surface topography or relative hardness, and they also produce nanopatterned surfaces with minuscule areas of differing properties. Onto this carefully designed surface they anchor assorted molecules using gold nanoparticles.

These molecules are positioned so as to create tiny islands on which only one receptor (a cellular "antenna" through which cells connect to the world outside their walls) can gain a foothold at a time. "With these materials, we see exactly which molecules the receptors recognize and interact with," says Geiger. In recent studies, the scientists have discovered that the placement of the binding molecules affects the ability of the cell receptors to work together either to keep the cell stuck to the surface or to help it move. The method has the added advantage of providing a relatively large surface - a centimeter or so square (several football fields to a cell) - to work with.
 
Prof. Benjamin Geiger.
Life Sciences
English
  • Benjamin Geiger
  • Cell
  • Cellular communication
  • Molecular Cell Biology

Double Agent

English

Dr. Atan Gross and his team. Ligfe or death decision

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In the life of a cell, just as in the course of a person’s life, there are times that call for a break in the routine; a moment to run a “self-check” to review the state of one’s internal health and settle on a course of action. When the genetic material of the cell is damaged, the cell needs to assess the extent of that damage and decide whether to turn on the DNA repair machinery or commit suicide to prevent the possible development of cancer. If this crucial self-evaluation stage is skipped, wrong decisions are likely to result.

 

The process of self-checking, decision making and action is managed by a crack team of proteins. Depending on the circumstances, certain members of this team may be given more than one assignment. In research published in the journal Cell, Dr. Atan Gross and his research team in the Biological Regulation Department at the Weizmann Institute showed that one prominent protein called BID lives the life of a double agent. BID plays two different roles: one in the chain of events that leads to cell suicide, and another in the chain that ends in survival. How is this one protein able to perform two, seemingly opposed missions?

 

In its better-known role as a regulatory protein in the suicide chain, BID begins to act when an enzyme, caspase-8, cuts a piece off the protein, leaving a smaller protein, tBID, that is primed and ready to carry out its assigned task in the cell’s suicide.

 

Gross and his research team began to learn of the protein’s double role when they asked what happens to the suicide chain if BID does not undergo cleavage. To answer this question, they inserted into embryonic mouse cells a gene that encodes for a mutant BID protein, one that resists cutting by the caspase-8 enzyme. To their surprise, the mutant, uncut BID was still activated. Gross and his team then tracked the activities of this protein and soon discovered that BID hooks up with another protein, ATM, a “player” for the anti-suicide side. ATM is a crucial manager of the DNA repair process in the cell nucleus; its role is so vital we can’t survive without it. It is called into action in response to toxins that severely damage DNA and cause breaks in both strands of the double-stranded chain. ATM, in turn, recruits a whole emergency crew to join in the rescue effort. Postdoctoral fellow Dr. Rachel Sarig, a member of Gross’s research team, found that along with the rescue workers, some of which science has not yet identified, ATM activates the full, uncut version of BID. If this is indeed the case, BID might play an important role in the chain of events that leads to DNA repair and cell survival.

 

Illustration of cell life cycle and BID

 

 

 

 

 

 

 

 

 

 

 

 

 

 

What is this role? To continue the investigation, research student Iris Kamer examined how the cell life cycle was managed in embryonic mouse cells lacking the gene for BID. These cells were exposed to a DNA-breaking toxin. The result: The BID-deficient cells skipped the critical self-check stage. Only when the scientists reintroduced BID into the cells did they take a break in the cycle to run a self-check.

 

The researcher’s investigations into the activities of this double agent revealed further insights into its whereabouts and dealings. They refuted current thinking, which maintains BID resides only in the body of the cell, showing that it also frequents the nucleus. The research team, which included Dr. Yehudit Zaltsman, Dr. Hagit Niv and research students Galia Oberkovitz, Limor Regev and Gal Haimovich, also found that BID can postpone the decision to commit suicide by a few hours, granting the cell’s DNA repair machinery a chance to undo the damage (a process in which BID might play yet another role). Although such a delay may seem inconsequential, pausing to seize the chance to preserve cell life rather than rushing into a decision to commit suicide may have some advantages.

 

When the cell is improperly managed, the upshot might be unsound decisions that could lead, for example, to the replication of damaged DNA or a delay in cell death – mistakes that can result in uncontrolled cell proliferation and the development of cancer. Gross hopes that the findings of his research team will contribute to a better understanding of cancer progression and the resistance of some tumors to chemotherapy and radiation, as well as helping to explain genetic diseases in which ATM is absent or has been inactivated.  

