They do this by binding to messenger RNA molecules, preventing them from carrying out protein synthesis. RNA interference, as this process is called, provides the cell with a way of controlling the levels of hundreds of different proteins by turning genes off at the appropriate times.

“Now we understand that miRNAs are important in regulating the processes inside the cell, inside the organ, and inside the organism,” says Dr. Eran Hornstein of the Weizmann Institute of Science’s Department of Molecular Genetics. “When these components are malfunctioning, you end up with a disease.”

Dr. Hornstein and his team study how miRNAs regulate the activity of genes during the development of the pancreas, bone, and cartilage, and how malfunctions may contribute to diseases.

Before joining the Institute in 2006, Dr. Hornstein received his MD/PhD from the Hebrew University–Hadassah School of Medicine in Jerusalem. He started out with the goal of becoming a physician, but was ultimately drawn to basic science research and completed his postdoctoral studies in the Department of Genetics at Harvard Medical School.

While at Harvard, he helped provide some of the earliest evidence that miRNAs play a role in vertebrate development—specifically, in the development of limbs. The study of miRNAs is so new that at the time of Dr. Hornstein’s postdoctoral research, the first miRNA had been identified only a decade earlier.

Dr. Hornstein’s current investigations include studying the role of miRNAs in diabetes. “We know now that miRNAs are highly relevant to the regulation of insulin gene expression in beta cells that are key to controlling the body’s glucose levels. And we think we also have a clue about particular miRNAs that are highly relevant to the development of diabetes in mice,” he says.

Along with his colleagues, he is also looking at the role of miRNAs in amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). ALS is a neurological disorder that affects motor neurons—the nerve cells in the brain and spinal cord that control muscle movements—causing muscle weakness and paralysis. “It’s a very devastating disease and the genetics of it are completely unknown, so we don’t yet know how to cure it,” says Dr. Hornstein. “But we have now developed a very nice model, in mice, to show that loss of miRNA activity may generate ALS.”

He believes this research could shed light on the role of miRNAs in other neurodegenerative conditions, such as Alzheimer’s disease. “It seems that miRNAs are extremely relevant to the functionality of neurons,” Dr. Hornstein says. He explains that mi-RNAs seem to work not at the cell nucleus, but at the periphery. Neurons sometimes need to regulate their functionality at a distance, very far away from the center of the cell. It now appears that regulatory RNAs—particularly miRNAs—might specialize in regulating cell functions at a distance from the center.

A better understanding of miRNAs, which are now thought to regulate more than a third of all human genes, could eventually be useful for the treatment of a wide range of illnesses ranging from osteoporosis to cancer. “Down the road, I hope the findings in my lab will come together with technologies that are being developed in order to generate new therapeutics for diseases,” says Dr. Hornstein.

One Weizmann Institute of Science research success story features the multiple sclerosis (MS) drugs Copaxone® and Rebif®. These two medicines—results of decades of hard work and experimentation by Weizmann scientists —are now frontline treatments for MS, but the beneficial effects of this research extend far beyond the medications themselves.

Production of these drugs has significantly contributed to the Israeli economy, helped establish and drive the country’s crucial biotechnology industry, and provided opportunities for new scientists to build thriving research careers.

THE COPAXONE® STORY
In the 1950s, the Weizmann Institute’s Prof. Ephraim Katzir (later the fourth president of the State ofIsrael) began researching proteins—the basic building blocks of all bio- logical systems. This work led to the design of synthetic models of proteins, called poly-amino acids.

Prof. Michael Sela, Katzir’s former research student, decided to test the influence of these synthetic molecules on the immune system. He theorized that giving mice certain poly-amino acids, or copolymers, might cause their immune systems to reproduce the symptoms of autoimmune diseases such as MS.

Along with Prof. Ruth Arnon and Dr. Dvora Teitelbaum, Sela synthesized several copolymers that mimic a component of myelin, the protective coating of nerves. Because the component was believed to trigger MS, the scientists hoped that their molecules could create a much-needed animal model for the study of MS; unfortunately, their experiment did not work.

Despite the initial failure, the scientists persisted. Their determination paid off when they stumbled on a surprising finding: Rather than causing MS symptoms, the copolymers were actually blocking an MS-like disease. Arnon says the results were “overwhelming ... at that early stage, we realized that this might eventually lead to a therapeutic agent.”

The team then conducted years of experiments with a molecule called copolymer-1, or Cop-1. Their studies ultimately led to the development of the drug Copaxone®, with clinical trials carried out by Teva—Israel’s largest pharmaceutical company—proving its efficacy in treating MS.

In 1996, Copaxone® became the first original Israeli drug to be approved by the U.S. Food and Drug Administration (FDA). Today, after more than a decade of active sales around the world, Copaxone® has made a major contribution to the Israeli economy and provided a significant boost to the country’s important biopharmaceutical industry.

But the story is still unfolding at Weizmann: Using molecular genetics, Prof. Doron Lancet recently identified a genetic basis for the positive effect of Copaxone® on many MS patients. These findings may help develop the field of personalized medicine. Prof. Michal Schwartz has used Copaxone® to stop the progressive loss of sight in animals with a glaucoma-like disease, suggesting that the drug may also aid people with glaucoma. The nature of basic research is that one never knows where the science will lead.

THE REBIF® STORY

Prof. Michel Revel was just a teenager when interferon—so named because interferes with viral activity—was discovered, and by the time he came to Weizmann in 1968, scientists still knew very little about the substance. It was difficult to produce, and no one had succeeded in generating it in large quantities. Looking for a challenge, Revel decided to explore exactly how interferon disrupts viral proteins ... and as soon as the mid-70s, the Weizmann team was known as a world leader in interferon research.

The team concentrated on a form of interferon called interferon beta. While other groups around the world were studying interferon alpha, Revel felt that the beta form might have a special role. However, interferon beta does not show up in blood when injected, and so scientists had predicted that it would never be developed as a drug. But Revel and company soon proved that injected interferon beta actually does leave evidence in the genes it activates—a finding that saved their research.

While Revel believed that interferon beta had unique potential, there was still no way to generate the large quantities needed—until the group used genetic engineering to produce interferon beta in animal cells. This technique has since become a mainstay of the biotech industry.

The team began to pursue medical applications in earnest. They learned that a researcher in the U.S., who thought MS might be caused by a virus, was treating patients with anti-viral interferon beta. The Weizmann group’s research had shown that interferon can influence immune activities even if no virus is present. They realized the virus theory was wrong, but that interferon beta might nonetheless prevent the symptoms of MS, and Revel convinced pharmaceutical giant Serono to conduct trials.

As a result, Rebif®, the interferon beta-based treatment for MS, entered the market in 1998. Produced for many years at Interpharm in Israel (in 2005, production moved to Switzerland), it made a major contribution to Israel’s economy and biotech sector. The impact of Revel’s research is huge: Today, interferon beta-based drugs for MS are a $4.6 billion industry, and are taken by three-quarters of MS sufferers.

Weizmann research continues on interferon beta, already leading to the discovery that a topical application can prevent recurrence of genital herpes symptoms. It also has shown promise for treating hepatitis C—a use for which Serono has recently completed clinical trials. The story of interferon and its wide-spread impacts is not yet over.

The normal function of blood vessels greatly depends on the dynamic properties of the endothelial cells that line the vessel. These cells are firmly attached to the underlying membrane as well as to their neighbors via specialized adhesions, which play a crucial role in regulating vessel formation (angiogenesis), stability and repair. When given a message by angiogenic factors, or following a pathological loss of cell-cell adhesion, endothelial cells extend flattened protrusions with motile properties, form new adhesions and migrate. This physiological response is essential for blood vessel maintenance.

This process can be simulated in the laboratory by an in vitro wound model, where cultured endothelial cells are allowed to migrate into and close a gap that has been artificially introduced into the endothelial layer. Under pathological conditions such as diabetes, the normal maintenance of blood vessels is severely disrupted, leading to increased fragility and malfunction of the vascular system.

Prof. Benjamin Geiger of the Molecular Cell Biology Department is investigating the mechanisms regulating endothelial adhesion and motility. Current studies in his laboratory address the mechanisms underlying these dynamic processes, in healthy and diseased vessels. A better understanding of the molecular mechanisms underlying the generation of new blood vessels and wound closure may point toward possible targets for drug development.

In related research, the work of Prof. Michal Neeman of the Biological Regulation Department may help address the necrotic wounds in the extremities, characteristic of diabetes. Neeman is working on the use of quantitative magnetic resonance imaging (MRI) methods for the analysis of vascular growth in limbs deprived of blood supply. Her objective is to generate criteria for testing the effi cacy of therapeutic approaches for blood vessel growth.

Working with bone marrow transplants for terminal leukemia patients, Prof. Yair Reisner of the Immunology Department has found a way to overcome residual immunity even in the case of transplants from unmatched donors. His method removes the main obstacles limiting the use of mismatched transplants – namely, graft failure and an adverse immunological reaction called graft-versus-host disease.

Normally, a donor and recipient are considered compatible when they are matched for all six immunological markers on their chromosomes – three inherited from the mother and three from the father. In Reisner’s method, developed in collaboration with Prof. Massimo Martelli of Italy’s Policlinico Monteluce, the donor and the recipient need to be matched for only three markers. Such a partial match is always found between parents and children, and there is a 75 percent chance of finding it between siblings.

To date, hundreds of patients throughout Europe have been treated using this approach, yielding significant success rates, as reported in the New England Journal of Medicine, Blood, and other publications. Following these encouraging results, Phase 1 clinical trials are currently under way in major centers in the United States, and the European Bone Marrow Transplantation Society has recently launched a formal prospective study in 35 centers throughout Europe.

A key element of this method is the use of extremely large doses of donor marrow that literally overwhelm the recipient’s rejection mechanism. The donated stem cells are “cleansed” to erase the characteristics contributing to rejection in mismatched transplants. But why does it work? How does bombarding the patient with a megadose of donor stem cells prevent transplant rejection?

A new study by Reisner and his team at the Weizmann Institute’s Department of Immunology provides insights into this riddle. They have shown that certain stem cells, using a “veto” mechanism, are capable of protecting themselves against attack by the body’s immune system. In addition to offering a possible explanation of how stem cells aid in preventing immune rejection, this finding may prove vital in targeting another longstanding research challenge – to lower the radiation dosages accompanying transplant therapies in a range of diseases, from advanced diabetes to leukemia.

Date: September 02, 2007

Time: 01:00 PM - 02:00 PM

Station: Fox News Channel

Location: Network

Program: Weekend Live

STEVE CENTANNI, co-anchor: How many times have you been told that cell phones are not bad for your health? Probably a lot. But hold on a second, there's a new study out this week that challenges that notion. Researchers at the Weizmann Institute of Science in Israel have found evidence cell phone radiation does react with your brain cells and that could lead to cancer.

Now here to help us sort all this out, all the facts from the fiction, is Dr. Leigh Vinocur. Thanks, Doctor, for coming in.

Dr. LEIGH VINOCUR (Physician): Absolutely.

CENTANNI: So we heard for a long time that cell phones are not dangerous; this study in Israel says they may be; how do you know what to believe?

Dr. VINOCUR: Well I think the older studies, what they saw was heat damage, that it caused a lot of thermal injury. And this is the first study where they show some biologic effect that is not related to heat. And what they did is they decreased the dosage by 1/10 so heat wasn't a factor.

CENTANNI: I see.

Dr. VINOCUR: But the effect they saw was the start of an enzyme chain that sort of leads to cell division and cell
growth. But I still think there is a long way to go between normal cell growth and the abnormal cell growth that you see in cancer.

CENTANNI: Do you know if anybody has actually had a brain tumor that you can definitely tie to cell phone use?

Dr. VINOCUR: I don't think they've ever been able to definitely tie it to cell phone use, but there have been people who have had brain cancers on the same side that they held their cell phones. The presidential advisor, I believe, had one for the first Bush administration; I'm not 100 percent sure which administration, but circumstantial evidence (sic).
But if you think about how cell phone use has gone up exponentially--and I spoke with the National Cancer Institute--and primary brain cancer, that's what we're talking about, has not changed in the last 20 years; and cell phone use in the last 20 years has skyrocketed.

