It was during those early days of her research in the laboratory of microbiologist and Nobel laureate David Baltimore that she realized, she says, “that science is one of the most exciting things one can do—you can really pursue your dreams.”

Since then, Prof. Rotter, who is head of the Weizmann Institute’s Department of Molecular Cell Biology, has devoted her career to this gene, now known as the “guardian of the genome” because it protects us from developing cancer. She was one of the first to develop antibodies against p53, along with other genetic tools, laying the foundations for the study of its function.

In its normal form, p53 plays a pivotal role in protecting cells from becoming cancerous. “The p53 is a very smart gene,” says Prof. Rotter. It can sense when cells have damaged DNA (from exposure to ultraviolet radiation or chemicals, for example) and signal them to either repair that damage or undergo a process of self-destruction. When p53 is mutated, however, it loses this function; as a result, cells carrying damaged DNA can go on dividing and eventually transform into tumor cells. Mutant forms of p53 are found in more than 60 percent of human tumors.

Although p53 is possibly the most studied gene ever—thousands of papers on it have been published—Prof. Rotter finds that some basic questions have still only been partially answered: What is the function of p53 in the normal cell? How does mutant p53 contribute to cancer development? She believes that if we can understand exactly how p53 works, we can find ways to use it to stop the proliferation of cancer cells. Ultimately, her   goal is to come up with new kinds of therapies that she describes as “made just for you and your cancer.”

She has already made progress toward this goal through her research on the possibility of tailor-made chemotherapy. Prof. Rotter and her team conducted an  experiment in which they treated cancer cells with chemotherapy. Some of the cancers died, but others were very resistant to the chemo. The researchers evaluated the status of p53 in the cancers, and found that different types of mutant p53 exhibited different levels of resistance to the therapy.

Prof. Rotter thinks it may be possible, in the future, to increase the effectiveness of cancer therapy by evaluating the specific type of mutant p53 the patient is expressing and choosing a chemotherapy drug that is suited to it. Her team is now creating a library of chemotherapy drugs targeted to various mutant forms of p53.

Since 2000, Prof. Rotter has also directed the Weizmann Institute’s Women’s Health Research Center, which promotes basic research on gender-related physiology and diseases and has supported studies of cancer, fertility, and osteoporosis. For example, several of the research groups have examined the buildup and breakdown of bone mass and described a number of enzymes that affect the balance of bone accumulation or loss. Understanding how bone degradation is regulated may help in developing better treatments for osteoporosis.

Prof. Rotter is optimistic that basic research will continue to lead to better cancer treatments. For her part, she will continue to search for new kinds of therapies that could compensate for the malfunction of tumor suppressor genes.

Her ongoing goals include designing genetic methods for coping with cancer and making our genes stronger—possibly through inserting better genes, strengthening existing genes, or fighting the bad genes. “When we find a way to design this kind of tailormade therapy,” she says, “I think we will solve the problem of cancer.”

Recent research in Amsterdam’s laboratory has revealed that theophylline, a widely used asthma drug, makes ovarian and lung cancer cells more vulnerable to such common anticancer medications as cisplatin and gemcitabine HCl. Apparently, theophylline helps induce massive programmed death in the cancer cells. Therefore, by giving theophylline together with common cancer drugs, it may be possible to use the cancer drugs at lower concentrations and so minimize their harmful side effects. Clinical trials in which theophylline is administered to lung cancer patients in combination with cisplatin and gemcitabine HCl are under way at the Tel Aviv Sourasky Medical Center.

Weizmann Institute scientists have made seminal contributions to understanding the role of p53 in normal and cancerous cells. It is now known that p53 acts as the cell’s damage control and as a “guardian of the genome.” When genes are damaged by radiation, chemicals or other means, threatening to set the cell on a course toward malignant transformation, p53 senses the damage and its supply builds up. The p53 protein activates numerous genes that prevent tumors from forming; by so doing it either blocks the growth of damaged cells, allowing for the correction of DNA damage, or commands these cells to commit suicide. But if the cell has no healthy p53, the road to cancer remains open.

Prof. Moshe Oren of the Molecular Cell Biology Department, together with the Weizmann Institute’s Prof. Emeritus David Givol and Prof. Arnold Levine, then of Princeton University, was the first to clone p53 - in other words, to isolate the gene and determine the sequence of its genetic letters - in 1983. The p53 clone and its genetic sequence provided laboratories around the world with one of the most frequently used tools for studying cancer. Subsequently, Oren was the first to show that reactivation of p53 in cancer cells can prompt them to self-destruct, a principle that underlies the ongoing p53 gene therapy trials. Oren is now focusing on elucidating the biological processes that allow this gene to function as a tumor suppressor. Among the questions studied in his lab: How does p53 interact with other genes? How are the levels of p53 regulated in a cell? Usually, p53 is present in minute amounts, but its levels soar in response to DNA damage and other types of stress. Oren has discovered the role of a major regulator of p53 activity, called MDM2. He found that MDM2 is responsible for the elimination of p53, and he now seeks to clarify how exactly MDM2 achieves this. Oren predicts that interfering with MDM2 will strengthen p53, thereby boosting the natural anti-cancer defense mechanisms.

