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President's Introduction

Richard A. Lerner, M.D.

The efforts of our nation's scientific community in the 20th century have been responsible for remarkable discoveries resulting in innovative medical treatments and important diagnostic tools, improving the quality of life and increasing life expectancy for all Americans. Further, basic research has boosted this nation's technology base, fostered the vibrant biotechnology industry and substantially reduced health care costs for certain diseases through the development of improved health-related strategies and procedures.

Although the fruits of scientific labors are plentiful and have led to a quality of life unimagined not many years ago, a great deal more needs to be done. The achievements in molecular biology have been numerous, and the output of scientists has been prodigious, but many questions are as yet unanswered.

The United States must maintain its preeminence in biomedical research. To do so, we must encourage talented, young people to pursue the exhilarating and sometimes difficult field of scientific inquiry. We must provide them with adequate resources to appropriately use the plethora of new technologies available to advance knowledge. While the National Institutes of Health continues to receive modest annual funding increases--in the midst of the drive toward a balanced federal budget and fierce competition for discretionary government funding--much more needs to be done. Scientists must communicate with their constituents such that private industry, foundations, and philanthropists understand the importance of their roles in the research effort in this country.

This year is the first in the innovative research alliance with Novartis, and by all accounts, it has already been a remarkably productive collaboration. This alliance is a great match of institutions, with numerous examples of complementary scientific interests and a strong start to what we hope will be a long-term relationship. We are confident that our combined efforts will spark important discoveries and insights that will be transferred into useful medical therapeutics, with consequences for improved health and quality of life.

The monumental commitment of $100 million from the Skaggs family could not have come at a more momentous time in the history of the scientific community and The Scripps Research Institute. Scientists are in the midst of an explosion of scientific knowledge, with a concomitant pace of research discovery that is unparalleled. The synergy that has been created by TSRI scientists who hold dual appointments at the Skaggs Institute, as well as the exceptional investigators who have been recruited this year to join the Institute's ranks, promises to yield results that will have profound consequences for generations to come.

Indeed, this organization is extremely fortunate to have attracted researchers of the caliber of those who have recently joined us. Their expertise will add significantly to the depth and scope of the scientific activities here.

They are Paul Schimmel, Ph.D., former John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics, Massachusetts Institute of Technology; Jeffery W. Kelly, Ph.D., former Professor, Department of Chemistry, Texas A&M; James R. Williamson, Ph.D., former Associate Professor, Department of Chemistry, Massachusetts Institute of Technology; Martha J. Fedor, Ph.D., former Assistant Professor, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical Center; and Erik J. Sorensen, Ph.D., former National Science Foundation Postdoctoral Fellow, Memorial Sloan-Kettering Cancer Center.

A member of the National Academy of Sciences, Dr. Schimmel's major research activities have concentrated on the decoding of genetic information, with emphasis on the rules of the universal genetic code that are established through aminoacylation reactions catalyzed by aminoacyl tRNA synthetases. These synthetases are thought by many to be among the first enzymes to arise on this planet in the early stages of the evolution of life forms. Dr. Schimmel is the recipient of numerous prestigious awards, the author of many scientific papers and of a widely used three-volume textbook on biophysical chemistry. Having a longstanding interest in the applications of basic biomedical research to human health, he holds several patents and is a cofounder of four biotechnology companies.

Dr. Kelly, Lita Annenberg Hazen Professor of Chemistry, is an expert in the structure of amyloid peptides and the dynamics of their aggregation as they relate to amyloid diseases, including Alzheimer's. By engineering compounds that could bind selectively to the amyloid proteins and block other compounds from binding, Kelly and others hope to develop a compound that could stop the dense plaque formation found in the brains of patients with Alzheimer's disease.

The research interests of Dr. Williamson focus on determining RNA structure by using nuclear magnetic resonance spectroscopy. Additional research activities include nucleic acid chemistry, kinetics of RNA folding, RNA-protein interactions, and interaction of ribosomal proteins with rRNA.