CENTANNI: So you think by now we would see a spike.

Dr. VINOCUR: You would start to see an increase or a spike in incidents. But I think you just have to be smart about it. Kids are having cell phones today, so you know; don't let them use it all the time. Keep it for an emergency.
We're just learning a little bit more, so I think what this is saying is yes this is a biologic effect, it's not thermal, maybe we should do more research on it. But be smart about it. Right now, Steve, you still have a higher chance of dying using your cell phone while you are driving than developing cancer probably.

CENTANNI: Yeah, you have to be careful about that.

Dr. VINOCUR: Absolutely.

CENTANNI: But there is new evidence, and you are saying we should be cautious, so people should take precautions?

Dr. VINOCUR: Well, I just think if you have a child that you have given a cell phone to, let them use it for emergency reasons only. Don't let them be on it all the time.

CENTANNI: What if they're using the hands-free device or the speakerphone?

Dr. VINOCUR: Well, they haven't really looked at hands-free, but you're still getting a signal close to your head. So that's another place to do it. But I think--to do the studies--but I think what they're saying is now we've shown there is a small biologic effect, OK, but it's normal. You know the enzyme cascade that was started was just for normal cell growth.
Cancer is not normal cell growth, it's abnormal cell growth, and they haven't seen that. In fact, the researchers said they didn't see cancer-causing effects on it; what they saw is it just promoted cell growth in a very short term.

CENTANNI: So the bottom line, more studies need to be done.

Dr. VINOCUR: More studies need to be done. Don't jump to conclusions, but be smart about it.

CENTANNI: Dr. Leigh Vinocur, thanks for joining us.

Dr. VINOCUR: Absolutely.

Prof. Doron Lancet of the Department of Molecular Genetics at the Weizmann Institute of Science is one of Israel’s most prominent genome researchers. The head of the Crown Human Genome Center, Prof. Lancet has directed research on DNA chips, disease genes, and genes responsible for smell and taste, and is currently working to develop a computational model for the origin of life on earth. Because the Weizmann Institute was Israel’s liaison to the international Human Genome Project, Prof. Lancet and his colleagues have unusually intimate knowledge of the field of genomics and its implications.

What are some of these implications? Prof. Lancet sees the genome revolution as leading to a “new tomorrow.” In the first part of this revolution, says Prof. Lancet, science concerned itself with discovering smaller and smaller bits of living organisms – from the body to cells to genes, and finally down to the level of DNA. “Now we are going in the opposite direction,” he says. “We are trying to understand how DNA makes us.”

Prof. Lancet compares the human genome to an encyclopedia: the volumes are the chromosomes, the pages are the genes, and the letters are the chemical components that make up the alphabet of the genomic code. Unlike a print encyclopedia, however, genetic material can reproduce itself. This reproduction happens when the two strands of the DNA molecule pull apart, acting as mirror-image templates for what will become two new, identical, double-stranded molecules of DNA. During this process of replication, errors (mutations) can be introduced into the sequence of chemical units (or nucleotide bases) that compose the two complementary DNA strands.

Scientists are trying to determine which of these errors might lead to particular diseases. Given that there are approximately three billion base pairs in the human genome, this would seem to be a daunting task. Luckily, scientists now have at their disposal some powerful tools and technologies, including what Prof. Lancet calls the “workhorses of genomics”: polymerase chain reaction (PCR) machines, which amplify DNA, and automated fluorescence-based DNA sequencers, which read the chemical language of DNA automatically.

As the current medical paradigm of mass treatment of patients shifts towards individualized medicine tailored to each person, it will become increasingly important for doctors and researchers to be able to identify specific genetic patterns that lead to disease. Many disease mutations are already well known, particularly those responsible for the so-called single-gene diseases. These diseases, such as Fragile X syndrome, cystic fibrosis, Tay-Sachs disease, or Gaucher disease, result from a mutation in a single gene.

Far more common — and more complicated to comprehend and diagnose — are multiple-gene diseases, which include high blood pressure, heart disease, osteoporosis, Alzheimer’s disease, schizophrenia, asthma, and cancer. These diseases, Prof. Lancet says, result from “combinations of small DNA changes, none of which can be honestly called a mutation.” None of these changes causes harm by itself, but they do have the potential to cause harm in combination.

The small changes that lead to multiple-gene diseases are called single nucleotide polymorphisms, or SNPs (pronounced “snips”). SNPs can combine in many ways, leading to a bell-curve distribution of disease severity within a population. Using schizophrenia as an example, Prof. Lancet points out that one percent of all humans have the disease, which can cause delusions, hallucinations, and incoherence, but that there are “several types of schizophrenia, with no one characteristic to them all.” Research at the Weizmann Institute has already identified a link between schizophrenia and SNPs within a gene known as AHI1, which could be a step toward new treatments for this devastating illness.

Just as there is variation in how genetic factors can contribute to disease, there is also variation in how a person’s genetic profile can influence his or her reaction to a drug. Like multiple-gene diseases, drug reactions are also distributed along a bell curve in populations. The promise in teasing apart an individual’s SNPs and genetic drug profile, says Prof. Lancet, lies in a new field called pharmacogenetics.

Pharmacogenetics would allow doctors to look at a person’s genetic profile to decide what medication that person will receive, in what dose, and potentially even in combination with other drugs, in a personalized cocktail.

Whether it is the search for more SNPs contributing to disease, or the creation of portable databases of individual DNA profiles, the future of medicine is contained in each person’s encyclopedia of genetic information — that’s Prof. Lancet’s vision for the “new tomorrow” and the dawn of individualized medicine. “Ten years from now, you might walk around with a card that says exactly what genome you have, and based on that, your medications and treatment will be prescribed,” he says.

Dunaliella bardawil, a single-celled alga so resistant to salt and sunlight that it can even survive in the hostile environment of the Dead Sea, is turning out to be a very versatile little creature.

It was Weizmann Institute scientists ? the late Prof. Mordhay Avron and his co-worker Dr. Ami Ben-Amotz ? who studied Dunaliella and learned to exploit the hardy alga's ability to produce vast quantities of beta-carotene, a natural pigment and source of Vitamin A. The Weizmann findings became the basis of a thriving export industry. Nature Beta Technologies, an algae-growing enterprise in Eilat owned by the Japanese company Nikken Sohonsha, produces beta-carotene-rich Dunaliella powder and other products that are sold as health food in Japan. And now two research teams headed by Profs. Ada Zamir and Uri Pick of the Biochemistry Department are exploring methods to boost and expand the alga's productivity in order to further increase its commercial value.

But beta-carotene is just one of the assets of this lowly plant. According to the scientists, Dunaliella?s unique survival strategies could make this alga a rich source of other high-value biochemical items. Furthermore, they believe that Dunaliella has the potential to become a vehicle for creating "smart" genetically engineered substances for biotechnology industries. Because its high-salt environment is nearly sterile, mass production of the alga and its potential products holds little risk of contamination. Once the method is perfected, Dunaliella could serve as an economical natural "factory" for an unlimited number of genetically engineered products, including vaccines, drugs and hormones.

As a first step in mining the alga for useful biochemicals, the Weizmann researchers have isolated an enzyme and a transport protein in Dunaliella that are capable of carrying out a variety of biochemical processes under high salt and temperature conditions.

The alga research is being done within the framework of the Magnet Consortium, a program of Israel's Industry and Trade Ministry aimed at building partnerships between Israel's scientific research institutes and high-tech industries.

The Magnet Algae Consortium is made up of the Weizmann Institute of Science and Nature Beta Technologies (the Eilat-based company) collaborating on Dunaliella, and Israel's Oceanographic and Limnological Research Institute, working together with a kibbutz and a chemical firm on a related alga project.

"We are all investigating basic issues regarding the biology of algae," says Prof. Zamir. "But belonging to the Consortium has made the scientists more aware of the practical economic implications of our work, so that what we do has two aspects ? basic and applied."

When Prof. Ada Yonath of the Weizmann Institute of Science was recovering from a concussion suffered while riding her bike, she read an article about hibernating polar bears, which led her to consider the physical processes that enable and support a dormant state. It occurred to her that in order for the bears to go in and out of hibernation, it was possible that ribosomes were packed in an orderly manner – an idea that went against then-current thinking. And she wondered, “Why do they do this?”

More than 20 years later, Prof. Yonath won the 2009 Nobel Prize in Chemistry for her work deciphering the structure of ribosomes.

She began with the realization that in order to investigate ribosomes, they first needed to be crystallized. Often called the cell’s protein factories, ribosomes are composed of a large number of protein molecules loosely bound to giant chains of nucleic acids. Ribosomes are also notoriously unstable and tend to disintegrate, and crystallization should allow them to be imaged and their action studied. At the time – the 1970s – most scientists thought this was impossible.

“Top teams around the world, such as those at UCLA and MIT in the United States and the Medical Research Council in England, had been trying to crystallize ribosomes since the 1960s – with no success. I thought, this is such a delightful group of ‘unsuccessful’ people – they were all Nobel Prize winners – I would like to be among them,” Prof. Yonath recalled.

“People called me a dreamer,” she said, but she believed in her unconventional idea and pressed onward. Fortunately, she was conducting her studies at the Weizmann Institute of Science, where curiosity-driven research is actively encouraged.

Prof. Yonath needed strong ribosomes for her crystallization experiments, which led her to use ribosomal material from hardy bacterial strains isolated from the Dead Sea. These tough, thermophilic (heat-loving) and halophilic (salt-loving) bacteria proved ideal candidates. “After all, they’ve been around almost unchanged for five million years,” she explained.

In order to get the stable ribosomes she needed, she pioneered a new approach that involved exposing ribosome crystals to cryo-temperature during x-ray measurement. This method, called cryo-crystallography, is now a standard research procedure in structural biology. Prof. Yonath and her team made a staggering 25,000 attempts before they succeeded in creating the first ribosome crystals in 1980.

Over the next 20 years, using a sophisticated technique called x-ray crystallography, Prof. Yonath and her colleagues would continue to refine their studies. In 2000, teams at Weizmann and the Max Planck Institute in Hamburg, Germany – both headed by Prof. Yonath – solved, for the first time, the complete spatial structure of both subunits of a bacterial ribosome. Science magazine counted this achievement among the ten most important scientific developments of that year.

Later, Prof. Yonath’s team discovered the mechanism of action of five antibiotic drugs: they identified exactly how each of the antibiotics binds to the bacterial ribosome, shutting off protein production. Proteins are the cell’s primary component and the basis of all enzymatic reactions; thus, blocking their production kills the bacterium.

Prof. Yonath has said that her goal is to “to try to understand the principles of life from the inside by unraveling the detailed structure of ribosomes.” But why are ribosomes so important?

They are essential to life, and solving the ribosome’s structure gives scientists unprecedented insight into how the genetic code is translated into proteins. Upon receiving genetically encoded instructions from the cell nucleus, the ribosomal factory churns out proteins. Understanding protein biosynthesis is therefore the gateway to grasping life itself – including what happens when things go wrong and disease results.

The science done by Prof. Yonath and her co-winners of the Nobel Prize in Chemistry, Thomas Steitz of Yale University and Venkatraman Ramakrishnan of the Medical Research Council Laboratory of Molecular Biology in Cambridge, could lead to benefits such as more advanced and effective antibiotics and better ways to fight the pathogenic protein biosynthesis characterizing cancer cells. The three scientists separately used x-ray crystallography to reveal the atomic structure and inner workings of the ribosome.

This discovery will hopefully also help in the struggle against antibiotic-resistant bacteria, a problem that has already proven fatal to many and that is recognized as one of the most central medical challenges of the 21st century.

Prof. Yonath is the first woman in the world since 1964 to become a chemistry laureate, and only the fourth in history. She is also Israel’s first woman laureate. However, while she admires and respects the female laureates before her, she does not feel her gender is important: it is all about the research. “I am a scientist, not male or female,” she said. “A scientist.”

For more information on Prof. Ada Yonath, please visit:  http://www.weizmann.ac.il/YonathNobel/

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.   