 

Dr. Atan Gross’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the Dolfi and Lola Ebner Center for Biomedical Research; the David and Fela Shapell Family Center for Genetic Disorders Research; the Willner Family Center for Vascular Biology; the Jeans-Jacques Brunschwig Fund for the Molecular Genetics of Cancer; the Harry and Jeanette Weinberg Fund for Molecular Genetics of Cancer; the Louis Chor Memorial Trust Fund; the Abisch Frenkel Foundation for the Promotion of Life Sciences; la Fondation Fernande et Jean Gaj; la Fondation Raphael et Regina Levy; and Mr. and Mrs. Stanley Chais. Dr. Gross is the incumbent of the Robert Armour Family Career Development Chair.

 
Left to right: Dr. Atan Gross, Iris Kamer, Dr. Rachel Sarig, Limor Regev, Galia Oberkovitz, Dr. Hagit Niv and Dr. Yehudit Zaltsman. Cellular self-check
Life Sciences
English
  • Atan Gross
  • Biological Regulation
  • Cell
  • DNA damage and repair›DNA repair

Ironing Genes

English

High levels of Ferritin show up in red, low levels in blue

 

 

An iron storage molecule in the cell, with the help of magnetic resonance imaging (MRI), can serve as an advanced tool for mapping gene expression.
 
Prof. Michal Neeman of the Weizmann Institute's Biological Regulation Department, together with Dr. Batya Cohen of the Molecular Genetics Department, altered the iron-bearing ferritin molecule to serve as a sort of gene “spy.” The scientists rendered ferritin sensitive to tetracycline, a common antibiotic, which serves as a switch, turning ferritin ON or OFF. As MRI is sensitive to magnetic particles such as iron, the cells' increased uptake of iron when ferritin is turned ON can be tracked, effectively exposing the genetically modified cells.
 
This method grew out of a joint vision that originated 10 years ago in a collaboration with the late Dr. Yoav Citri. It has far-reaching implications for monitoring the progress of gene therapy and for tracking gene expression in the central nervous system or during embryonic development.
 
Prof. Michal Neeman’s research is supported by the M.D. Moross Institute for Cancer Research; the Willner Family Center for Vascular Biology; the Mark Family Foundation; and Mr. and Mrs. Stephen Meadow.
 
 
MRI image: High levels of Ferritin show up in red, low levels in blue
Life Sciences
English
  • Biological Regulation
  • MRI
  • Michal Neeman

Making a Heart

English
 
Right from the beginning, life is all about choices. The decision to proceed down one path eliminates the possibility of taking others, and consequences can be lifelong.
 
Cells in a developing embryo must make such critical, final decisions. The thousands of different tissues that make up the body are all derived from one original cell type, and in the earliest stages of development the possibilities are wide open. A cell can decide to become any part of the body, such as heart or bone. But cells do not take the decision-making process lightly. A complex orchestration of events underlies each choice, and these “defining moments” are as yet poorly understood. Mistakes can cause innumerable problems, and if we understood how cells determine their fate during embryonic development, we could perhaps guide them to make better decisions.
 
Dr. Eldad Tzahor of the Biological Regulation Department heads a team of researchers working to identify the series of events occurring during normal embryo development that leads to the formation of heart or skeletal muscle tissue. Among the lab’s sophisticated equipment is a standard white refrigerator full of farm-fresh fertilized eggs. At early stages of development, all vertebrate embryos, from alligators to humans, share remarkable similarities, so the chick embryo, with its short gestation period and easy accessibility, is an ideal model to study developmental biology.
 
Eldad Tzahor. Element of choice
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tzahor and members of his group are able to isolate so-called progenitor cells from a developing chick embryo and follow their development and differentiation into the various types of tissue. “When I started my research in this field, I tried to isolate cells that should normally develop into skeletal muscle. To my surprise, I saw beating heart cells in the culture dish. Suddenly we realized that the textbook definition of the developmental fate of a certain type of cell was no longer black and white but fairly gray,” says Tzahor. His research revealed a cell’s destiny is not only fate: there’s also an element of choice. The decision depends, in part, on its developmental context: its stage in development, the signals it receives from its neighboring cells and the sequence in which those signals are exchanged. Thus a cell’s proximity to other types of cells at critical stages in its development guides its developmental choices.
 