Prof. Varda Rotter of the Molecular Cell Biology Department was the first to develop antibodies against p53, laying the foundations for the study of this gene’s function. She also provided some of the earliest evidence that p53 is a tumor suppressor. At present, Rotter is working toward two major goals: to decipher the function of p53 in the normal cell and to clarify the behavior of mutant p53 in tumor cells. In particular, she seeks to understand how p53 can induce three different processes: blockage of growth, cell differentiation or cell death. She is working to clarify whether all three processes can occur in a single cell, or whether different cells respond differently to p53.

The state of a patient’s p53 may determine whether conventional cancer treatments are likely to be effective. Several years ago, oncologists made a surprising discovery: radiation therapy and some chemotherapies, rather than directly killing cells as had previously been thought, in fact work by activating p53, which in turn orders cells to self-destruct. Therefore, patients with intact copies of p53 are more likely to be helped by these treatments. In the absence of p53, the cancer is resistant to chemotherapy. Prof. Emeritus David Givol of the Molecular Cell Biology Department has conducted several studies exploring the effects of p53 on different chemotherapies. Givol is now using DNA chips to determine which other genes are activated by p53. He discovered new cell suicide genes that are turned on by p53 in response to DNA damage. If p53 is defective, alternative means may be used to activate such genes.

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.

When cancer cells metastasize or tissues become damaged through inflammation, it’s likely that enzymes called matrix metalloproteinases (MMPs) are involved. This family of enzymes cuts through various bodily materials, including the tough collagen fibers that hold our tissues together.

One member of the family in particular – MMP-9 – is often produced by migrating cancer cells and in certain autoimmune diseases, and scientists have long believed that finding a way to inhibit its activities might be useful for treating these diseases. A team led by Prof. Irit Sagi of the Structural Biology Department in the Faculty of Chemistry has now employed an unconventional combination of techniques to reveal the structure of the entire MMP-9 protein. The team included Gabriel Rosenblum of the Structural Biology Department, Drs. Phillippe Van den Steen and Ghislain Opdenakker of the University of Leuven, Belgium, and Dr. Sidney Cohen of the Institute’s Chemical Research Support.

Their findings revealed a linker whose extreme flexibility and contortions “would impress even a swami yogi,” in the words of a scientific reviewer. The distinctive MMP-9 linker may turn out to be its Achilles’ heel: The team has already designed a molecule that binds directly to this domain to neutralize its activity, and Yeda, the business arm of the Weizmann Institute, has applied for a patent for this molecule. 

One Hundred Times Stronger
Natural interferon is widely used to treat a number of different cancers, but its effectiveness is rather modest. Weizmann Institute scientists have now succeeded in engineering a new version of interferon whose activity is 100 times stronger than that of the natural molecule.

Prof. Gideon Schreiber of the Institute’s Biological Chemistry Department was originally interested in a basic research question concerning interferons: How do these proteins produce two different kinds of effects inside the cell – either serving as the body’s first line of defense against viral infection or inducing programmed cell death, called apoptosis? Schreiber revealed that the different types of activity stem from the way interferon binds to its receptor. Moreover, his team identified the precise amino acids and structural features that affect the binding.

The scientists then created versions of interferon with different degrees of binding ability and different types of activity: They manipulated the interferon-receptor bond by replacing various amino acids in the interferon’s binding site and then testing the resulting interferon versions. Using this approach, they managed to create an interferon molecule, called YNS, that binds to cellular receptors much more strongly and, in a laboratory dish, is 100 times more effective than natural interferon at triggering the death of cancer cells. The scientists then found that the YNS molecule effectively eliminated human breast cancer cells in laboratory mice, while the natural interferon did not.

Yeda Research and Development Company, the Institute’s technology transfer arm, has patented the YNS molecule. If the new interferon proves sucessful at eliminating cancer cells in humans, it could be developed into an effective anti-cancer drug.

Deadly Repeats
Huntington’s disease is a genetic time bomb. Programmed in the genes, it appears at a predictable age in adulthood, causing a progressive decline in mental and neurological function, and finally death. There is, to date, no cure. Huntington’s, and a number of diseases like it, collectively known as trinucleotide repeat diseases, are caused by an unusual genetic mutation: A three-letter piece of gene code is repeated over and over in one gene. By the number of these DNA repeats, one can predict, like clockwork, both the age at which the disease will appear and how quickly it will progress. But what is the mechanism behind this remarkable precision?