Eating Machines
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.

As a result, about 6,000 people a day — most of them children — die from water-borne diseases. Vestergaard Frandsen, a Danish textile company that supplies water filters to the Carter Center guinea worm eradication program and mosquito-killing plastic tarps to refugee camps, has come up with a new invention meant to render dangerous water drinkable.

The invention is called Lifestraw, a plastic tube with seven filters: graduated meshes with holes as fine as 6 microns (a human hair is 50 to 100 microns), followed by resin impregnated with iodine and another of activated carbon. It can be worn around the neck and lasts a year.

Lifestraw isn’t perfect, but it filters out at least 99.99 percent of many parasites and bacteria, the demons in most fatal cases of diarrhea. It is less effective against viruses, which are much smaller and cause diseases like polio and hepatitis, and it wouldn’t protect American backpackers against the parasite giardia. Nor does it filter out metals like arsenic, and it has a slight iodine aftertaste (not necessarily a bad thing in the large stretches of the globe with iodine deficiency).

It can be manufactured for about $3, but it needs more field-testing. Only about 100,000 have been handed out, 70,000 to earthquake victims in Kashmir last year. Already in the works, however, is a Lifestraw toddler version — which will be squeezable.

The brain is made up of a network of neurons that “talk” to each other via synapses – specialized junctions that act like electric wires, explains Prof. Schwartz. Originally, scientists widely accepted that no new nerves are formed after the birth of an individual.

However, over the last few decades, researchers have found that certain brain regions are able to renew their neurons throughout life, including the olfactory region, spinal cord, eyes, and a certain region in the adult brain – the hippocampus – believed to be the area responsible for our cognitive ability, learning, and memory functions.

“The mechanisms which allow the formation of these new neurons in the adult brain are not fully understood,” says Prof. Schwartz. “Research is still in its infancy.”

However, about ten years ago, Prof. Schwartz and her colleagues found evidence to support their suggestion that cells normally involved in immune responses can promote the healing of damaged neurons in the central nervous system (CNS). Prior to that time, the scientific community thought immune cells should be kept away from the brain, because they were perceived as a threat to the organ’s delicate networks. “Our discovery therefore ran against the dogma,” she said.

The researchers asked themselves what kind of immune cells are needed to generate this healing and found that the answer seemed to be T cells (a type of white blood cell produced in the bone marrow and which are part of the body’s immune defense system) that recognize self-proteins in the brain.

Originally, researchers hypothesized that the thymus deletes all T cells that recognize the body’s own proteins, as they could ultimately cause autoimmune disease. Over the years, however, scientists have found the presence of autoimmune cells in healthy individuals and the debate has been whether they are an outcome of a failure of deletion or a purposeful selection.

Prof. Schwartz and her colleagues suggest that, based on their evidence, autoimmune cells are needed in everyday life to fight off enemies arising within the body, such as toxic substances generated by damaged nerve tissues. But the level of these autoimmune cells must be controlled; if they are not, they can cause autoimmune disease, she explains.

Prof. Schwartz and her colleagues first observed the presence of autoimmune cells in the CNS of animals recovering from optic nerve injury in the 1990s. Shortly thereafter, they found that animals receiving a vaccination of T cells experienced a better recovery from spinal cord injury than animals that did not receive vaccinations.

In their latest research, published in Nature Neuroscience, Prof. Schwartz and her colleagues showed that these autoimmune T cells may also be key players in the body’s maintenance of a normal, healthy brain, enabling the brain regions to form new nerve cells, maintaining the person’s cognitive capacity.

They already knew from earlier research conducted by other groups that rats kept in an enriched environment with mental stimulation, socialization, opportunities for physical activity, and proper nourishment, exhibited increased formation of new neurons close to the hippocampus region, when immune cells were present in the brain.

Therefore, to test their theory, Schwartz and colleagues repeated the experiment using genetically engineered mice that lacked T cells. Significantly fewer neurons were formed in those mice, even though they lived in an enriched environment.

They then used engineered mice possessing all of the other important immune cells except for the T cells that recognize brain-specific antigens. They found impairment of brain-cell renewal, confirming that the missing T cells appear to be an essential requirement for this process, and can be partially restored by replenishment of the immune-cell pool.

In another set of experiments, the researchers found that mice possessing the relevant CNS-specific T cells performed better in some memory tasks than mice lacking CNS-specific T cells, suggesting that the presence of these T cells in mice plays a role in maintaining learning and memory abilities in adulthood.

Based in part on this research, Prof. Schwartz speculates that as people age and the effectiveness of their immune systems declines, safely boosting autoimmunity via a vaccine using a weak self-antigen may be a way to preserve neurogenesis.

In animal models, this approach is already being tested for the neurodegenerative diseases Alzheimer’s, Parkinson’s, and glaucoma. It may help boost a weak autoimmune response to these diseases and slow down chronic neurodegeneration, explains Prof. Schwartz. Such a vaccine may be used in combination with stem cell therapy to create a synergistic effect, she added.

Prof. Schwartz anticipates that this research will lead to many different ways to prevent brain senescence, development of dementia, and halt the progress of neurodegenerative diseases. “The bottom line is that we all hope that this research will translate into a healthy brain and a healthy immune system,” she says.

While the topic of neuroscience could be perceived as daunting, the half-day seminar, which featured four prominent scientists, attracted about 150 people to the Helen & Martin Kimmel Center for University Life at NYU. This large turnout is perhaps because, as Prof. Ilan Chet, President of the Weizmann Institute of Science (WIS), Israel, indicated in his welcoming remarks, brain research is one of the areas of science that attracts the most interest from the public. We all want to know who we are, and what makes us “us,” both as a species and as individuals.

Prof. Yadin Dudai, head of the Weizmann Institute’s Department of Neurobiology, performs globally recognized neuroscience work, particularly with respect to the processes and mechanisms of learning and memory. In his presentation entitled “The Hidden Life of Memories,” Prof. Dudai led the audience through the lifespan of a memory, or, as he prefers to call it, “the biography of an item in our memory.”

When we encounter a stimulus (such as observing a face or a building), it takes about a fraction of a second to register that stimulus. If you record that information for slightly longer – two or three seconds – it becomes short-term memory, which lasts for a few minutes.

Next is the vital stage called “consolidation.” This is the phase in which short-term memory becomes stabilized as long-term memory. This can take from a few minutes to a few weeks, and involves interaction between the cortex and the hippocampus brain regions. If something goes wrong in this interaction, the memory remains short-term.

Once a memory is long-term and stable, how do we actually “remember”? Typically it is through exposure to a stimulus (for example, smelling and tasting hot chocolate), which then triggers “associative recall” so that the stimulus calls up an existing long-term memory (ice-skating with your sister and drinking hot chocolate to get warm).

Each item in our memory has a distinct biography, including properties such as content and age (how old the memory is). But no matter what the memory is about, the lifespan of a memory can be described in terms of phases. These phases are crucial, as Prof. Dudai’s research shows that at these points we may be able to modify or erase a long-term memory.

First, the memory must be called up. When a long-term memory is retrieved, it shifts from the inactive, stable state to the active, unstable state (in other words, it is again short-term), after which the memory may then be reconsolidated. This has clinical promise for persons who live with harmful memories. Interference with damaging, long-term memories may be performed in a number of ways, including electroconvulsive therapy or medicines. This research could help people who suffer from severe, debilitating problems of memory, such as post-traumatic stress disorder (PTSD).

In this work on amelioration of traumatic memories, Prof. Dudai is collaborating with NYU’s Prof. Joseph LeDoux, who is a University Professor, the Henry and Lucy Moses Professor of Science, and a member of the Center for Neural Science and the Department of Psychology.

Prof. LeDoux, whose lecture was entitled “The Emotional Brain: Friend and Foe,” focuses on a topic long ignored by neuroscientists: emotion. By studying emotion and memory, Prof. LeDoux has learned that when we retrieve memories, we call up the last, most recent version of the memory; this is new and evolving research, as it was previously generally accepted that the original memory was the first to be retrieved. This research has implications for issues such as the reliability of eyewitness testimony and other situations where accurate memory is critical.

Another aspect of his research is the many effects of fear on the emotional brain and the problems (such as anxiety, depression, panic, obsessive-compulsive disorder, and other syndromes, such as PTSD) that may result.

Intangibles such as emotions have long been considered unmeasurable; however, thanks to new techniques in human brain imaging, these can now be studied empirically. The WIS/NYU collaboration involves core research in brain imaging and is providing extraordinary results, as David Heeger, Professor of Psychology and Neural Science at NYU, discussed in his presentation “Brain Imaging: A New Window into the Human Mind.”

Brain imaging by functional magnetic resonance imaging (fMRI) is similar to the MRIs performed for routine medical examinations. The difference between an fMRI and a standard MRI is that the fMRI has the ability to observe both the structures of the brain and also which structures participate in specific functions; for example, the part of the brain that responds to a given type of stimulation, whether it is physical, verbal, visual, or memory-related.

However, multiple parts of the visual cortex respond to optic stimulation. There are two locations in the brain that process motion, but they do it in different ways, enabling the brain to make inferences about motion and space.

Dr. Heeger stated that when the back of the brain – the visual cortex – is viewed via fMRI during a visual experience, the image shows a sweeping change across the cortex, proving that there is an actual physical change in the brain as a result of perception.

Such physical change as a result of perception is clearly demonstrated by the work of Prof. Rafael Malach and his group at the Weizmann Institute’s Neurobiology Department, whose research using “natural” brain conditions has drawn worldwide attention. His presentation, “Watching Brains Watching Movies: Studying the Human Brain under Free, Natural Conditions,” drew a great deal of interest from the audience, who were encouraged to challenge their own powers of perception.

Scientists, says Prof. Malach, are tempted to treat human psychology and the human mind as an engineering problem, because it is “very convenient” to believe that you have total control over the research and examine the brain as discrete parts.

His intuition, however, is that while this is indeed a powerful approach, it cannot provide the full picture since our minds work in creative, original, spontaneous ways that cannot always be considered in machinelike terms.

His solution? To study the brain under more naturalistic conditions. Prof. Malach thought films would be a good way to simulate natural vision: movies are streaming, are multidimensional, contain auditory stimulation, have emotional aspects, and are much more like our natural vision than the traditional stimulus/response studies.

Together with the Weizmann Institute’s Dr. Uri Hasson, who is now at NYU, and other students in his group, they performed an experiment that was both scientific and fun – they showed people 30 minutes of the classic Western, “The Good, The Bad and the Ugly.” All the subjects had to do was lie in an fMRI machine and enjoy the movie while Prof. Malach and his team performed scans to see what happens when the brain is engaged and taking in many stimuli.

The researchers were surprised by the results, which showed that people’s visual systems are remarkably similar when receiving the same sensory stimuli. In fact, the readouts from each of the participants were so alike that by observing a map of brain activity of one individual watching the movie, it is possible to tell, with a great degree of confidence, what all the other brains will do when watching the same movie. This phenomenon, called “intersubject synchronization,” extends across a variety of factors, including gender lines.

While our experience of a movie is of a continuous stream, fMRI shows that the activity in our brain is actually more like an orchestra – different areas rise and fall in response to cues, and each area is responding to a different scene or aspect of the movie.

These free-viewing studies also have great potential for use as diagnostic tools to find brain abnormalities. For example, could movies diagnose or reveal what goes on in the autistic brain? Again, Prof. Malach showed intriguing preliminary results from a study in collaboration with Uri Hasson and Prof. Marlene Behrmann. The brains of autistic persons showed a drastic reduction in the “synchronization” effect of the movies.

However, the autistic brain was not quiet and inexpressive – rather, it appeared to be engaged in spontaneous action, which the fMRI displayed in washes of color representing vast waves of activity. The mystery is that this change was generated from inside the autistic brain, not from outside stimulation such as the movie.

It is not yet understood why this happens, but Prof. Malach’s further studies could shed light on this effect. Very little of this activity is seen in the “normal” brain. Such research is a promising tool with great potential to reveal brain deficits in people not only with autism, but with conditions such as retardation and dyslexia.