Dr. Fedor works primarily in the area of structure and function of catalytic RNA. Her numerous honors include the Leukemia Society of America Postdoctoral Fellowship and the Bank of America Giannini Foundation Postdoctoral Fellowship.

Dr. Sorensen recently completed a postdoctoral fellowship at Memorial Sloan-Kettering Cancer Center, but he is not a stranger to TSRI. He completed his graduate studies at TSRI and the University of California, San Diego, in the laboratory of K.C. Nicolaou. His research interests include the development of strategies and methods for the synthesis of biologically active natural products and the design and chemical synthesis of mechanism-based inhibitors of enzymes.

The extraordinary generosity and vision of the Skaggs family have enabled this organization to welcome these outstanding researchers to the scientific community at TSRI. In an environment in which excellence is the norm, these scientists and others provide this organization with an opportunity to unlock a deeper understanding of life than has ever been possible.

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Senior Vice President's Overview

William H. Beers, Ph.D.

This past year at The Scripps Research Institute was punctuated by a steady stream of important scientific discoveries, the acquisition of additional land to plan for future expansion needs, the first full year of operation of The Skaggs Institute for Chemical Biology, and the recruitment of a group of exceptional new faculty to our ranks. The excitement and enthusiasm generated by this level of activity are palpable as TSRI continues to exceed expectations for excellence.

As Dr. Lerner discusses in his remarks, the extraordinary generosity of the Skaggs family has enabled us to create an important new institute, which has already made significant scientific contributions at the interface of chemistry and biology. Under Dr. Rebek's leadership and with the addition of Drs. Schimmel, Kelly, Williamson, Fedor, and Sorensen, the Skaggs Institute is forging new ground in areas as diverse as prebiotic chemistry, drug design, molecular modeling, catalysis, and molecular recognition. As it moves into year 2, new scientific targets--including the areas of novel biomaterials and human genomics--are being investigated with an eye toward developing long-term, broad-based programs of significance and merit.

We were fortunate, too, this year to receive a $5 million contribution from the estate of the late Buddy Taub, a Carlsbad businessman, to construct a basic research facility to house the world's most powerful nuclear magnetic resonance instrumentation. The 12,000-square-foot Buddy Taub Center for Molecular Structure and Design will be built at the Lita Annenberg Hazen Science Center. With the construction of the new facility and the installation of additional spectrometers, TSRI's nuclear magnetic resonance facilities will be the world's most extensive and best equipped biomolecular facility. In addition, a gift of $5 million from long-time TSRI supporters and benefactors Jean and Keith Kellogg will be used to maintain facilities and instrumentation at the leading edge.

In an attempt to plan for the future expansion of laboratory facilities, TSRI has purchased more than 12 acres of land contiguous to our existing campus on the east side of North Torrey Pines Road. It was one of the last remaining parcels of land zoned for biomedical research on Torrey Pines Mesa. Also, we have initiated a project to lease a 110,000-square-foot, developer-owned, built-to-suit research facility on 5.5 acres in the La Jolla Pines Technology Center, adjacent to this property. We anticipate the completion of construction in April 1999.

Scientifically, this past year was marked by a number of important and insightful discoveries. K.C. Nicolaou's group, for example, reported the first solid-phase synthesis of the promising anticancer agent epothilone A, the total synthesis of epothilone B, and the production of a small library of epothilones that could be screened for compounds of pharmaceutical interest. The epothilones have shown activity against breast and colon tumor cell lines in the in vitro antitumor screening program of the National Cancer Institute and appear to work well even within cells that are resistant to the antitumor drug Taxol.

Additionally, Dr. Nicolaou's laboratory performed the first total chemical synthesis of a number of new anticancer compounds first isolated from rare species of corals and related marine organisms. The scientists assembled the compounds by using a multistep strategy with simple chemical building blocks such as carvone, an oil readily available from caraway or dill seeds. Eleutherobin, one of the novel compounds, appears similar to Taxol in its mechanisms of preventing cells from dividing.