Tzahor unraveled some of the mystery of the decision-making process by identifying the role of a group of protein molecules called Wnt in managing cell fate decisions. Wnt are signaling molecules that instruct cells not to form a particular cell type - heart, for instance - causing them to follow a different path. Tzahor and his research team are now pursuing the identification and classification of other “general managers” of the differentiation program of embryonic heart cells. Their findings could be an important key to future progress in stem cell research seeking to generate specialized cell types for organ or tissue repair.
 
 
“Cells have to walk and talk together to make decisions that lead to their ultimately separate developmental paths,” says Tzahor. “The molecular crosstalk between cells leads to a perfect orchestration of events that results in the creation of our bodies, but it's in a language that we don't yet understand. Despite the wealth of information we have in the textbooks, the deeper, real-life dynamics of embryonic development are much more complicated.”
 

From Farm fields to Research Fields

 
Growing up on a kibbutz has its advantages: From a young age Tzahor made observations about the cycles of life. His childhood experiences and early interest in veterinary biology help explain why a successful career scientist changed paths to pursue embryonic development research. Tzahor says this career shift has been crucial to his development as a scientist, enabling him to apply and inject new themes and perspectives across a range of fields.
 
In 1988, Tzahor completed a Ph.D. in the Weizmann Institute's Molecular Cell Biology Department under Prof. Yosef Yarden. Following a postdoctoral fellowship at Harvard Medical School in boston, he returned to the Institute as a senior scientist in the biological Regulation Department in 2003.
 
Tzahor is married to Talia and the father of Noam (9) and Roy (4).


 
Dr. Eldad Tzahor’s research is supported by the Estelle Funk Foundation and Mr. and Mrs. Charles Stephens, Somers, NY. Dr. Tzahor is the incumbent of the Philip and Gertrude Nollman Career Development Chair.
 
Dr. Eldad Tzahor. Molecular crosstalk
Life Sciences
English
  • Biological Regulation
  • Cell differentiation
  • Eldad Tzahor
  • Embryonic development
  • Yosef Yarden›Yosef Yarden

Dying to Live

English

 

Wallach and his research tem. Understanding the mechanisms of cell life and deathj

 

How does one define the borderline between life and death?” asks Prof. David Wallach of the Biological Chemistry Department. Most doctors agree that cessation of heartbeat or brainwaves is the standard indication of human death. For the body’s cells, too, scientists have clear ideas as to the signs that indicate death. For instance, they can point to specific molecules that are intimately associated with the cell death process. But, as Wallach and an international team of researchers have recently demonstrated, at least one of the molecules most closely linked to cell death may be just as necessary for maintaining cell life.
 

Caspase-8 is a member of the caspase family of enzymes, known to play a central role in the complex process leading to cell death, also called apoptosis. This enzyme’s activation is, in itself, taken as a sign that the cell is on an irreversible path to suicide.
 

In the 20 years that Wallach has been studying apoptosis, he has brought to light some of the more important biological molecules and processes involved, including caspases. Around six years ago, he and his research team used a technique called “gene knock-out” to create mice lacking the gene that produces caspase-8. However, rather than breeding mice with immortal cells, as would be the case if caspase-8 was merely a link in the cell-suicide chain, they found their mice didn’t make it past the embryo stage. Apparently, this “cell death” enzyme also had important roles to play in growth and development.
 

“Unfortunately, when knocking out a gene causes so much havoc in the organism, it's very hard to study its function,” says Wallach. But a recent advance in knock-out technology inspired the team to try once again to unravel caspase-8's role. Called conditional knock-out, it allowed the scientists to delete the gene in only one organ at a time or to turn it off at a specific time.
 

When the caspase-8 gene was knocked out from the liver, the result was, indeed, the creation of cells that refused to die, giving scientists further proof that caspases are crucial to apoptosis in living mammal cells. In contrast, knocking out the caspase gene from the circulatory system produced nearly opposite results. Cells did not grow and develop properly, and the fine capillary blood vessels failed to form as they should. Similarly, knocking out the caspase gene from the stem cells that become various types of blood cells resulted in the complete arrest of blood-cell generation, while deleting it in unformed macrophages (a type of white blood cell) kept them from maturing, showing the “death” gene may be a “life” gene after all.