Shai Kaplan in Prof. Ehud Shapiro’s lab in the Biological Chemistry, and Computer Science and Applied Mathematics Departments, realized the answer might lie in the buildup of mutations that occurs in our cells throughout our lives. The scientists realized that the longer the initial disease sequence, the greater the chance of additional mutations. In this manner, the genes carrying the disease code might accumulate more and more DNA repeats over time, until some critical threshold is crossed.

Shapiro, Kaplan and Dr. Shalev Itzkovitz of the Computer Science and Applied Mathematics Department have created a computer simulation that predicts, from the given number of genetic repeats, both the age of onset and the disease progression. The new disease model appears to fit all of the facts and to provide a good explanation for the onset and progression of all of the known trinucleotide repeat diseases. This explanation may, in the future, point researchers in the direction of a possible prevention or cure.

Ancient Throwback: New Technology
Today the management “posts” in the cell are occupied by proteins; but eons ago, when single-celled organisms were beginning to make their mark on Earth and life was simple, the living world might have been an “RNA world.” Recent findings suggest that RNA molecules, single strands of nucleic acids that are far less sophisticated than proteins, are capable of performing many of the cell’s main regulatory functions.

Riboswitches, discovered several years ago in bacteria, are segments of RNA that can bind to certain substances, thereby regulating the levels of these substances in the cell. Only one riboswitch has so far been found in higher organisms: The thiamin (vitamin B1) riboswitch regulates thiamin biosynthesis in numerous organisms that produce this vitamin – from the most ancient bacteria to highly developed plants. Dr. Asaph Aharoni and Samuel Bocobza of the Plant Sciences Department investigated this lone plant riboswitch. The scientists revealed the mechanism by which the riboswitch senses the presence of thiamin in the cell nucleus and makes sure the levels of this essential vitamin are neither too high nor too low by turning its production on or off as needed.

They may be ancient mechanisms, but riboswitches could be the basis of sophisticated future biotechnologies. Aharoni and Bocobza engineered reporter genes – genes that glow in fluorescent colors under the microscope when activated – that responded to thiamin levels as the riboswitches did. When inserted into plants, these reporters lit up whenever thiamin levels fell. This sort of reporter gene-riboswitch combination could pave the way to the design of live biosensors for all sorts of applications. 

At first glance, cancer and Alzheimer’s disease appear to have little in common. Cancer is a group of over a hundred diseases in which cells grow out of control and spread throughout the body. Alzheimer’s is a progressive neurodegenerative disease caused by the abnormal buildup of protein in the brain. The common link between the diseases is the role played by enzymes called proteases, which cut long strands of protein into fragments. Cancer cells secrete proteases that dissolve collagen, creating holes in the surrounding cell matrix that enable the cancer cells to bulldoze their way through tissue and into other cells. In Alzheimer’s disease, insoluble fragments of a protein snipped from a larger protein by proteases accumulate in the brain, interfering with cognitive function and memory.

The proteases involved in both cancer and Alzheimer’s disease utilize a zinc ion to execute their harmful activity. Because little information on how this works was available, Weizmann scientists decided to find out. They developed a method that enables the process to be seen in real time – that is, as it is actually taking place.

“We used high-intensity monochromatic x-rays to study the environment around a metal ion during protease activity,” Prof. Irit Sagi explained to an audience of supporters of the American Committee for the Weizmann Institute of Science (ACWIS). “This allowed us to make molecular movies showing how a metal atom is activated inside a protease by water and other key protein residues. Our tools can be used to characterize the reaction elements that drive an increase in the rate of a chemical reaction in individual Alzheimer’s and cancer enzymes.”

Up to this point, scientists studying the workings of ultra-microscopic forms had to rely on the scientific equivalents of still photos, something like trying to fathom the concept of driving by looking at a photograph of a car. The resolution of Prof. Sagi’s animated “video clips” of enzyme molecules at work is so fi ne that the scientists are able to see the movements of individual atoms within the molecule.

The challenge facing the Weizmann team was to capture, step-by-step, the complex process (the whole of which takes place in a tiny fraction of a second) that an enzyme molecule goes through as it performs its work. Their pioneering method, published in Nature Structural Biology, was hailed as the first of its kind, and a potentially important tool for biophysicists. 

To obtain the “live action” footage, Prof. Sagi and her team use a technique akin to stop-action photography, but on an infi nitely smaller scale. They literally freeze the process at certain stages, using advanced methods of chemical analysis to determine the exact molecular layout at each stage. The most diffi cult part, says Prof. Sagi, was figuring out the correct time frames that would allow them to see each phase of enzyme activity clearly. She compares it to attempting to capture on film the swirling of syrup being mixed into cake batter — one has to gauge the points at which individual stages of the process will be most visible.

