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lerner/Photo President's Introduction

Richard A. Lerner, M.D.

It is a great honor to congratulate Kurt Wüthrich, visiting professor at The Scripps Research Institute and member of The Skaggs Institute for Chemical Biology, on receiving this year's Nobel Prize in Chemistry for his work in applying nuclear magnetic resonance to solving the structures of biological macromolecules. Currently also a professor of biophysics at Eidgenössisch Technische Hochschule Zürich, in Switzerland, he is scheduled to become a full-time faculty member at TSRI in 2004. A true pioneer in the field, Kurt continues to push the boundaries of structural biology in new and innovative ways. In an institution in which structural work plays such a pivotal role, Kurt's presence creates extraordinary opportunities for increased collaborations across numerous disciplines.

It seems that each year brings with it a new scientific initiative at TSRI, and this year is no exception. In April, the Center for Integrative Molecular Biosciences opened at the Institute, bringing together the talents of several research groups with seemingly divergent interests in chemistry, biochemistry, structural biology, and cell biology. What unites the members of the new center is their interest in the combined use of x-ray crystallography and electron microscopy as a means to unravel the structure and mechanism of action of the large molecular assemblies of the cell. The centerpiece of the facility, which is directed by Ron Milligan, professor, Department of Cell Biology, is a suite containing 6 state-of-the-art electron microscope rooms, a unique feature that makes the facility one of the most advanced biological microscopy centers in the world.

TSRI's graduate studies program continues to be ranked among the top in the country, according to a study by U.S. News & World Report. The publication ranked the program 6th overall in chemistry, 2nd in the specialty of organic chemistry, 9th overall in the biological sciences, and 16th in the specialty of biochemistry. That a program launched only 13 years ago can successfully compete with the most established graduate schools in the country is testimony to the extraordinary leadership of the founding dean, the late Norton B. Gilula, and of its current dean, Jeffery Kelly.

This year the graduate studies program took on a name that is synonymous with excellence in graduate education. In honor of their extraordinary contributions to TSRI, science, and education, the Institute named the graduate college the Kellogg School of Science and Technology for philanthropists Janet R. (Jean) and W. Keith Kellogg II. For many years the Kelloggs have been not only great beneficiaries of TSRI but also two of the country's most devoted philanthropists, giving generously to several institutions of higher learning in California and the Chicago area. Locally, they established an endowed chair in chemistry at TSRI, made significant contributions to the Beckman Center for Chemical Sciences, and funded the continuing care unit at Scripps Memorial Hospital-Encinitas.

I continue to be impressed by the breadth of the research discoveries made by TSRI scientists, who have published their findings in more than 1000 articles in prestigious peer-reviewed journals. Two scientists, John Yates and Laurence Florens, led a collaborative effort involving 18 researchers at numerous laboratories in the United States and the United Kingdom to determine the "proteome" of the most deadly form of the malaria pathogen. Knowing which proteins are expressed could help scientists understand how the parasite causes malaria and potentially how to thwart it. In a related study, researchers at TSRI and the Genomics Institute of the Novartis Research Foundation, San Diego, used a relatively new technology to detect markers in the DNA of the most deadly type of malaria pathogen. This discovery by Elizabeth Winzeler and her colleagues could enable scientists to identify the particular strain of malaria during an outbreak and determine if the strain is drug resistant. This work should make it easier for health officials to follow the spread of drug resistance around world and develop strategies to deter this spread.

A group of TSRI scientists this year was awarded a 5-year, $9.6-million grant from the National Eye Institute to study the leading causes of blindness and to develop treatments for patients with neovascular eye disease. Most diseases that cause catastrophic vision loss do so as a result of abnormal angiogenesis, the uncontrolled growth of new blood vessels. Currently, no effective treatment exists for most patients with these diseases, but researchers have been seeking compounds that could inhibit angiogenesis and reduce the vision loss associated with vascular proliferation, fluid leaking, and bleeding.