 

While this study raised some new questions about the mechanisms that control life, another study recently published by Wallach and his team settled the long-standing question of how a protein they had previously discovered helps the cell resist death. Called NIK, this protein relays messages from the immune system outside the cell to an intracellular “messenger service” called NF-kB, which sparks the production of proteins that, among other effects, endow cells with death resistance. But NIK works only some of the time, and the circumstances of its employment were the subject of scientific controversy. Wallach’s team showed that NIK comes into play only if specific receptors on the cell membrane - those tied to the functioning of white blood cells known as lymphocytes - are activated. Because an accumulation of death-resistant lymphocytes is tied to such problems as graft rejection and various autoimmune diseases, NIK is a promising target for new drugs to treat a variety of conditions.

 

Prof. David Wallach’s research is supported by the Kekst Family Center for Medical Genetics; the Dr. Josef Cohn Minerva Center for Biomembrane Research; the David and Fela Shapell Family Center for Genetic Disorders; the Joseph and Bessie Feinberg Foundation; and the Alfred and Ann Goldstein Foundation.

(l-r) Parameswaran Ramakrishnan, Dr. Wangxia Wang, Prof. David Wallach, Tehila Ben Moshe and Dr. Tae Bong Kang. Resisting death
Life Sciences
English
  • Apoptosis
  • Autoimmune
  • Biological Chemistry
  • David Wallach
  • White blood cell

Crossing the Divide

English
Dr. Sima Lev. Separation protein
 
 

 

From life's very beginning, when the ovum starts dividing into two primal cells, our existence depends on cell reproduction. In adults, billions of cells divide every day to replace cells that wear out or to meet a sudden demand. Yet the most critical moment, when the mother cell divides into two new daughter cells, remains a mystery.

The different stages of cell division -  a process so orderly as to appear almost choreographed -  have long been known. While tremendous advances in cell biology and genetics over the past few years have shed light on this process, its underlying molecular machinery is still not fully understood. The final step of this elegant performance, the separation into two cells, is called cytokinesis. Recently, Dr. Sima Lev of the Weizmann Institute of Science's Neurobiology Department discovered that a protein called Nir2 is essential for normal cytokinesis in human cells.

As a postdoctoral researcher at New York University, Lev discovered a protein called Pyk2, which plays an important role in cell signaling. Looking for proteins that interact with Pyk2, she discovered a protein family consisting of three members, which she called the "Nir"family. She then isolated the genes responsible for producing the proteins.

Highly conserved throughout evolution, the Nirs are found in fish, worms, flies, and mammals. Lev decided to dedicate her work todetermining the Nir proteins'function in the body. "No one in the world was working on the Nirs,"she says, "and I strongly believed that they had an important cellular function."

Upon her return to the Weizmann Institute, Lev spent nearly three years evaluating many possible roles for the protein, with team members Vladimir Litvak, Donghua Tian, and Shari Carmon. The breakthrough came with their identification of a particular fragment of Nir2, consisting of 219 amino acids out of the protein's full 1,244. When they expressed this fragment in human cells, it had adramatic effect on their shape and caused severe defects in cytokinesis. The cells failed to separate, forming long bridges between asymmetrical daughter cells. The fragment, Lev concluded, was inhibiting cytokinesis in some way, but its precise role remained obscure.


In a pinch


The scientists looked closely at dividing cells to determine exactly where the Nir2 protein was located during the process. They found that during normal cytokinesis Nir2 is present at the "cleavage furrow,"the pinched area of the cell at which the break into two daughter cells will eventually take place. But it's not alone. Beside it is an enzyme called Rho-GTPase, which plays a long-established role in cytokinesis. What, Lev wondered, was Nir2 doing there?

She found that Nir2's protein fragment is able to inhibit the activity of the Rho enzyme. She therefore designated it "Rid"(Rho inhibitory domain). It was already known that inactivation of the Rho enzyme is necessary for the final separation into two daughter cells, but it was not known what triggered Rho to move into an inactive state. Lev contends that Nir2 essentially subcontracts Rid to inhibit the activity of Rho when appropriate. If she is right, Nir2 -  by hosting Rid -  is vital for breaking the contractile ring between two daughter cells and thus is essential for successful cytokinesis.

The physical evidence supports Lev's assertion. When she cut off the end of Nir2 containing Rid, she saw that cytokinesis was severely impaired. The cells struggled to divide and eventually gave up, resulting in unseparated cells with multiple nuclei. The absence of Rid apparently short-circuited the cells'ability to separate.