Building an animated sequence from individual frames, the scientists are granted a rare peek into the intricate dance of life on the molecular level. “This method,” says Prof. Sagi, “represents more than a major breakthrough in the techniques used to understand enzyme activity. It changes the whole paradigm of drug formulation. Now we can precisely identify which parts of the molecule are the active regions [those which directly perform tasks], and the exact permutations of these molecular segments throughout the whole process. New, synthetic drugs can be designed to target specific actions or critical confi gurations.”

Prof. Sagi’s team is doing just that for one enzyme family known to play a role in cancer metastasis. Matrix metalloproteinases (MMPs) assist the cancer cells’ escape and entry into new tissues by breaking down the structural proteins that keep cells in place, a skill normally needed to clear out tissue in preparation for growth or repair.

The ability to visualize complex processes inside a molecule also paves the way for developing drugs that selectively stop the activity of metal ions — in this case, zinc — inside proteases. Prof. Sagi of the Weizmann Institute’s Department of Structural Biology is working with the pharmaceutical company Novartis to translate this research into drug design. More than just a pipe dream, the information derived from these “molecular movies” has already been put to good use.

“We recently designed an antibody to block the activity of proteases by constraining the zinc-protein dynamics required for effi cient enzyme activity, thereby minimizing uncontrolled collagen dissolving in cancer,” says Prof. Sagi.

Prof. Varda Rotter, head of the Institute’s Department of Molecular Cell Biology, studies p53, a gene that suppresses tumor growth and may one day open doors to the development of new cancer treatment drugs. “There is really a strong feeling that a critical breakthrough in preventing cancer and designing future therapies will occur once it is understood how this gene works,” said Prof. Rotter.

With the mapping of the human genome, knowledge of p53 is expanding: both biology and genetics as a whole have, in the past six years, undergone a major revolution. Prof. Rotter went on to explain that p53 is a very important gene and one of the major tumor suppressors in our genome.

She elaborated that the human genome is comprised of some 30,000 genes, which are present in each individual human cell. The beauty of biology is that each healthy cell can only “read” a certain part of the genome. For example, our skin cells can interpret the information needed to produce melanin and protect us from the sun, while ovarian cells will read enough information to know to secrete hormones in a coordinated way at a given time.

While healthy cells carry out their intended functions, researchers are asking themselves how cancer cells differ. For molecular biologists, understanding the unique features of the cancer cell is critical for recognizing the enemy.

A cancer cell, while similar to a normal cell, not only reads and translates genes at the wrong time and place, but also contains mutated genes, Prof. Rotter stated. Contributing to malignancy are oncogenes, which under certain conditions turn a normal cell into a cancerous one. “There is no simple answer as to why we carry oncogenes,” she said.

There about 150 oncogenes, all of which are supposed to be silent, explained Prof. Rotter, but certain incidents or accidents provoke the cells to start growing or multiplying in an uncontrolled way. In contrast, healthy cells know how to grow and reproduce themselves to a certain degree and then stop.

At least 300 mechanisms can awaken oncogenes, said Prof. Rotter. The most common is the occurrence of a genetic mutation which, although not necessarily inherited, can be passed down from parent to child. Environmental factors, such as exposure to too much ultraviolet light or x-rays, can also awaken an oncogene. Once a mutation in a dormant oncogene occurs and becomes functional, it cannot be turned off.

“Our cells knew about the problem of oncogene ‘awakening’ long before it was discovered by us,” she said. Healthy cells, having this knowledge, contain tumor suppressor genes such as p53 that fight oncogenes by scanning for genetic mistakes and signaling cells to repair the damage or stop replicating, and thus helping to prevent uncontrolled proliferation. Genes such as p53 also initiate cell death: a healthy cell knows when to die, noted Prof. Rotter. 

Researchers have found that many cancer cells do not contain healthy tumor suppressor genes. These genes are instead mutated and cannot execute their functions. They do not know how to sense damaged DNA or how to put repair or cell death into motion, she said.

“Some people are born with less-than- perfect tumor suppressor genes –that’s the concept of genetic predisposition to cancer,” said Prof. Rotter. “A parent can have a mutation in the p53 gene and can transmit it to his or her children.”

While p53’s role as a single gene is important, knowing how it interacts with the rest of the genome is crucial to understanding cancer development, Prof. Rotter said. “Cancer growth is not mediated by a single gene. Rather, it involves a multitude of genes,” she added.