A new class of antiangiogenic molecules, which may be useful in the treatment of neovascular eye disorders, was described this year by Martin Friedlander and Paul Schimmel, lead investigators on the new grant, along with professor of immunology David Cheresh. In a related development, the Friedlander group discovered a way to use stem cells from the bone marrow of adults to form new blood vessels in the eye or to deliver chemicals that could prevent the abnormal formation of new vessels. The technique, which involves injecting the stem cells into the eye, could be used to stimulate vessel growth, address inherited degenerations of the retina, and treat ocular diseases due to abnormal retinal angiogenesis.

Peter Wright and Jane Dyson solved the structure of a protein crucial for the growth of tumors. Blocking the protein stops tumor growth in animal models, and the molecular details revealed by the structure will provide scientists with more information to develop future anticancer therapeutic agents. The protein, hypoxia-inducing factor, is a potential target for drugs that will stop tumor growth because it is extremely important for angiogenesis. In another study described in Nature, a group led by Dr. Wright solved the structure of 2 critical human proteins that are normally unstructured in the cell but fold synergistically, forming an active biological structure. This phenomenon, which had never been seen before, leads scientists to think that they can no longer merely equate structure with function. Further, the structures may lead to new therapies, because the proteins are important regulators of genes essential for development and reproduction and are implicated in cancer and other diseases.

Argyrios Theofilopoulos, a professor in the Department of Immunology, suggests a powerful new way to treat cancer. This method involves injecting fresh immune cells to replace the immune cells that die immediately after chemotherapy or irradiation. An injection of cancer cells at the same time serves as a kind of "immunotherapy," which induces the patient's immune system to attack existing colonies of those cancer cells. The study suggests that immunotherapy should be initiated shortly after chemotherapy or radiation therapy, because the reduction in the body's T cells is actually an advantage, helping the body to develop a strong T-cell response to the cancer.

Wendy Havran, an associate professor in the Department of Immunology, identified a major role in wound repair for a mysterious type of immune cell that resides mainly in the skin and gut: the ** T cell. Her findings should be important for scientists who are interested in treating diseases that arise from epithelial cell disorders, including asthma, psoriasis, cancers, and inflammatory bowel disease. The study indicated that when skin is cut or damaged, keratinocytes, a common type of epithelial cell, release the antigen that is recognized by the ** T cells, which then become activated. Once activated, the cells begin making a growth factor that binds to keratinocytes and other epithelial cells, helping the cells proliferate and leading to the closure of the wound.

Ernest Beutler, chairman of the Department of Molecular and Experimental Medicine, led one of the largest DNA-based genetic epidemiologic studies ever conducted, reviewing DNA and clinical data of some 41,000 patients, looking for the genetic disease hereditary hemochromatosis. Dr. Beutler concluded that although the mutation that causes the hereditary disease is common, the disease itself is rare, a finding that runs counter to conventionally held wisdom about the disease. Previously thought to be the most common genetic disorder of Europeans, hemochromatosis is a metabolic disorder in which excessive amounts of iron are deposited in the liver, pancreas, and other organs. It can lead to cirrhosis of the liver, diabetes, and cardiovascular disease; in the severe form, it can be lethal. Dr. Beutler's findings, obtained by working with the Health Appraisal Clinic at Kaiser-Permanente in San Diego, recently were confirmed in a large Scandinavian study. In recent years, there has been much interest in the possible benefits of screening for mutations like the one that causes hemochromatosis in order to prescribe preventive therapy. However, the cost-benefit ratio of screening healthy populations for this disease appears to be dramatically different in light of the results of these studies.

Scientists in the Department of Chemistry and The Skaggs Institute for Chemical Biology identified human antibodies against Bacillus spores, including spores of the bacillus that causes anthrax. The research group led by Kim Janda showed, for the first time, that human antibodies can recognize spore surfaces and suggest that the antibodies might make a powerful and convenient tool for detecting anthrax. Moreover, antibodies that bind to spores have implications for treating people exposed to anthrax. The antibodies could potentially be given for passive immunization; they would help clear spores from the body. And, because of the ease of producing and administering antibodies, this approach could be a simple and inexpensive therapy.