The WIS/NYU partnership is taking this and other research even further, into issues of time, narrative, consciousness, and diagnostic tools. This exploration of the inner workings of the brain will enable us to not only understand the basic ways in which our minds work, but will bring us closer to alleviating the suffering caused when something goes wrong, resulting in disorders such as Alzheimer’s disease, autism, and schizophrenia. New knowledge can lead to new therapies. The scientists allied in the WIS/NYU collaboration in neuroscience are truly using science for the benefit of humanity.

The genetic code specifies all the proteins that a cell makes. The second code, superimposed on the first, sets the placement of the nucleosomes, miniature protein spools around which the DNA is looped. The spools both protect and control access to the DNA itself.

The discovery, if confirmed, could open new insights into the higher order control of the genes, like the critical but still mysterious process by which each type of human cell is allowed to activate the genes it needs but cannot access the genes used by other types of cell.

The new code is described in the current issue of Nature by Eran Segal of the Weizmann Institute in Israel and Jonathan Widom of Northwestern University in Illinois and their colleagues.

There are about 30 million nucleosomes in each human cell. So many are needed because the DNA strand wraps around each one only 1.65 times, in a twist containing 147 of its units, and the DNA molecule in a single chromosome can be up to 225 million units in length.

Biologists have suspected for years that some positions on the DNA, notably those where it bends most easily, might be more favorable for nucleosomes than others, but no overall pattern was apparent. Drs. Segal and Widom analyzed the sequence at some 200 sites in the yeast genome where nucleosomes are known to bind, and discovered that there is indeed a hidden pattern.

Knowing the pattern, they were able to predict the placement of about 50 percent of the nucleosomes in other organisms.

The pattern is a combination of sequences that makes it easier for the DNA to bend itself and wrap tightly around a nucleosome. But the pattern requires only some of the sequences to be present in each nucleosome binding site, so it is not obvious. The looseness of its requirements is presumably the reason it does not conflict with the genetic code, which also has a little bit of redundancy or wiggle room built into it.

Having the sequence of units in DNA determine the placement of nucleosomes would explain a puzzling feature of transcription factors, the proteins that activate genes. The transcription factors recognize short sequences of DNA, about six to eight units in length, which lie just in front of the gene to be transcribed.

But these short sequences occur so often in the DNA that the transcription factors, it seemed, must often bind to the wrong ones. Dr. Segal, a computational biologist, believes that the wrong sites are in fact inaccessible because they lie in the part of the DNA wrapped around a nucleosome. The transcription factors can only see sites in the naked DNA that lies between two nucleosomes.

The nucleosomes frequently move around, letting the DNA float free when a gene has to be transcribed. Given this constant flux, Dr. Segal said he was surprised they could predict as many as half of the preferred nucleosome positions. But having broken the code, “We think that for the first time we have a real quantitative handle” on exploring how the nucleosomes and other proteins interact to control the DNA, he said.

The other 50 percent of the positions may be determined by competition between the nucleosomes and other proteins, Dr. Segal suggested.

Several experts said the new result was plausible because it generalized the longstanding idea that DNA is more bendable at certain sequences, which should therefore favor nucleosome positioning.

“I think it’s really interesting,” said Bradley Bernstein, a biologist at Massachusetts General Hospital.

Jerry Workman of the Stowers Institute in Kansas City said the detection of the nucleosome code was “a profound insight if true,” because it would explain many aspects of how the DNA is controlled.

The nucleosome is made up of proteins known as histones, which are among the most highly conserved in evolution, meaning that they change very little from one species to another. A histone of peas and cows differs in just 2 of its 102 amino acid units. The conservation is usually attributed to the precise fit required between the histones and the DNA wound around them. But another reason, Dr. Segal suggested, could be that any change would interfere with the nucleosomes’ ability to find their assigned positions on the DNA.

In the genetic code, sets of three DNA units specify various kinds of amino acid, the units of proteins. A curious feature of the code is that it is redundant, meaning that a given amino acid can be defined by any of several different triplets. Biologists have long speculated that the redundancy may have been designed so as to coexist with some other kind of code, and this, Dr. Segal said, could be the nucleosome code.

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.

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.

Numerous plants in nature are capable of recruiting bodyguards via a chain process, which involves a slew of enzymes and culminates in the plant releasing a mixture of volatile organic materials, among them substances called terpenoids. Terpenoid-producing plants include corn, apple trees, beans, cucumbers, cotton and strawberries. They attract a wide variety of predator insects, such as ladybugs, which devour aphids, and parasitic wasps, which lay their eggs in the larvae of harmful bugs.

The pathway of terpenoid production and release is extremely complex, making it possible for the plants to generate different terpenoids to attract assorted insects for all sorts of purposes - from pollination to the repulsion of harmful bugs. But what happens when terpenoid production is ineffective and does not sufficiently protect the plant? Can the pathway be corrected to adjust the time, place and quantity of terpenoid release? Such a correction would significantly improve the plants’ ability to protect themselves against their enemies. The scientists studied this possibility in a model research plant called Arabidopsis thaliana, the first plant to have its entire genome mapped and deciphered.

In attempts to jump-start the terpenoid release system, scientists around the world have tried equipping the cells of different plants with a gene that codes for a unique enzyme responsible for terpenoid production. These experiments, however, failed to produce the desired results because the enzyme "chose" to work in a particular area of the plant cells that was lacking in sufficient raw materials to make terpenoids. To overcome this difficulty, Dr. Aharoni decided to insert into the Arabidopsis plant a single strawberry gene to which he attached a "routing" genetic segment. This segment directed the enzyme to a part of the cell that was rich in the required raw materials - a strategy that allowed the enzyme to step up terpenoid production.

The engineered plant released large quantities - 25 times more than the natural plant - of a signaling chemical that recruits predator mites. At this stage, the scientists decided to test the effectiveness of the method. Predator mites were allowed to roam freely and choose between a genetically engineered and a regular plant. The result: On average, 388 mites rushed to the engineered plant, while only 191 flew over to the regular plant. These results were recently published in the journal Science.

Unlike natural plants, which produce terpenoids only on demand, the engineered plant releases the signaling chemical continuously, so that it cries "Wolf!" even when it’s not being attacked. This never-ending alert could conceivably create a problem, as predator mites have occasionally been known to become disappointed and lose their "trust" in the help-recruiting signals. To prevent this undesirable situation, the scientists are currently striving to engineer plants in which it will be possible to control when the signaling substances are released. 

Electroconvulsive therapy (ECT) has a far higher success rate, with some 80% of patients responding positively. ECT, however, is a highly invasive treatment involving general anesthesia, with many serious side effects ranging from dizziness and headaches to temporary or even permanent memory impairment.

Now an Israeli company, Brainsway, has developed a new non-invasive deep Transcranial Magnetic Stimulation (TMS) treatment that it claims can effectively treat depression without any of the negative side effects of drugs or ECT. The treatment, which Brainsway's founders believe could revolutionize the whole psychiatric care market, does not require anesthetic. Instead, users describe the experience as a gentle shaking or tickling of the scalp. "A bit like a massage," Dr. Abraham Zangen, one of the inventors of the device, told ISRAEL21c.

TMS is still a relatively experimental area of medicine that is primarily being used for research purposes and clinical trials only. Though widely recognized as a potential treatment for a number of mental disorders including depression, the problem until now has been that existing TMS devices can only penetrate about half an inch beneath the surface of the cortex. This is deep enough to treat some disorders like migraine (a new TMS device to treat migraines is now being tested in the US,) but not deep enough to treat more difficult mental health conditions.

Brainsway's founders, however, have invented a new TMS coil configuration that has been designed to generate sufficient magnetic field strength to stimulate neurons which are located 5 to 6 cm. inside the brain mass without posing a hazard. This, according to Zangen, means the device can potentially be used to treat a wide range of mental illnesses including depression, Alzheimers, Parkinson's disease, addiction, stroke, drug abuse, Post Traumatic Stress Disorder (PTSD), and schizophrenia.

The magnetic coil, which is placed on specific areas of the patient's scalp, sends strong directed magnetic pulses through the brain to stimulate the Nucleus Accumbens (the part of the brain responsible for positive stimuli) and the neurons connected to it. "By repeated artificial stimulation of electrical activity created by the coil, we boost the sensitivity of these circuits so they will work more efficiently," says Dr. Hilik Lewkovitch, at Brainsway.

The result is that the next time natural stimulation occurs, such as something pleasant that the brain responds to, the patient will respond more strongly, enjoy it more, and seek to repeat the experience. By intensifying sensitivity this causes the patient to respond normally to the environment.

What makes the device so unique in terms of treatment is that unlike ECT or drugs, it stimulates a specific area within the brain, rather than the whole brain or body. This is a well-known problem for drug therapies used to treat depression. Both ECT and drug treatments affect the entire body, even though the intention is to only stimulate certain locations deep within the brain which are thought to be the active agents for depression and other psychiatric illnesses.

Uzi Sofer, Brainsway's CEO, believes the company's device could become the first line of treatment for depression, a replacement not only for ECT, but also for anti-depressants themselves. "It may become the safe and effective treatment for a person's first depressive episode," he predicts.

Brainsway has undertaken successful animal trials at the Weizmann Institute of Science, where the device was tested as a treatment for depression, addiction, and PTSD. "These were a great success," says Lewkovitch. From June to November last year, the company held its first clinical trials to test the safety of the treatment. Thirty-five people took part in the study that was held at the School of Medicine at Tel Aviv University. "We found that not only was the device safe with no obvious side effects, but that even healthy patients who did not suffer from depression reported an improvement in positive feeling and some cognitive improvement," says Lewkovitch. "This was very good and encouraging news."

The company is now preparing to begin a multi-center clinical trial this month in three or four locations around the world. This will test the efficacy of the treatment, specifically related to emotional and cognitive improvements. The trial, which should take between seven to eight months, is for moderate to severely depressed patients who have not responded to medication.

Brainsway is now meeting with the FDA to approve its clinical strategy. The company hopes to receive FDA approval and CE approval at the same time, enabling the company to begin sales in both Europe and the United States in 2008 or 2009. The company's goal is to start by targeting depression, and then move to other areas of mental health.

In 2005, Brainsway carried out a study on a single Alzheimer's patient. The patient, who is the wife of a well-known physician in Israel, had been treated with every new cutting edge drug and cognitive treatment available, but her situation was getting worse. The family won approval for an emergency treatment with the Brainsway device. Brainsway carried out two weeks of treatment, directing the magnetic pulses at brain regions related to Alzheimer's. The patient was given 60 pulses of TMS a day in half-hour treatments.

"The case study was very promising," says Zangen. "The patient showed cognitive improvement in remembering names and in motoric exercises. When we tested her after treatment she was able to remember more family names and her score was in the normal range of memory for her age." The patient did not, however, show total improvement in other aspects of memory and cognition. The company plans to carry out another longer-term study with the same patient. The family of the patient has now applied for permission to continue the trial with the Israeli Health Ministry.

Brainsway is also now about to sign an agreement with a well-known US laboratory that plans to carry out a study of the company's device on patients suffering from Alzheimer's and autism.

The market for treatment of mental and brain diseases is enormous. Today the annual global market for Central Nervous System therapies is in the region of $65 million. Of this, every year, worldwide, some $15.9 billion is spent on depression therapies. Brainsway estimates that the worldwide deep TMS market for depression treatment alone could reach $20 billion over the next 10 years.

The technology behind Brainsway was invented by Israeli researchers, Zangen, and Yiftach Roth while they were working at the US National Institute of Health (NIH) in the late 1990s. It took four years to invent the new deep TMS coil, and their work was patented by the NIH in 2001. Soon after, articles began to appear in the science press about the new device.

The device attracted the attention of a well-known Israeli high-tech entrepreneur who was interested in creating a company to develop the patent. He set up Brainsway with a number of other investors, including Sofer, and incorporated it in Delaware in 2003. A short time later, he opened a subsidiary in Jerusalem.