To better understand how p53 prevents cancer, Prof. Rotter and her colleagues developed a system that makes it possible to change the status of the tumor suppressor gene in a controlled way at specific and defined stages of cancer development. They then analyzed how other genes expressed themselves at given time points in relation to p53 status using “gene chips,” which are small glass slides containing microscopic strips of DNA. One chip provides a printout of activity levels of about 10,000 genes, allowing researchers to observe which genes are involved at a given time point in the cancer’s development.

A group of physicists from the Weizmann Institute have developed computational tools in order to help the researchers make sense of the genes’ activity on these chips. These tools have enabled Prof. Rotter and her colleagues to identify ten clusters of genes that are altered in the course of cancer development. They found one group to be negatively regulated by p53 – a discovery that would have been impossible without the new computational tools, explained Prof. Rotter. “It’s like putting a new lens in your glasses and being able to see everything in an additional dimension,” she said. 

Understanding how a network of genes is affected by p53 may lead to the development of therapies that target these entire genetic pathways rather than just one specific gene. “We hope to one day develop therapies that will target specific networks of genes,” Prof. Rotter said. “Continued research of p53 and defining its role in preventing cancer growth is a fantastic challenge.”

Prof. Zvi Livneh and his team of Weizmann Institute scientists in the Department of Biological Chemistry have pinpointed an enzyme that plays a role in protecting individuals against lung cancer. Genetic differences in the activity of this enzyme may help explain why some get cancer and others don’t. The scientists hope the finding will be used to assess a smoker’s risk for lung cancer, making it easier to persuade high-risk smokers to kick the habit.
 

How cancer occurs
When we are young and growing, many of our body’s cells multiply constantly. After we reach maturity, cells begin to multiply for replacement only, rather than growth; they are programmed to know when to stop. Cancer occurs when cells lose their “brakes” and multiply in an uncontrolled fashion.

“Cancer means a genetic change (mutation) has occurred. You must control mutations to prevent cancer or slow its progression. This requires an understanding of what makes a normal cell suddenly transform into a cancer cell,” Prof. Livneh told an audience in Florida.

Human DNA is comprised of information bits that are chemically coded T,C,G, and A. DNA is formed in two long strands that are twisted together in a double helix pattern. When a cell multiplies, the DNA strands separate, and each strand then makes a copy to form a new double helix. The replication process is highly accurate, but not perfect: each cell averages 1 “typo” in 10 billion letters. These mistakes are greatly increased by external DNA-damaging agents, such as sun, tobacco smoke, or food additives, or internal processes, such as waste products left over from the body’s own metabolic processes.

“There is no way to avoid damage. It’s a part of normal life,” said Prof. Livneh.

When DNA damage is extensive, a cell might choose to commit suicide. Cells, however, prefer to continue replicating. To this end, sophisticated DNA repair mechanisms in the cell recognize damage, cut short segments out of the strand, and replace the damaged bits. Countless instances of damage are caught and repaired daily. Yet some escape proper repair. The replaced segment might contain mismatched letters, for example. If the mutation is passed on unrepaired, it can eventually lead to cancer. Five to 20 mutations must accumulate in a single cell before it begins to divide in an out-of-control fashion.

Finding a way to measure DNA repair
“Cancer can be caused by the excessive actions of DNA- damaging agents such as tobacco smoke or other external factors, the reduced ability to respond to this damage with DNA repair mechanisms or, more likely, a combination of both,” said Prof. Livneh. “We know this because as our ability to repair DNA decreases, cancer risk rises.”

Prof. Livneh and his colleagues have identifi ed an enzyme, known as OGG1, which plays a central role in repairing a type of DNA damage that can lead to lung cancer and head and neck cancers.

High levels of OGG1 are desirable – nonsmokers have an average OGG1 level of 7. Smokers with an OGG1 level of 4 have 124 times the risk of lung cancer than nonsmokers with normal OGG1 levels. (A high level, of course, is not a 100 percent guarantee that cancer will not develop, nor does it protect against other effects of smoking such as hypertension.)

The goal

Applying this information to medicine requires only the development of a simple blood test for OGG1 levels. “The test could be used to screen smokers. It might be a convincing tool to warn those most at risk to stop smoking. If you have low OGG1 levels, you should reduce your exposure to tobacco, ultraviolet radiation, and other carcinogens,” said Prof. Livneh. “It would also open the door to developing drugs to strengthen OGG1 levels.”

While knowing the role of OGG1 cannot, at present, prevent cancer or stop mutations from occurring, it might help those at risk postpone the development of cancer until it becomes irrelevant. “Since the incidence of cancer increases with age, if you reduce the rate at which mutations accumulate, you can delay the age at which cancer appears. Who cares if you get cancer when you are 120?” Prof. Livneh said.