A group led by John Tainer and Elizabeth Getzoff, in collaboration with colleagues at the Cleveland Clinic, has solved the structure of the active site of the enzyme that regulates the activity of nitric oxide. Because nitric oxide is an unconventional biological signal whose activities range from blood pressure regulation to antimicrobial defense to nervous system information and memory, understanding the structure of the enzyme that regulates it is critical to designing drugs to turn it on and off. Scientists predict that nitric oxide inhibitors may be used to treat such diseases as high blood pressure, septic shock, stroke, cancer, and impotence. Given its role in neurotransmission, nitric oxide may also be useful in treating memory disorders and learning.

A portable, handheld biosensor capable of detecting a wide range of medically important chemical compounds has been created by a team of TSRI scientists led by Reza Ghadiri and colleagues at the University of California, San Diego. Potential uses range from the screening of chemicals for drugs to diagnosing illness at the bedside without having to send samples to the laboratory. The new device is able to detect many of the classic biological reactions that involve the recognition and binding of one molecule to another partner molecule.

George Koob and colleagues in the Department of Neuropharmacology and in Spain have discovered that long-term use of marijuana produces changes in the brain that are similar to those seen after long-term use of other major drugs of abuse such as cocaine, heroin, and alcohol. These changes may increase a user's vulnerability to addiction to other abusable drugs by "priming" the brain to be more easily changed by drugs in the future. The specific brain areas that were activated during cannabinoid withdrawal also are active during withdrawal from other drugs of abuse and play a key role in stress responses in general.

A discovery by a team of scientists led by Steve Kay and collaborators at Brandeis University challenges the belief that 24-hour rhythms, or biological clocks, are centrally controlled from the brain. Using the fruit fly as a genetic model system, the researchers sought to determine if individual body parts would respond to changes in the light-dark cycle without any help from the head. In each separate segment, so-called clock genes turned on and off in unison, according to rhythms set by environmental light manipulations. These findings demonstrate that time-keeping genes may be active in tissues all over the body and may be controlled locally in the flies, and possibly in mammals.

The number of honors, awards, and accolades received by numerous members of the scientific faculty this year is testimony to the members' high-quality work and productivity. Roger Beachy was elected to membership in the National Academy of Sciences, and he now shares this honor with 11 faculty members at the Institute. Francis Chisari received the Ernst Jung Prize in Medicine and the Distinguished Scientific Achievement Award of the American Liver Foundation and was named a fellow of the American Association for the Advancement of Science. Two other TSRI scientists, Thomas Edgington and Michael Buchmeier, were also named fellows of the American Association for the Advancement of Science.

Michael Oldstone was elected to membership in the Institute of Medicine, National Academy of Sciences. Also, he was awarded the 1997 J. Allyn Taylor International Prize in Medicine for outstanding contributions to the understanding of virus-host interactions. Julius Rebek received the James Norris Award in Physical Organic Chemistry, Dale Boger was named a recipient of the Katritzsky Award from the International Society of Heterocyclic Chemistry, and K.C. Nicolaou received the Linus Pauling Award.

ScienceWatch named K.C. Nicolaou and Barry Sharpless among the world's most-cited scientists in chemistry/materials science for 1994--1996. Lisa Gold received the 1997 Joseph Cochin Young Investigator Award from the College on Problems of Drug Dependence, in recognition of outstanding research in the field of drug abuse by an investigator under the age of 40, and Roberta Sanchez-Gottlieb was named a 1997 Pew Scholar in the Biomedical Sciences by the Pew Charitable Trust.

It was another superb year for science at TSRI, made possible by the collaborative efforts of our scientific and administrative support staffs. We fully expect our track record for innovative and prolific discovery to expand in the coming years.

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