In an attempt to test a new general strategy for drug discovery, a research group led by K. Barry Sharpless, Nobel laureate, W.M. Keck Professor of Chemistry, and member of The Skaggs Institute for Chemical Biology, created a potent blocking agent against an enzyme implicated in Alzheimer's disease. The scientists used click chemistry, a modular protocol for organic synthesis developed by Sharpless, to make a druglike molecule that blocks the neurotransmitter destruction caused by the brain enzyme acetylcholinesterase. Unlike the situation in existing methods, in click chemistry, the target itself is mobilized to play a decisive role and select the final synthetic step. In this instance, the enzyme catalyzed the reaction that created its own inhibitor, resulting in the most potent inhibitor ever discovered for this widely studied brain enzyme.

Using a combination of chemistry and molecular genetics, members of the Skaggs Institute have discovered a way to attach a wide range of molecules to the surface of a virus, essentially enhancing the virus with the properties of those molecules. John E. Johnson and M.G. Finn's work may lead to the ability to build circuits of conducting molecules on the surface of viruses, forming a component of a molecular-scale computer, or a new type of "nanowire." In addition, the work may find applications in materials science, medicine, and molecular electronics. The technique can be used to immobilize large molecules, even whole proteins, on the viral surface.

Numerous members of TSRI's faculty were recognized this year for their scientific achievements. Two TSRI researchers, Francis Chisari and Chi-Huey Wong, were elected to membership in the National Academy of Sciences, bringing the number of members of the academy at the Institute to 16. Membership in the academy is one of the highest honors that can be bestowed on members of the scientific community. In addition, Dr. Chisari also was elected to the American Academy of Microbiology, K.C. Nicolaou received the Tetrahedron Award, Dr. Nicolaou and his graduate student Philip Baran were given the Nobel Laureate Signature Award for Graduate Education in Chemistry, Albert Eschenmoser received the Oparin Medal, and Julius Rebek was honored with the Chemical Pioneer Award. Ian Wilson was elected to the American Academy of Arts and Sciences; Ben Cravatt was named one of 100 young innovators in the United States by Technology Review, the magazine of the Massachusetts Institute of Technology; Eric F. Johnson was given the Brodie Award; Dale Boger received the Janssen Award; David Santoro was named recipient of the Burroughs-Wellcome Award; Mark Ginsberg received the Earl P. Benditt Award; Sandra Schmid received the Pinnacle Award from the Athena group at the University of California, San Diego; and I was given the Presidential Medal from the University of California and an honorary degree from Northwestern University. On an institutional level, TSRI was ranked second in the world among high-impact institutions in chemistry.

This year 5 new members were added to TSRI's Board of Trustees: Gary N. Coburn, Thomas E. Dewey, Jr., Frank Lowy, Claudia S. Luttrell, and Ralph J. Shapiro. These new members strengthen the board with exceptional leadership ability, financial expertise, and solid business acumen. For more than 12 years before his retirement, Coburn worked at Putnam Investments in Boston, where he had overall responsibility for global fixed income investment policy, portfolio management, research, derivatives, and trading. Dewey is a member of McFarland Dewey & Co., a New York investment banking firm specializing in advisory and agency services for corporate and governmental clients. Lowy is executive chairman and cofounder of Westfield Holdings Limited, a public company that has been listed on the Australian Stock Exchange since 1960. Luttrell is a businesswoman, philanthropist, and community activist. Shapiro is chairman of Avondale Investment Company. We are thankful for their active participation and collective wisdom as they assist in guiding the future directions of the Institute.

My kudos and congratulations to the members of TSRI's scientific community, and to the myriad technical and administrative support staff who work closely with them, for an extraordinary year of scientific accomplishment. At all levels, from graduate students to junior faculty members to senior investigators, from members of our core technical facilities to administrative directors, the level of commitment and achievement is extraordinary. Taken together, the collective enterprise, made possible by the contributions of the entire staff, is what makes TSRI such an exciting, vital, and dynamic place to conduct scientific research. There is reason for great optimism that it will remain so for many years to come.

 

 







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