The company now employs eight full-time workers and numerous sub-contractors from the Weizmann Institute amongst other places. So far the company has raised several million dollars in investment from three internal investors, Dr. David Zechut, a gynecologist at Hadassah Medical Organization; Avner Hagai, Brainsway's president; and Sofer.

Sofer admits that the company has started looking for large multinational partners such as medical device companies that can help the company take the device to the market. Already Brainsway has been approached by a number of companies who are interested in the device.

"My goal is that Brainsway will become a multi-centre of development, creating a number of different applications for this technology," says Sofer. "Depression is only the first step for Brainsway. We hope to develop many new applications for Alzheimer's, PTSD, and addiction. We want to specialize in R&D, and hope to find strategic partners that can do the other work of marketing and sales."

"Within a decade hopefully it will be clear that this is a revolution in psychiatry," says Zangen. "This will become the standard way of treating many diseases that today are treated poorly and with too many side effects."

If true, boosting the immune system may be one way to protect against age-associated learning and memory problems, said Michal Schwartz, lead author of a paper on the research published this month in Nature Neuroscience.

Schwartz, a professor of neuroimmunology at the Weizmann Institute of Science in Israel, and colleagues discovered that immune cells in the blood called T-lymphocytes are critical to brain cell proliferation. It is an unusual autoimmune response, she said.

T-lymphocytes normally enter the brain to patrol for signs of infection. But scientists have discovered that these immune cells recognize a normal brain protein as foreign and mount an immune response by pumping out activated microglia, cells that produce inflammation. These microglia support the birth of new neurons in these brain regions.

Schwartz came to this idea when she identified large amounts of activated microglia in the brain regions that give rise to new neurons in the adult brain. One of these regions, the hippocampus, is the seat of learning and memory.

She studied animals born without an immune system and found production of new brain cells in adulthood was severely limited. She repeated the same study in animals lacking the ability to make T-lymphocytes. Again, the animals had trouble growing new neurons.

As she expected, stimulating the production of T-lymphocytes led to the birth of even more neurons than expected.

In both cases, the animals showed marked differences in their ability to learn. Those without the T-lymphocyte autoimmunity failed to learn a simple water maze task. Animals with large numbers of T-lymphocytes learned to navigate the water maze much faster than even normal animals.

"It's a novel idea that's backed up by strong data," added Michael Chopp, vice chairman of neurology at the Henry Ford Hospital in Detroit. Schwartz suspects that similar immune processes are at work in the human brain and that an aging immune system could set the stage for dementia.

It all started with glaucoma. Once thought to result primarily from high pressure in the eyeball constricting the optic nerve, the disease has lately come to be seen as a form of neurodegeneration, propagating from the injured optic nerve to healthy cells in the brain. Before monkey studies had demonstrated as much, neuroimmunologist Michal Schwartz of the Weizmann Institute in Rehovot, Israel, observed in the late 1990s that crushing a small portion of a rat optic nerve creates a large zone of sickened cells. She and her team also found that T cells, the immune system's attackers, gathered at these wounds.

Curious if the small accumulation was helpful or hurtful, the researchers injected different types of T cells into rats with optic nerve injury. Surprisingly, rats given T cells specific to myelin, the fatty sheath coating neurons, retained three times as many functional retinal ganglion cells as rats injected with other T cells. In subsequent experiments, rats genetically engineered to lack T cells, as well as rats insensitive to myelin autoimmune reactions, fared worse in glaucoma models than normal rats did.

Introducing antimyelin T cells to people would most likely cause brain inflammation, so Schwartz looked for a compound that would induce a weaker reaction. Copaxone, a peptide drug approved for the treatment of multiple sclerosis, fit the bill because the body's immune response against it also weakly targets myelin. And indeed, rodents vaccinated with Copaxone after insults to their optic nerves retained more retinal ganglion cells than untreated animals did.

Schwartz argues that the effect exploits a natural "protective autoimmunity" and has championed it as a more general measure for protecting the brain from disease. Too much autoimmunity causes brain disease, but too little may exacerbate the gamut of neurodegenerative conditions, she asserts. "It's a beautiful hypothesis," remarks Hartmut Wekerle of the Max Planck Institute for Neurobiology in Martinsried, Germany, but one that has split neuroimmunologists. "I think Schwartz's theory is right because it's been shown in a number of animal models," says Howard Weiner of the Center of Neurologic Diseases at the Brig­ham and Women's Hospital in Boston. "There's a reasonable chance it'll work in humans." In further support, Gendelman's group reported in 2004 that transferring Copaxone-specific immune cells to mice protects neurons in a model of Parkinson's disease.

The evidence is mixed, however. Spinal cord researcher Phillip Popovich of Ohio State University has been unable to mimic results from Schwartz's lab, in which transferred T cells protect spinal cord tissue. "We get what the conventional wisdom would expect: we get more problems," Popovich reports. The discrepancy probably results from subtle differences in the models employed, which implies that the effect is not robust enough to treat spinal cord injuries, he contends.

Mice have been cured of their versions of many diseases that still afflict humans, notes neuropathologist V. Hugh Perry of the University of Southampton in England. And unlike lab rat strains, individual people vary in their immune responses, creating the risk that vaccination will cause harmful autoimmune reactions, as occurred in the interrupted Alzheimer's trial. Perry acknowledges, however, that in some cases, "the regulation of inflammation is not as precise as it might be. If you can induce T cells to produce anti-inflammatory molecules, that may be a good thing."

Gendelman sees obstacles ahead before the great potential of protective autoimmunity, as he describes it, can be exploited. "How this occurs is a big black box," he says. The positive evidence has piqued some biotech interest, though: Israel's Teva Pharmaceutical Industries is investigating Copaxone and a similar peptide in models of glaucoma and several other neurodegenerative conditions. If the company moves ahead with clinical trials, that black box may open up.

Type 2 diabetes is a complex disorder characterized by the body’s inability to utilize sugar efficiently. Two stages of the disease have been identified: In the first, “silent” stage, the body’s cells lose their ability to respond properly to the crucial hormone, insulin, responsible for moving sugar from the blood into cells. If sugar remains in the bloodstream, the insulin-producing beta cells in the pancreas compensate by stepping up production. Eventually this leads to beta cell exhaustion, reduced insulin output and the appearance of full-blown diabetes.

Elevated fat in the bloodstream appears to accelerate both stages of the disease. Exactly how does this happen? Beta cells are attuned to changes in blood sugar levels, responding to after-meal surges with a sharp increase in insulin production. But a recently discovered protein, a receptor on the surface of the beta cell called GPR40, responds not to sugar, but to fatty acids. When fat is present in addition to sugar, the GPR40 receptor causes an even higher spike in insulin output. If beta cells are frequently overstimulated and overworked, persistently elevated insulin levels may hasten the onset of the disease.

To investigate GPR40’s role, Prof. Michael Walker and students Nir Rubins and Reut Bartoov-Shifman of the Weizmann Institute’s Biological Chemistry Department teamed up with Prof. Helena Edlund and postdoctoral fellow Dr. Per Steneberg of the University of Umea in Sweden. Together, they developed two types of lab mice with modified GPR40 activity. In the first, the scientists used a technique known as gene knockout to prevent production of the GPR40 receptor. In the second type, overactive GPR40 genes created a surfeit of fat-signaling receptors that tricked the beta cells into sensing high fatty acid levels, even on a normal diet.

Throughout the trial, the GPR40 knockout mice remained healthy, apparently suffering no adverse effects from the deletion of the receptor, even when the fat content of their diet was raised substantially. In contrast, normal mice on a high-fat diet displayed typical symptoms of the first stage of diabetes. But strikingly, in the animals with extra GPR40 receptors, the disease progression was swift: They soon began to exhibit the classic symptoms of full-blown diabetes, including failure of the beta cells to produce adequate amounts of insulin.

Walker: “Our results establish GPR40 as an important link between obesity and diabetes. This gives us a new tool to combat the diabetes epidemic: It might be possible in the future to treat the condition using drugs that block the action of this receptor.”

HIV is a master of attach silencing the T-cells that usually alert the immune system at the moment of invasion. But until now, little was known about how it did this.

Irun Cohen and his colleagues at the Weizmann Institute of Science in Rehovot, Israel, and Harvard University reasoned that the mechanism for binding the virus to its target might also disable the T-cell's alarm call. If so, it could be used to inhibit the overactive immune response seen in autoimmune diseases.

The team focused on the FP fragment, part of the GP41 protein that HIV uses to dock with T-Cells, and used fluorescent markers to find out where on the T-cell surface it binds.

"What we discovered is that it doesn't just insert anywhere, but precisely at the part of the T-cell that is searching for attackers," says Cohen. The researchers also found that the FP fragment is able to silence the T-cell response to several different known antigens.

They then injected the FP fragment into rats suffering from a syndrome similar to rheumatoid arthritis in humans. Sure enough, the treatment reduced join swelling (The Journal of Clinical Investigation, vol 115, p 2149).

Cohen believes a treatment of this kind could be developed for humans. It wouldn't be a danger to patients because, without the rest of the virus, the FP fragment cannot infect cells or reproduce.

"What's different and interesting about this is that it's an experiment that has already been carried out in humans − by HIV in nature," says Edwin Gale, a specialist in type 1 diabetes at Bristol University in the UK. "It's a route that is worth investigating for the future." But it would be a long time before results in rats could be translated to a practical treatment for humans, he says.

Cohen agrees, but points out that there is plenty to be learned from the virus. "HIV is the world's most expert immunologist," he says. "All the wisdom of evolution is inside this virus. Let's see what it can teach us." GP41 is also a promising target for future HIV therapies that stop the virus binding to T-cells.

LONDON − Eggheads from the world-renowned scientific center the Weizmann Institute in Israel, conducting research into the brain activity using excerpts from “The Good, the Bad and the Ugly” as stimulus, have made some startling discoveries.

Using 30 minutes from Sergio Leone’s classic Western and state-of-the-art MRI scanning equipment, the Weizmann research team − led by professor of neurobiology Rafael Malach − have found a striking similarity between brain activity patterns in all viewers, no matter what age or gender they are.

Malach presented his research at a layman’s lecture last week in the auspicious surroundings of the Royal Institution in London. He claimed there are several portions of Leone’s movie for which everyone tested recorded the same brain response.

For instance, when Clint Eastwood is loading his six-shooter, the area of the brain that deals with touch is invariably stimulated.

Malach tested 15 people, male and female, ages 22 to 52. He says his research throws up several findings, but perhaps the most intriguing is that, while many people think they interpret movies in their own individual ways, his research indicates that the brain is “almost mechanical” in dealing with the imagery of film.

"The bit of the brain that is activated when you touch something is activated during watching a movie when the people on screen touch something,” Malach told a packed audience. “But the tsunami of the common visual area is the ‘suspense and surprise’ signal part in the brain. Everyone tested was the same for this, responding to it from the same part of the brain.”

The professor says his results could mean that in the future, moviemakers could use his data in their craft. “From the readings from the brain, you could eventually get to the point where you could cut the perfect trailer from all the footage that activates the parts you want,” he suggests.

The Royal Institution was established in the late-18th century, and today offers a platform for scientific discoveries and pioneering research to be presented to the public. The audience for Malach’s demonstration was visibly wowed by his work.

Malach also revealed which areas of the subjects’ brains were active during love scenes or gunfights. “In the long run, this type of research will certainly be used to help the entertainment industry,” he predicts.

But he warns that using such data from the brain raises moral and even privacy issues. “People tend to think that they are very different in their response to movies, but if it’s an engaging film, we all respond to it in the same way,” he says.

It’s enough to make you think.

When friends of the Weizmann Institute - and of Israel - ask me for some good news from our region, I have no difficulty in responding. The irrepressible energy and boundless ingenuity of Israeli inventors and entrepreneurs are there for all to see, but to none are they more evident than to those of us immersed in science and research.