Prof. Scherz and his colleagues hope that this vascular targeting photodynamic treatment (VTP) can be used as a first-line therapy for prostate cancer. If this is accomplished, patients could avoid surgery or radiation, which can cause side effects that negatively impact sexual function and quality of life. In the Phase II studies, which are sponsored by Steba Biotech of France, the treatment destroyed cancerous tissue and spared vital organs, such as the urethra, in men with prostate cancer who had not benefited from prior radiation therapy. VTP took an average of 20 minutes and did not cause significant side effects. Approximately 50% of the patients appear disease free at one year after a single treatment.

One advantage that this treatment has over other forms of photodynamic therapy (PDT) is that the chlorophyll-containing drug clears the system within hours, rather than days. This helps to reduce side effects to the skin, such as sunburn, and should allow for multiple treatments within a short period of time, explains Prof. Scherz. Additionally, one optic fiber is able to treat a tumor up to 3 to 4 centimeters in diameter, which is larger than tumors treatable by conventional PDT.

Researchers also plan to treat about 30 patients in a clinical trial in England. These men are not undergoing any treatment for prostate cancer, other than watchful waiting to make sure the disease doesn’t spread. They want to avoid surgical removal of the prostate and receive the bacteriochlorophyll-based PDT. Prof. Scherz hopes that this form of PDT for prostate cancer will be available in the United States, England, France, Canada, and Israel in the near future. In the meantime, he and his colleagues are evaluating how this treatment might help treat breast, liver, pancreatic, kidney, and brain cancers. “The therapy will have to undergo modification for each type of cancer,” he explains.
Prof. Scherz points out that the strides in his research would not have been possible outside of the special habitat of the Weizmann Institute. The congregation of different disciplines within a supportive multidisciplinary infrastructure allowed for the rapid development and implementation of the project.

To better benefit from the PDT modality, researchers have to understand the ways some molecules, when excited by light, transfer energy to create radicals.(Radicals are entities that are able to destroy larger chemical entities, such as proteins or membrane lipids.) Then researchers must decipher the impact of such processes on the tumor tissue and normal blood tissues and, finally, define the treatment targets – cells, blood vessels, interstitial tissue.

Prof. Scherz explains, “We then asked ourselves – first, how can we make PDT with the new reagents and, second, how can we make this general modality most effective?” They arrived at the idea of targeting the tumor vessels with molecules that will not leave the blood vessels, but will clear rapidly from the treated patients. Chlorophylls of photosynthetic bacteria appeared to be the best choice, as nature adapted them for efficient light harvesting and radical production at near-infrared, where light penetrates deeply into animal tissues.

Creating a team that could meet on a daily basis to answer such questions was crucial, and the readiness of researchers and students at the Weizmann Institute to enter such multidisciplinary efforts made it easy. Profs. Scherz and Salomon succeeded in gathering students with experience in chemistry, as well as staff scientists and colleagues in biology and physics. The Institute’s technology transfer arm, Yeda Research and Development, provided the critical connection to the pharmaceutical industry, and Steba Biotech undertook the development of Tookad, the first candidate in the modified-chlorophyll series.

Prof. Scherz concludes, “The Weizmann Institute helps to bring ideas forward and helps those ideas become realized.”

Taking advantage of recent advances in DNA technology, the researchers are working to fi nd out what goes wrong, at the molecular level, when colon cancer develops — what are the defects in genes, or in the “expression” of those genes, that allow abnormal cells to grow out of control?

Speaking at an American Committee for the Weizmann Institute of Science (ACWIS) forum in New York, Prof. Eytan Domany of the Weizmann Institute’s Department of Physics of Complex Systems, likened DNA — that familiar double-stranded carrier of genes inside every cell of the body — to a cookbook. Each gene is like a single recipe for a dish which is akin to a protein, whose chemical formula is “written” on the gene. The gene is expressed when the corresponding protein is actually produced.

As Prof. Domany noted, there are many opportunities for errors in this cookbook, just like a misprinted ingredient in one of the recipes. In cooking, the result is a ruined meal; in the body, the result is a fl awed protein, leading possibly to cancer.

To try to discover where the recipes are going wrong in colon cancer, Prof. Domany and his colleagues have begun with tissue samples from 144 individuals — including samples of colon cancer, colon growths called polyps that can become cancerous, and normal colon tissue. The job of creating an initial “profi le” of gene expression for each of these individuals goes to Dr. Daniel A. Notterman, a professor of pediatrics and molecular genetics at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School.

To do this, Dr. Notterman focuses on the amount of messenger RNA (mRNA) in the cells of each tissue sample. mRNA is the molecule that takes the instructions from a gene in the cell’s nucleus and carries the information to the cell’s protein-making machinery, which in turn churns out the appropriate protein. Sticking with the culinary analogy, mRNA is a photocopy of the recipe, sent to the cook.