Lev's findings shed new light on the Nir proteins as well as on the process of cytokinesis. But many open questions remain regarding the clinical implications of her results. It is well known that cytokinesis plays a critical role in animal development, and that defects in this stage of cell division can lead to instability of the genome, a phenomenon associated with cancer. In addition, recent experiments have shown that mouse embryos which lack the Nir2 protein do not survive. Thus her findings may provide insights into the necessity of this protein for normal embryonic development. "The challenge now,"says Lev, "is to translate these results into practical medicine."
 

Cells lacking the separation protein

 

Dr. Lev's research is supported by Mr. and Mrs. Nathan Baltor, Bensalem, PA; Minna James Heineman Stiftung, Germany; the Carl and Micaela Einhorn-Dominic Institute for Brain Research; and the Nella and Leon Benoziyo Center for Neurosciences. She holds the Helena Rubinstein Career Development Chair.

 

 
Daughter cells struggling in vain to break apart
Life Sciences
English
  • Cell division
  • Molecular Cell Biology
  • Neurobiology
  • Protein
  • Sima Lev

Looking for Trouble

English
Dr. Ronen Alon. Simulating blood flow
 
 

 

It looks like Monday morning rush hour viewed from high above. Hundreds of tiny dots are scurrying down the screen while a parallel fleet heads north. Every once in a while, one of these bright spots stops in its tracks, turns left or right, and subsequently disappears from view.

It's not a traffic update, but an image captured by a system that simulates blood vessel functioning. This type of video footage is increasingly shedding new light on the traffic-law-like mechanisms governing immune cell behavior. Developed by a team headed by Dr. Ronen Alon of the Weizmann Institute's Immunology Department, this modeling system is made up of cells coupled with sophisticated imaging and data processing machinery.

"By building blood vessels from scratch outside the body, we essentially construct a highly controlled and selective environment for examining how key circulatory players interact," Ronen explains. "We're focusing our efforts on one of the most mysterious processes in immunology -  how immune cells squeeze through blood vessels on their way to fight infection."

Every minute, millions of white blood cells, the immune system's "soldiers, "leave the circulatory vessels to patrol body tissues, looking for signs of infection or injury. They respond to special "stop-sign"molecules displayed on blood vessel walls.

Unfortunately, this efficient system is exploited by cancerous cells, which also migrate through the blood, metastasizing in distant parts of the body. The cancer cells are able to identify and respond to the stop-sign molecules, gaining access to neighboring tissue. Identifying these signaling molecules and understanding how they function may therefore yield a powerful tool for controlling the immune system and blocking the spread of metastatic cancer cells.

In responding to a signal from infected tissue, a migrating immune cell first rolls to a halt and begins to flatten on the blood vessel wall. It must then squeeze through the layer of endothelial cells that make up that wall. Using their modeling system, Alon's team, which included graduate student Guy Cinamon and Dr. Vera Shinder of the Institute's Electron Microscopy Unit, has now revealed how stop-sign molecules, called chemokines, control this process.

Arriving from neighboring tissues, chemokines enter the circulatory system, where they display themselves on the vessel wall. Each chemokine flags down a different type of immune cell, using cell-specific "passwords" to recruit the cell best suited to the immune task at hand, similar to the way a traffic policeman would call in an ambulance, fire engine, or tow truck, according to need. The team's study, published in Nature Immunology, shows that chemokines also provide directions into the tissue, guiding the immune cell along its short migratory route, from the time it slows down and stops on the blood vessel wall until its point of exit.

To their surprise, however, the team discovered in subsequent experiments that the chemokine signal is not in itself enough for cell migration to occur. It turns out that even if the right chemical signals are present, the immune cells won't exit the blood vessel unless they sense certain mechanical factors inherent to blood flow.

This finding challenges the traditional perception of blood flow. While pausing on the vessel wall, immune cells are continuously exposed to blood flow, which threatens to carry them away from the exit site, much like a stone is swept along a riverbed. But this new study demonstrates, for the first time, that blood flow actually plays a vital role in helping them across vessel walls: When flow is absent in the model system, the immune cells remain "stuck"at the exit site for a short while, after which they return to the circulatory system.

These new insights into cell migration from the circulatory system may contribute to future therapies that fine-tune migration processes -  enhancing beneficial immune responses while blocking undesirable migration, such as that of cancerous cells. 

Dr. Alon's research is supported by the Abisch Frenkel Foundation for the Promotion of the Life Sciences, Switzerland. He holds the Tauro Career Development Chair in Biomedical Research.
 
Dr. Ronen Alon. Taking the right exit
Life Sciences
English
  • Immunology
  • Ronen Alon
  • Signaling molecule
  • White blood cell

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