Israel is home today to about 500 communications technology companies, 200 in medical instrumen-tation, 100 in fabless circuit design plus a number of circuit production giants, and 50 in digital printing and imaging. It has become a veritable superpower in data security, with some major companies in the field and about 80 start-ups. There are hundreds of companies developing an impressive range of programming applications - for trading in foreign currency options, for Internet applications and a great deal more. In my own field of plant science, the long tradition of Israeli innovation is being carried forward by a growing number of biotechnology companies devoted to advanced crop improvement and the production of plant-derived products. In drug design and development, Teva Pharmaceuticals leads as a major player in the world arena and is Israel's largest and most successful commercial company ever. All this, and more, in a country of less than 6 million people!

What drives this phenomenal technological dynamism and entrepreneurship? Of the many reasons I could cite, one is most relevant to our endeavor: the strength of Israeli scientific education and technological training, in which the Weizmann Institute of Science plays such a dominant role - through its emphasis upon basic research (the root of its multivaried achievements since its earliest days), its practical inventions, its science education programs and its network of graduates throughout Israel.

Clearly, the cultivation of our only abundant natural resource, our brain power, is critical to our economic and social well-being. At the Weizmann Institute we also believe that this cultivation is of value in itself, beyond its immediate utilitarian impact. We believe that knowledge and its pursuit are the crowning achievements of every society, and should always be a priority.

Put in this perspective of aspirations and achievements, the past year has been a good one for the Weizmann Institute. Let me touch on some highlights.

Following his earlier astounding development of the world’s smallest biological computer consisting of DNA, the material of genes, Prof. Ehud Shapiro took a dramatic step into futuristic medicine by showing how this molecular device, of which about a trillion can fit in a drop of water, might one day function as a tiny medical kit. Made entirely of biological molecules, this computer was successfully programmed to identify - in a test tube - changes in the balance of molecules in the body that indicate the presence of certain cancers, to diagnose the type of cancer, and to react by producing a drug molecule to fight the cancerous cells. It may well take decades before this concept of “a doctor inside the cell” can be converted to a system operating inside the human body, but its potential is thrilling. This research was supported, among other sources, by the M.D. Moross Institute for Cancer Research.

Having obtained FDA clearance last year, Prof. Hadassa Degani's work in magnetic resonance imaging (MRI) for the non-invasive diagnosis of breast and prostate cancer is now being developed commercially for clinical use. Recently, she directed her attention to an entirely different application - kidney function. Standard MRI scanners found in hospitals and clinics work by imaging water molecules in the body, but in water-logged kidneys, the image may not distinguish between different functional parts. By scanning sodium ions rather than water, Prof. Degani's method may enable tomorrow’s doctors to pinpoint exactly where a problem lies, reveal a disease before symptoms occur, or evaluate how a drug affects a patient. Prof. Degani’s work was supported by the Willner Family Center for Vascular Biology and other generous donors.

Prof. Yair Reisner's breakthrough research in inducing porcine stem cells to grow new kidney tissue in a mouse stands to benefit from Prof. Degani's innovation, which could greatly facilitate the difficult task of assessing how well such kidneys are, in fact, functioning. Other aspects of Prof. Reisner's pioneering work, namely in bone marrow transplantation, are featured in this Annual Report. Again, both Prof. Degani's and Prof. Reisner's research benefited from the support of the M.D. Moross Institute for Cancer Research. Prof. Reisner also received major support from the Gabrielle Rich Center for Transplantation Biology Research and other generous donors.

It is a pleasure to acknowledge here, with thanks, the generous gift of the Skirball Foundation of Los Angeles for its challenge grant of $1.5m toward the purchase of a new MRI machine for Prof. Degani and half a dozen additional research groups. The new equipment will give a great boost to a significant segment of our biomedical researchers. We have received a number of matching gifts, most notably from Mrs. Rita Markus of New York, Mr. Hans Rausing of the UK and the Harry M. Ringel Foundation of California. We are still looking for additional donors to come forward with funds that will help meet the Skirball Foundation's challenge.

Further clinical progress in cancer therapy was achieved by the team of Profs. Avigdor Scherz and Yoram Salomon, who conduct (Phase I/II) clinical trials for prostate cancer in collaboration with Steba Biotech (France). They have developed a novel substance for use in photodynamic therapy (PDT), which effectively destroys tumors by destroying the blood vessels that supply them with oxygen and nutrients. The work is presently carried out in medical centers in Canada, England, France and Israel.

In neuroscience, sophisticated use of MRI techniques is yielding insights into the mechanisms of perception and visual experience. Prof. Rafael Malach showed volunteers a segment of a movie while they were undergoing brain scans with functional MRI equipment. Interestingly, the brain scans revealed that in viewing a movie, the various regions of the brain each actively view different movies. Each area is activated by a specific kind of visual cue, and therefore only picks up on those bits that “speak” directly to its specialized preference. For instance, a region known to be involved with face recognition lit up only when close-ups appeared on the screen, whereas scenery elicited a response from the part of the brain that helps us navigate in three-dimensional space. The scientists noted a third area that seemed to be activated when delicate hand motions were performed; this area, they think may be part of a network of brain regions used to understand the actions and intentions of others. Thus the unified percept we experience is, in fact, the coordinated result of a tremendous “jam session” played out by our different, highly specialized brain regions.

Also in Neurobiology, Prof. Amiram Grinvald - widely regarded as a world leader in functional optical imaging and, as such, of having exercised a tremendous impact on brain research - was awarded the prestigious Dan David Prize for 2004. Prof. Grinvald's method of intrinsic optical imaging on the molecular level makes it possible to visualize electrical activity in the living brain. This technique is currently advancing clinical applications in neurosurgery operating rooms in the US, Europe and Japan. Both Prof. Grinvald and Prof. Malach are supported by the Murray H. and Meyer Grodetsky Center for Research of Higher Brain Functions.

Another possible future application of Institute research in neurosurgery comes from an entirely different direction. Prof. Elisha Moses of the Physics of Complex Systems Department, postdoctoral fellow Dr. Stephan Thiberge, and Institute graduate Dr. Ory Zik have devised a method to view samples of biological materials under the beam of the scanning electron microscope (SEM) in their natural, untreated (i.e. “wet”) state. The SEM's superb ability to distinguish the delicate structure of a living cell could thus be utilized, for example, in making a quick decision during brain surgery as to the borders between a malignant tumor and healthy tissue, or between a malignant and a benign growth.

Since the discovery was made, Dr. Zik, in cooperation with Yeda, the Institute's business arm, has founded a company, called QuantomiX, based on this technology. The findings of the team were published this year in the Proceedings of the National Academy of Sciences (PNAS) USA. This is just one fine example of the Institute's leadership in advanced imaging and microscopy techniques, a field that is of vast importance for science, medicine and industry. I urge the Institute's friends to support our efforts in this sophisticated - and costly - endeavor through such projects as the proposed Electron Microscopy Center or the Bioimaging and Diagnostics Center.

Gratifying acknowledgement of our work in nerve regeneration was recently received from the Christopher Reeve Paralysis Foundation (CRPF), which awarded its first grant in Israel to Dr. Michael Fainzilber. “The Weizmann Institute, as I saw first-hand when I visited Israel last year,” said Christopher Reeve, “has established pre-eminence in the field of paralysis research.” Applying a unique peptide, Dr. Fainzilber will identify changes in genes that are activated very early in the regenerative process, in order to modulate injury-induced changes. The data generated using this innovative model has the potential to identify new molecules important for regenerative growth in patients with nerve injuries.

In the coming year, our work in neuroscience will be significantly enhanced by a major gift from Mrs. Nella Benoziyo toward the establishment of a new research center dedicated to neurological diseases. This is in addition to the existing Nella and Leon Benoziyo Center for Neurosciences, from which Prof. Malach's work has benefited, and the Y. Leon Benoziyo Institute for Molecular Medicine, which has supported Dr. Fainzilber's research. In appreciation of this magnanimity, the brain research building has now been named the Nella and Leon Benoziyo Building for Brain Research.

Basic science is the heart and core of our work, and is particularly characteristic of young scientists in the early stages of their careers. This issue of the Annual Report features outstanding work in structural biology by two young scientists, Dr. Deborah Fass and Prof. Gideon Schreiber. Dr. Fass, whose work was recently featured in the prestigious journal Cell, is applying X-ray technology to study newly-discovered enzymes taking part in protein folding - the fateful process by which “newborn” proteins fold into precise three-dimensional structures to become functional. Proteins are also a central theme in the work of Prof. Schreiber, who is applying both theoretical and experimental techniques to examine how cells “talk” to one another. Amongst his findings, Prof. Schreiber has achieved valuable insights into how interferons, proteins serving as the body’s first line of defense, convey their messages into the cell.

We are eager to promote this vigorous activity in structural proteomics. Elucidation of the 3-D structure of proteins - so critical for understanding their function in health and disease - is an enormously complex process. When Sir John Kendrew and Sir Max Perutz received the Nobel Prize in 1962 for the first solving of a protein’s 3-D structure, they had spent over 20 years on the task. Though some aspects of the process have since become more efficient, scientists may still spend months, sometimes years, in similar efforts.

Having received initial support for a pilot project in this area from Israel's Ministry of Science, the European Union, and a visionary private Israeli donor - Board member Yossi Hollander - we now seek to establish an endowed research institute that will serve Israeli science as a whole. The institute will serve researchers from the Weizmann Institute as well as from other scientific research institutes and the biotech industry in their attempts to elucidate the structure of proteins involved in disease. Their findings might prove essential to future applications in drug design, diagnostic tests, biosensors, agrochemicals and more.

Providing a boost to the efforts of all such research-ers is an outstanding new facility for visualizing proteins three-dimensionally, in their enormously complex structure and internal movement: The Jean Goldwurm Scientific 3-D Visualization Theater in the Wix Auditorium building.

Prof. Israel Rubinstein of the Faculty of Chemistry has demonstrated how minuscule particles of gold, silver and other materials can serve as building blocks of tiny cylinder-shaped structures called nanotubes (a nanometer is one millionth of a millimeter). Characterized by unique electrical and optical properties, these nanotubes can be tailored for diverse applications, such as future nanosensors, catalysts and chemistry-on-a-chip systems. This work was supported, among other sources, by the Clore Center for Biological Physics.

Our efforts in nanoscience received an important boost this past year through the magnanimous gift of Helen and Martin Kimmel of New York establishing the new Helen and Martin Kimmel Center for Nanoscale Science. Additional notable support ($2.9m) for nanoscience, in particular for the renewal of equipment in the Braun Submicron Center, but also for research in the Faculty of Chemistry, has been assured by the TELEM (acronym for National Science Infrastructures) Committee of the Israel Academy of Science. More than two years ago, the Wolfson Foundation had committed a large seed gift toward this fund, to be matched by the Israel Academy of Sciences and Humanities and five institutions of higher learning, including the Weizmann Institute, with the aim of making a significant investment in Israeli nanotechnology. We continue to seek donor assistance in this mega-project for advancing the Institute's world-class nano-electronics research.

The Physics Faculty celebrated its 50th anniversary this year with a rich record of achievements. This Annual Report features the work of two young theoreticians, Profs. Micha Berkooz and Ofer Aharony, who both work in the most fundamental area of string theory. This generation of young scientists is propelling us toward more focused efforts in particle astrophysics, where we hope to attract additional talent and establish a dedicated research center. The Physics faculty also has a strong tradition of commitment to science education - we are proud that this year’s EMET Prize is being awarded to Prof. Haim Harari for his outstanding leadership in this area.

I mention with pride that Prof. David Harel, Dean of the Faculty of Mathematics and Computer Science, received this year's Israel Prize for his work in several diverse areas of computer science, including the invention of languages and methods for developing complex systems and his widely-acclaimed expository writing. The citation described him as “one of the leading computer scientists in Israel and in the world.” Prof. Adi Shamir, co-inventor of the famous RSA encryption system, and his student Eran Tromer have been busy listening to computers. They are working on a system that could enable certain kinds of encryption techniques for securing classified information to be cracked by analyzing the faint sounds produced by tantalum capacitators on the motherboard. Additional achievements in mathematics and computer science are highlighted later in this Annual Report.

Young scientists
Of the six scientists featured in this report, you will note that four belong to the young generation of recently-tenured professors. This young face of the Institute is a genuine emerging trend, following a few years of difficulty in recruiting a sufficient number of young scientists, due mainly to the political and economic situation. It is heartwarming to witness young people's eagerness to join the Institute.