Proteins are the workhorses that actually carry out all the functions in the body. When a gene acquires a defect, the result may be an abnormal protein or protein levels within a cell that are too high or too low — that is, a problem in the way the gene is being expressed. Cancer arises when such cells continue to grow and spread unchecked.

For technical reasons, it’s easier to study a gene’s expression by looking at RNA levels in the cells of a tissue sample rather than by studying proteins, Dr. Notterman explained at the briefi ng. Using a DNA “chip” that allows the simultaneous analysis of thousands of RNA molecules over a matter of hours, his lab was able to create expression profiles for the roughly 30,000 genes in each of the 144 tissue samples.

Those data, in the form of what looks like a sea of numbers, then go to Prof. Domany, whose job is to find meaningful patterns in the “noise” — pulling out the relative handful of “candidate” genes most likely to play essential roles in colon cancer. To begin to make sense of the numbers, Prof. Domany color-codes the data, with different shades of color representing the expression levels of the thousands of genes in each patient.

The aim, as Prof. Domany explained, is to separate the patients into groups based on similarities in their gene expression profi les. “We take a picture that looks very random and reorganize it so that we can reveal the structure,” he said. What his lab has come up with so far is roughly 200 genes that are altered at the level of RNA and appear key in colon cancer progression.

That list of genes then moves on to Dr. Francis Barany of the Weill Medical College of Cornell University, who tries to uncover the changes in DNA — the master cookbook — that contribute to colon cancer. “The problem is, how do you distinguish the really important cancer-specifi c defect from the ‘bystander’ defect,” said Dr. Barany. The foundation of this research project, he explained, is that “candidate genes that are consistently altered at the DNA level are likely to be cancer-specific.”

Cancer-gene research, Dr. Barany noted, generally focuses on three types of genes: oncogenes, which promote cancer growth; tumor suppressor genes, which act like the name implies; and genome integrity genes, which act like the body’s “mechanic.” Among the problems that can arise are mutations in the structure of the DNA, as well as so-called “epigenetic” changes, which refer to alterations in the way genes are expressed in the absence of structural defects in the gene.

The future of cancer treatment, Dr. Barany said, is to move away from “blanket treatments” that try to slow down cancer cells — and harm healthy cells in the process — toward targeted drugs aimed at specifi c gene defects in cancer. The ultimate hope is to be able to test a patient for the specifi c molecular characteristics of his or her tumor, and then choose the right treatment from an arsenal of targeted drugs.

Reaching that goal will, of course, take a continuing effort to identify the genetic culprits in cancer. As Prof. Domany noted, colon cancer, on the molecular level, varies widely from person to person, and much work remains in untan- gling the genetic underpinnings. The collaboration he and his colleagues have undertaken is currently in the early, data acquisition and “data mining” phase of what is expected to be a 5- to 10-year effort.

Between April 2004 and February 2005, 28 men with prostate cancer showed up at three Canadian hospitals for one-time injections of an experimental drug designed to eradicate their deadly tumors. Radiation had already failed them.

By December tumors in the earliest-treated patients had shrunk by as much as 84%. But the real test began in March, when doctors started studying tissue samples. If they find the tumors are gone or reduced to a manageable level, it may indicate that the drug is reliable over time, and researchers could be on their way to a radical advancement in localized prostate cancer treatment.

The drug, trademarked Tookad (a Hebrew word suggesting "the warmth of light"), is an innovative twist within the established cancer-drug class called photodynamic therapies. These drugs work their way through the bloodstream but become toxic only when exposed to light. When doctors shine a laser light onto either the skin or an internal tumor using catheter-inserted optical fibers, the drugs kill just the illuminated tissue and leave unexposed tissue relatively undamaged.

Tookad was designed to eradicate bulkier tumors, with fewer side effects than those caused by existing photodynamic drugs. Once illuminated by laser light, it clogs the tiny blood vessels feeding the tumors, starving the cancer of oxygen and nutrients. If it proves successful, Tookad will be a welcome addition to existing prostate treatments such as surgery, freezing and radiation, which can cause impotence and incontinence or kill healthy cells. So far Tookad has produced none of these side effects.

Photosensitizers have been used for a decade against esophageal, bladder, lung and skin cancers, but they leave the body so slowly that patients must avoid outdoor light for up to six weeks after treatment or risk skin burns. Tookad degrades more easily in the liver and exits the body within hours.