One of our most important tools for the successful recruitment and absorption of young scientists is our ability to provide them with equipment for their research needs. Such equipment costs may run into the hundreds of thousands, in some cases, even millions, of dollars. The Institute's major source of equipment funding, the Israel Science Foundation, has drastically reduced its support in the past few years, as part of the overall cut in government allocations to research and education. Our dream is to establish a large endowed fund that will enable us to respond effectively and quickly to such needs.

Recruitment of young scientists, particularly women, could be further boosted with greater attention on our part to the work/family balance. Specifically, we would like to expand the recently-established childcare facility, which has proven highly successful but is unable to meet the demand by Institute staff and scientists. We are seeking a donor gift for this project.

Major issues resolved
I am pleased to report that three of the four issues that have been hanging menacingly over our future during the past few years have been satisfactorily resolved. Of grave concern, primarily to our sister universities in Israel, has been the Ministry of Education's requirement to change the governance of Israel's institutions of higher learning. We have successfully convinced the Ministry that the Weizmann Institute's structure was already largely in line with the new requirements, principally, the unification of responsibilities for the organization's fiscal and academic functions. Thus, we have not been called upon to change our governance structure.

This year, it was officially confirmed that we would not be subjected to any tax liability for our income stemming from Yeda royalties. The State Comptroller General had for some time been questioning the fact that this income was not taxed. After a lengthy process of presentations and clarifications to the State Comptroller and the income tax authorities, the Institute succeeded, with the invaluable aid of our Board Member Moshe Gavish, in making a compelling case for its position, resulting in confirmation by the tax authorities of the accepted position that a not-for-profit organization like the Institute should continue to maintain this tax exemption. Needless to say, the individual scientists who receive royalty income do pay taxes on it.

A third major issue that was resolved this year was our six-year-long disagreement with the State Comptroller on reporting procedures for external grants. Having now obtained the Comptroller's agreement to a reporting procedure that takes into account the inherently fluid nature of cash flow from external grants, our scientists can continue to compete for international grants with a reasonable degree of flexibility. Regrettably, the dispute with the Municipality of Rehovot regarding tax payment is still pending, notwithstanding the considerable progress we have made.

Financial situation
The Israeli government has continued to impose cuts on the national budget. For us, this meant that in 2003/4 the government’s share in our operating budget fell to 36 percent, necessitating a further reduction in expenses from the previous year’s budget. Even though governmental cuts were announced twice in mid-year, we continue to maintain a balanced budget, thanks largely to the discipline and cooperation of the Institute's scientific and administrative staff. My warm thanks also go to the Institute's loyal friends, who have continued to give generously to the President's Contingency Fund - a resource the importance of which I cannot exaggerate. Part of the shortfall in government support was also made up for by an increased injection of funds ($15m, or 8.5 percent of our budget) from Yeda's royalty income. All this has enabled us to maintain an acceptable level of support for research and infrastructure and, most importantly, not to be forced to reduce our support for new scientists and graduate students.

The Institute's income from Yeda is based primarily on three products: two drugs for multiple sclerosis (Copaxone® and Rebif®) and the satellite television encryption card. In keeping with the Institute's far-sighted policy, this highly volatile income - the dependability of which is entirely outside our control - was not used to increase expenditures. Rather, as indicated above, it partially offset the shortfall in the operating budget created by the government's drastic cuts in support of basic research. The rest was put toward future-oriented purposes: the development and maintenance of our infrastructure, facilities and equipment, and the enlargement of our endowment.

Yeda's earnings testify to the talent and enterprise of Institute scientists. Given that all three products listed above have a manufacturing base in Israel, they also point to the coming of age of Israeli industrial, financial and business capabilities. We can be proud that with only 250 principal investigators, we lead all Israeli institutions of higher education in technology transfer, and that even on a global scale, our successes are remarkable. It is also most gratifying that the basic research behind Rebif® was recognized this year by the award of the EMET Prize to Prof. Michel Revel.

External research-funding sources constitute 25.6 percent of the budget, a figure that has remained steady in the past year. But steady-state in this case is by no means trivial news. If we bear in mind that major Israeli funding entities, such as the Israel Science Foundation and the various government ministries, have severely reduced their support in the past two years, it is clear that the continued high level of external support sources can only be ascribed to increased funding from abroad. Grants from the NIH have been increasing steadily and today reach $1.8m, and grants from the European Union, where we have done better than any other Israeli institution of higher learning, have reached $6m.

I would like to mention here an $8.5m competitive grant awarded by the Flight Attendants Medical Research Institute (FAMRI) of the US to a Weizmann Institute team working with the Chaim Sheba Medical Center on the harmful effects of passive smoking.

Our success in obtaining such large external grants may be partially attributed to the leverage afforded by philanthropic sources, notably in this case, the M.D. Moross Institute for Cancer Research. This success in the highly competitive world science arena can surely be taken as an objective indicator of the high quality of Weizmann Institute researchers. This quality was again reaffirmed this year by the comparative study of the “impact factor” of scientific publications: Israel ranks third, after the US and Switzerland, in its number of scientists cited (in relation to the country's population). Of the 37 Israeli scientists most often quoted by others (out of 250 worldwide), 11 - nearly one third - are at the Weizmann Institute.

As to ongoing (not endowed) donation income, we have been experiencing a declining trend in the past five years, from a high of close to $24m in 2000/1 to an estimated $17m in 2003/4. This is partly due to the fact that during the Jubilee Campaign, we oncentrated our efforts on increasing our endowment, as opposed to raising consumable funds. Thus, both the endowment itself has grown, currently standing at close to $600m, and the annual yield it provides to the Institute has risen, from about $18m five years ago, to close to $29m today. W-GEM, the Institute's arm for the professional management of its investment portfolio, has yielded excellent results in the past year.

Campus infrastructure and development
We are moving forward with our plans for constructing a major new transgenic plant growth facility, which should give a significant boost to our research in plant science. This project is still seeking donor support and I would like to take a moment to make the case for it once again.

Making a Mark
Eleven of the world’s 250 most quoted scientists are at the Weizmann Institute:

-Prof. Moshe Oren

-Prof. Oded Goldriech

-Prof. Benny Geiger

-Prof. Ehud Dochovni

-Prof. David Harel

-Prof. Ilan Chet

-Prof. Irun Cohen

-Prof. Giora Mikenberg

-Prof. David Peleg

-Prof. Amir Pnueli

-Prof. Itamar Procaccia

We are justly proud that Israel has been a powerhouse of agricultural development - surely one of the most amazing features of Israel's rebirth in its arid land. We are witnessing exciting new trends in this field. Since the 1980s, it has become clear that it makes little sense for us to engage in intensive agriculture, where (fortunately) we no longer can or wish to compete with the low wages that prevail in less developed countries; nor do we have the large land and water reserves required. Instead, Israelis have identified the enormous potential of advanced agricultural research - a kilogram of seeds sells for 1,000 times more than a kilogram of fruit - and are developing new crop seeds with high added value, such as resistance to disease, adaptability to various climate conditions, increased yields, improved nutritional value, etc. Being myself in the field of plant biological control, I can personally affirm that such characteristics have enormous impact globally in protecting the environment (fewer pesticides, fewer fertilizers) and in their potential for feeding a hungry world.

Most of this research in Israel is carried out by academic institutions, rather than by industry, and there can be no doubt that Israel's innovativeness in plant science owes much to this fact. We must give the Institute’s plant researchers the advanced high-tech facility that their talents and efforts so fully merit.

We are also finalizing plans for a new facility for pre-clinical research, scheduled for construction in the northern campus area recently acquired from the Jewish Agency. This is an enormously costly project, for which we are seeking donor support. Our major existing facility was built in the 1960s and is now obsolete beyond our ability to refurbish it. Inter-national standards of ethics - to which the Institute adheres strictly - and the technical capabilities for housing, treating and monitoring of mice and rats undergoing pre-clinical experiments have improved dramatically since then. In addition, there are many new research projects today in cancer, genetics and immunology that require upgraded facilities.

The clean-up and refurbishment of the Arnold Meyer Building is progressing well, and should be completed by mid-2005.

In May 2004, we had the pleasure of dedicating “Oasis,” a lovely water sculpture given to us by our former graduate student, Dr. Barton Rubenstein of Washington, DC. In November 2004, we will dedicate three new campus installations: the Ruthie and Samy Cohn Student Residence, the Joe Weinstein and Major Max L. Shulman EcoSphere in the Clore Garden of Science, and the Jean Goldwurm Scientific 3-D Visualization Theater.

The campus and the community

This year, with abatement in the fury of suicide bombings inside Israel, we saw an increase in the number of visitors from abroad, as well as an increase in the number of scientific gatherings held on campus. In May alone, we held ten conferences with international participation, including one in honor of former Institute President Prof. Michael Sela's 80th birthday.

Educational activities for young people are as dynamic as ever. The annual Shalhevet Freier Physics Tournament, where youngsters must figure out how to crack safes, had a record number of participants, including, for the first time, two teams from Canadian schools. Our Science Mobile traveled extensively this year to schools and centers in peripheral areas, partly thanks to the Rehovot-based Israeli division of Applied Materials, Inc., which not only gave financial support but also actively involved its management and staff. Our most public event, the Science Festival held during the Passover holiday, attracted some 15,000 participants.

We have initiated a number of appealing lectures for wider Institute audiences: the Helen and Martin Kimmel Center for Archaeological Sciences had standing-room-only attendance at its series on the civilizations of the eastern Mediterranean; Prof. Itamar Procaccia of the Chemistry Faculty offered an illuminating talk on Zen and the Arts of East Asia, featuring a number of scrolls from his own collection; and the Faculties of Biology and Biochemistry began a series of noon lectures “Biology at Eye Level,” where Institute scientists present their work to the campus community.

On June 10, 2004, the Feinberg Graduate School celebrated its largest ever graduation ceremony: 117 Ph.D. and 146 M.Sc. degrees were conferred. At this year's ceremony, the keynote speaker was Mr. Benny Landa, founder and former chairman of Indigo, a world leader in digital color printing. Benny and Patsy Landa are enthusiastic supporters of education in Israel, with a particularly attentive eye for students whose economic background has made higher education a difficult goal to reach. Earlier this year, we opened the Ruthie and Samy Cohn Student Residence to help relieve the demand for on-campus student housing for singles and couples. The school continues to attract the best students in Israel in Mathematics, Computer Sciences, Physics, Chemistry and Biology. The large number of applications and their exceptionally high quality led us to increase the size of the M.Sc. class entering in October 2004.

Under the banner “Administrative Excellence in the Service of Scientific Excellence,” we have launched an organizational development program for Institute personnel. Initially, we are focusing on enhancing management skills. This effort goes hand-in-hand with our implementation of an ERP (Enterprise Resource Planning) program. Together, we expect these initiatives to significantly increase the effectiveness and efficiency of our administration.

The Global Partnership Campaign
For the past year, we have been preparing to launch the Global Partnership Campaign, perhaps our most important fundraising initiative since the Jubilee Campaign. The Global Partnership Campaign is intended to bring together our lay leadership, our administration, our committees and our scientific community for the purpose of ensuring the excellence of scientific research and education conducted at the Institute. We have put together a dynamic Campaign leadership group under the gracious and talented team of Gershon Kekst, Global Chair, and Bob Drake, Executive Chair, and will be sharing the Campaign's goals with our Governors during our meetings on campus in November. Under the banner “Partners through Time,” we will discuss how each of us can make a difference in ensuring the future of the Weizmann legacy.

Thanks
For their friendly cooperation, good counsel and steady support, I thank Stu Eizenstat, Chair of the Board of Governors, Abraham Ben-Naftali, Chair of the Executive Council, Deputy Chairs of the Board, Chairs and members of the Board committees, and the entire Board membership; Prof. Michael Kirson, Chair of the Scientific Council, the Institute Vice Presidents, Deans of the Faculties and Department Heads.

I am particularly grateful to the Weizmann Institute family of scientific, technical and administrative staff, who have given me their generous support and friendship.

I am indebted to our supporting committees at home and overseas, who work unflaggingly for the Institute's welfare throughout the year - the devoted lay leaders, the outstanding Executive Directors, and all the enthusiastic members of their professional staffs.

I thank all of our friends in Israel and abroad for their interest, devotion and generosity over the past year. May the Institute's scientific and humanitarian achievements continue to fuel our aspirations and efforts in the year ahead.

For people suffering from fatal diseases, such as leukemia or kidney failure, the scarcity of available transplants is often the cause of feelings of hopelessness. Thousands of people in the U.S. alone languish on waiting lists, tied to dialysis tubing, hoping for the transplant that may save their lives.

But if there were a way to make transplants immediately and widely available to all who need them, suddenly, it would be something everyone could afford, and something that would be accessible to all.

This is what Prof. Yair Reisner is trying to achieve. Having recently garnered international attention for growing functional kidneys in mice out of human stem cells, Prof. Reisner has long been finding ways to foil the human immune system into accepting transplants that it would otherwise reject.

Prof. Reisner began his long career by researching alternatives to bone marrow transplants. Since bone marrow harbors immune cells, bone marrow transplants are exceptionally tricky. Not only can the immune system attack the foreign marrow — known as graft rejection — but in some cases, immune cells in the marrow actually attack the patient, causing a sometimes-fatal condition called Graft Versus Host Disease (GVHD). Four out of 10 patients needing a marrow transplant cannot find a matching donor, putting them at risk for either never receiving a transplant, facing devastating complications, or GVHD from a poorly matched donor.

Prof. Reisner tackled this problem by using a hormone to mobilize the patient’s bone marrow cells, instead of the traditional method of attempting to kill them with radiation. He then used a special filter to remove every last one of the cells to prepare the patient for the new marrow. By following this procedure with a “megadose” transplant that infuses up to a liter of donated marrow — a quantity large enough to overcome the body’s rejection mechanism — he substantially reduced the rejection rate of transplants. Not only did the patients go into remission, but further studies show that they continue to do well. This method saved the lives of leukemia patients and “bubble” children and is now in clinical trials in Europe. At a recent lecture at ACWIS headquarters, Prof. Reisner was pleased to report on clinical success. “Now we have experience to show the patients survived. The rest is up to the clinicians.”

Not satisfied with that major advance, Prof. Reisner continues to pursue his interest in circumventing the human immune system to allow it to accept transplants. His latest achievement is growing tiny, functional kidneys in mice out of human stem cells. The trick to growing the kidneys is timing. Implant too early and the implanted cells grow into a mass of mixed tissue cells; too late, and the body rejects the kidney. Prof. Reisner and his team discovered a window of opportunity during which the transplant can occur. The cells already know how to become kidney cells, but are not so developed that the body will recognize and reject them.

If organs could be grown on demand from stem cells, rejection would be a thing of the past, and transplants could be done quickly, safely, and less expensively than now. Over 50,000 people in the U.S. are on the kidney transplant waiting list, and more than 2,000 die annually waiting for a match. Prof. Reisner hopes that eventually organs can be grown to supplement damaged or diseased organs, such as a pancreas that would produce insulin for diabetics. The procedure he developed is now in the pre-clinical study stage. If all goes well, new treatments may ensue in the near future.

Prof. Michal Schwartz, working in the Weizmann Institute's Neurobiology Department, came up with a novel idea. She suggested that toxic substances triggered by the initial damage are responsible for the ongoing nerve degeneration. These substances spill out of the damaged nerve cells and adversely affect healthy neighboring cells. Schwartz suggested activating the immune system – known to defend the body against external invaders such as bacteria – to combat the body's own toxic substances. She showed that in complete contrast to the generally accepted concept of autoimmunity (i.e., activity against the self) as inherently  harmful, it can serve as a defense mechanism against damaging self-compounds. Autoimmune disease results when control of this mechanism breaks down.

On the basis of these findings, Schwartz developed a method of boosting this defense mechanism without risking autoimmune disease. She showed that using Copaxone* (a drug that induces a “beneficial” autoimmune response) as a vaccine protects the optic nerve from neuronal degeneration.

This innovative procedure will soon undergo clinical trials. In the  past her approach resulted in a therapy for spinal cord injuries now being tested in clinical trials.

A team of researchers led by Prof. Irun Cohen of the Weizmann Institute of Science has developed a vaccine that halts the progression of Type I (juvenile or insulin-dependent) diabetes. The vaccine functions by blocking the destruction of insulin-secreting pancreatic cells.

Diabetes is a chronic disease associated with elevated blood sugar levels, in which the body does not produce or improperly uses insulin - a hormone needed to convert sugar, starches and other foods into energy. Recent data show that between 120 and 140 million people suffer from diabetes worldwide. Type I diabetes usually results from an autoimmune disorder in which the immune system mistakenly attacks the body's own insulin-producing pancreatic cells, reducing and ultimately eliminating all insulin production. All Type I diabetes patients eventually must receive insulin injections to compensate for their loss of natural insulin production.

For the past several years researchers at the Weizmann Institute's Department of Immunology led by Cohen have been studying the mechanism by which the immune system destroys the insulin-producing pancreatic cells. Working with mice, the scientists discovered that a particular protein called HSP60 was closely linked to this destructive process.

The protein acts like an antigen, prompting the immune cells to attack. Further investigation by Cohen, Dr. Dana Elias (first a graduate student and then a postdoctoral fellow at the Institute), and other students and colleagues revealed that injecting sick mice with p277, a small peptide fragment of the HSP60 protein, shut down the immune response, preventing the progression of Type I diabetes. This led Peptor Ltd., a biopharmaceutical company based in Rehovot, Israel, to develop the experimental drug DiaPep277, designed to prevent or treat Type I diabetes.

A combined clinical study performed recently by researchers at Hadassah-Hebrew University Medical School, Peptor Ltd., and Cohen proved that DiaPep277 is successful in arresting the progression of Type I diabetes in newly diagnosed patients. The research findings were published in the Lancet.

The study involved 35 patients newly diagnosed with Type I diabetes. Eighteen patients received injections of DiaPep277 - at the beginning of the study, after one month, and after six months; 17 patients received three injections of an inert substance (a placebo). Patients in the treatment group (those receiving DiaPep277) showed a delay or even a cessation in the attack by the immune system upon their pancreatic insulin-producing cells. These results were evident in the level of the body's own insulin production and a decreased need for insulin injections. The researchers were able to trace the mechanism of this improvement to changes in the patients' immune lymphocytes called T-cells. In contrast, patients receiving the placebo showed a significant decline in their natural insulin production and a persistent rise in the need for insulin injections. No significant side effects as a result of injecting DiaPep277 were found.

'The idea of using p277 stemmed from the discovery that the immune system has different options to choose from in responding to an antigen,' says Cohen. 'It can act to destroy the antigen or alternatively protect it from being destroyed. In the latter case it protects the antigen, thereby indirectly preventing damage to the pancreatic cells. The peptide essentially acts to 'reeducate' the immune cells, switching off their destructive activity.'

The scientists participating in this study are: Prof. Itamar Raz and Dr. Muriel Metzger of Hadassah-Hebrew University Medical School; Dr. Dana Elias (now VP R&D at Peptor Ltd.); and Drs. Ann Avron and Merana Tamir, also of Peptor Ltd.

Prevention rather than replacement
Back in 1920 Dr. Federick Banting and Charles Best of the University of Toronto made a discovery that would change the course of medical history. They had succeeded in obtaining a pancreatic extract which proved to have potent anti-diabetic characteristics when tested on dogs. Within two years their team would isolate and purify the extract's key ingredient, a hormone known as insulin, and the first human trial would begin, extending the life of Leonard Thomson, a fourteen year-old-boy who lay dying in hospital, for an additional 13 years.
Today extensive research efforts have yielded dramatically improved high-quality insulin as well as better delivery methods. Nevertheless insulin is not a cure, it merely helps to maintain blood sugar levels in check. A cure would be to stop the autoimmune destruction, sparing the insulin-producing beta cells. In contrast to the replacement therapy offered by insulin, the vaccine currently in development by Prof. Cohen's team has been shown to prevent the destruction of pancreatic cells.

Researchers from the Weizmann Institute of Science and Germany's Max-Planck Society have discovered exactly how each of five antibiotic drugs bind to the bacterial ribosome - the cell's protein factory - shutting off protein production. Proteins are the cell's primary component and the basis of all enzymatic reactions; blocking their production kills the bacterium.

The research team headed by Prof. Ada Yonath of the Weizmann Institute's Structural Biology Department and the Max-Planck Research Units for Ribosomal Structure in Hamburg and Berlin has uncovered the exact mode of action of these drugs. Yonath had earlier revealed the detailed structure of the two subunits forming the ribosome, the first ever accomplishment of its kind, in a study described by the prestigious journal Science as one of the most important scientific discoveries of the year 2000. Elucidating the structure of the ribosome - a notoriously unstable, giant nucleoprotein complex - was a goal that had eluded scientists for years.

Armed with their extensive understanding of ribosomal structure, Yonath, Dr. Anat Bashan, and Ph.D. student Raz Zarivach decided to examine precisely how different antibiotics bind to the ribosome and shut off its protein production. To do so they treated bacteria with one of five different antibiotics and then created crystals that captured the individual complexes formed between each drug and the bacterial ribosome.

To examine these microscopic structures the scientists bombarded the crystals with high-intensity X-ray beams, analyzed how the rays diffracted, and then worked backward to decipher the crystal's exact structure - a technology known as X-ray crystallography. Using this method the researchers were able, for the first time, to view how the antibiotic drugs bind to a specific site of action on the ribosome, shutting off its machinery. These findings were recently reported in Nature.

A better understanding of the mode of action of antibiotic drugs may improve the treatment strategies of existing drugs and lead to the design of antibiotics that target bacterial agents at the ribosomal level.

The Max-Planck scientists collaborating in this study are Francois Franceschi, Joerg Harms, Ante Tocilj, Renate Albrecht, and Frank Schluenzen.

According to one theory, memory loss and other cognitive deficits in Alzheimer patients result from degeneration of the nerve cells that release the message-carrying chemical, acetylcholine. The acetylcholine shortage that ensues is compounded by the action of AChE, the enzyme that breaks down acetylcholine in the body. Two Alzheimer drugs approved by the U.S. Food and Drug Administration, tacrine (Cognex) and E2020 (Aricept), work by inhibiting AChE.

A Qian Ceng Ta extract has recently captured the attention of researchers and physicians in China and the West because it too inhibits this brain enzyme, although it differs markedly in chemical structure from both tacrine and E2020. The extract is currently under investigation in China and elsewhere as a possible Alzheimer drug.

What the new Weizmann Institute study has shown is precisely how a chemical purified from this extract, called Huperzine A (HupA), blocks the enzyme. Using a method known as X-ray crystallography, the scientists solved the 3-D structure of the complex formed by HupA and the enzyme and found a strikingly good fit between the two: HupA slides smoothly into the active site of AChE where acetylcholine is broken down, and latches onto this site via a very large number of subtle chemical links. This binding closes off the enzyme's "cutting" machinery and keeps acetylcholine out of danger.

"It is as if this natural substance were ingeniously designed to fit into the exact spot in AChE where it will do the most good," says crystallographer Prof. Joel Sussman, one of the authors of the study.

"The good fit also means that HupA could be a potent drug even when used in small quantities, so that the risk of side effects would be minimal," according to fellow author, neurochemist Prof. Israel Silman. In any case, these risks are relatively small because HupA is believed to have low toxicity.

The research was carried out by graduate student Mia Raves together with crystallographer Dr. Michal Harel and Profs. Sussman and Silman, all of the Weizmann Institute. It involved close collaboration with Prof. Alan Kozikowski, a medicinal chemist at Georgetown University in Washington, D.C., who was the first to synthesize HupA in a test tube, and Dr. Yuan-Ping Pang, a chemist at the Mayo Clinic in Jacksonville, Florida, who had made theoretical predictions of the HupA-AChE interaction.