"This is one of the most promising treatments for recurrent prostate cancer after radiation I've ever seen," says John Trachtenberg, director of the Prostate Centre at Princess Margaret Hospital in Toronto and principal investigator for Tookad's worldwide trials, which are also under way in Britain, France and Israel. Results are due early next year. Successful results will also spotlight Steba NV, the family-owned Dutch company that has licensed Tookad and poured tens of millions of dollars into its development since 1996.

Tookad was developed over several years by biologist Yoram Salomon and plant photochemist Avigdor Scherz of the Weizmann Institute of Science in Israel. Their breakthrough was in using a bacteria-derived photosensitive agent instead of the traditionally used heme, the red pigment found in hemoglobin. Heme can be activated by visible light at a wavelength of 630 nanometers, which can penetrate thin tumors but nothing much thicker. Tookad is derived from bacteriochlorophyll, the bacterial equivalent of the green plant pigment chlorophyll, which drives photosynthesis. It is activated by near-infrared light at a wavelength of 763 nanometers, long enough to penetrate deeper, up to 2 centimeters, into the tissue. Lighting up several fibers, doctors can treat even larger tumors.

"People tried chlorophyll before but failed since they used the native green pigment from plants," says Salomon, a professor with the institute's biological regulation department. "Avigdor and I modified bacteriochlorophyll to adapt it as a drug."

Tookad also fits into a burgeoning class of vessel-targeting cancer drugs that includes Genentech's successful Avastin. But, while Avastin requires patients to remain on the drug, Tookad can be administered once. In animal tests it has shown the ability to work against tumors that have become chemotherapy resistant; early work is under way on liver and lung tumors. Says Solomon Hamburg, a clinical professor of medicine at UCLA Medical Center: "This is not the kind of technology that will revolutionize outcomes. But it may change options. If I was 65 and had prostate cancer, and I had a choice between this drug and surgery or radiation, I'd strongly consider using this drug first."

"The goal is the same: to block blood flow to the tumor," says Salomon. "But we blow up the bridges. They [Avastin developers] slowly narrow the streets until no one can go through. If you stop their drug, the vessels grow back."

Thanks to technology developed in Prof. Hadassa Degani's laboratory, that relief may be had without the invasive, painful procedures that have accompanied cancer diagnosis methods until now. Prof. Degani discussed her breakthrough diagnostic method in a talk at MIT sponsored by ACWIS New England.

Prof. Degani's MRI-based method may someday be an alternative to mammography, presently the most widely available tool for breast cancer diagnosis. "The truth is mammography is not accurate. If the breast tissue is dense, as is the case for younger women, then mammography can miss malignant tumors. It also can't always differentiate between malignant and benign tumors. Too often pieces of a tumor must be removed for further testing. In 65 to 80 percent of cases these biopsies are unnecessary, because the tumors are benign," Prof. Degani said.

Prof. Degani uses MRI as a non-invasive way to differentiate between benign and malignant tumors at very early stages, sometimes even when tumors are undetectable by other methods. Unlike mammography, which uses X-rays to take a snapshot from two to three angles, MRI gives a three dimensional image of the whole breast at high resolution. MRI also provides high contrast in soft tissues, thereby generating the clearest and most detailed images.

A doctor can then use a computer to manipulate the image and look at "slices" of breast tissue from any angle or direction to pinpoint a tumor. Besides providing physical information about size and location of a tumor, MRI can also give information about location of blood vessels, blood flow, and density of cells in tissue.

To test for breast cancer, a patient is injected with a liquid that circulates in the blood and shows up on a MRI image. For the most accurate measurements, MRI images are taken at three time points: one before injection and two after injection of the fluid. As the fluid flows into breast tissue, it will move differently through cancerous cells than through normal tissue. "If you find tissue with densely packed cells and a lot of leaky blood vessels, then it indicates cancer," Prof. Degani explained. A computer takes the information from the MRI readings and analyzes it and then color-codes the image for easier interpretation.

Prostate Cancer
In theory, this MRI technique should be applicable to many types of cancer and other diseases. She and her colleagues have already successfully extended the technology to diagnose prostate cancer. Until recently, the only way to confirm a suspicion for prostate cancer has been to do biopsies on tissues that are taken from up to eight different places. But merely by optimizing the time points when the three MRI images were taken, the researchers were able to identify malignant tumors and predict the type of treatment necessary.

"Literally, we are trying to improve early detection and diagnosis of malignancy and thereby help extend the life of patients around the world. Thanks to our many collaborations, we have images coming to our labs in Israel from clinical trials in such diverse areas as Chicago and Vienna. I hope someday this will be a widely used diagnostic tool," Prof. Degani concluded.

Update:
Prof. Degani's method, known as 3TP (Three Time Point), has received FDA clearance for use in the detection of breast and prostate cancer. The 3TP technology is being licensed worldwide by 3TP LLC of New York, a privately held company.