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President's Introduction

Richard A. Lerner, M.D.

Each year, new events in the life of an organization enrich its substance and enhance its character. This year, The Scripps Research Institute's establishment of the Institute for Childhood and Neglected Diseases is just such an event. The purpose of the new institute is to apply the new molecular understanding of biology to address, reduce, and treat recalcitrant illnesses in 2 major categories: childhood diseases and neglected diseases that affect populations primarily in developing countries. This initiative will build on the strength that TSRI already has achieved at the nexus of biology and chemistry through the work of The Skaggs Institute for Chemical Biology.

The initial funding for the new institute has been contributed by businessman, San Diego Padres owner, and philanthropist, John Moores, and his wife Becky. They have graciously donated a rare collection of 26 exceptional automobiles, and proceeds from the sale of these vehicles will fund faculty, facilities, and programs. This extraordinary generosity will make it possible for TSRI to take the deluge of knowledge amassed by the Human Genome Project and uncover a deeper understanding of the mechanisms underlying human disease than has ever been possible. Scientists will systematically study not only the genes themselves but also the interactions between the genes. Over the long term, we expect that this approach will lead to medical achievements unimaginable with current technology. Further, our ability to integrate the activities of the new facility with the Skaggs Institute should enhance our efforts to alleviate human suffering through a multiplicity of scientific discoveries.

Scientists think that biology and medicine in the coming century will look very different from the way the disciplines do now. The human genome, the totality of genetic information inside the human body, is expected to be deciphered in the next 3 years. Scientists have been isolating individual genes for several years now, lately at an accelerating pace. The identity of these genes has yielded glimpses into the machinery of the body. But, looking at genes in the larger context of how they interact with each other and with their surroundings in the cell and the body has been difficult. Further, the regulatory mechanisms that have been discovered often are small parts of the larger, more complex cascades.

As the language of the genome becomes a common currency, the science of biology will flourish as never before. The Human Genome Project is nearing completion, and scientists are contemplating what to do with the information.

Scientists at TSRI are preparing to apply the burgeoning knowledge of genes and gene interactions to specific childhood and early-onset diseases. The creation of the Institute for Childhood and Neglected Diseases will bring together scientists from throughout the world to investigate such diseases as childhood cancers and leukemias, cystic fibrosis, Duchenne's muscular dystrophy, and autism. In addition, TSRI and Children's Hospital and Health Center, San Diego, have begun discussions on ways in which the 2 organizations can collaborate to improve the health of children locally and internationally.

The majority of the world's population--those who live in developing countries--have not yet reaped the benefits of the genetic revolution. But, some effective initiatives have been launched, and the new Institute for Childhood and Neglected Diseases will use the latest advances in biology in an effort to find novel treatments for widespread and often devastating parasitic diseases.

As they have begun to learn how human genes function, biologists also have begun to investigate the genes of parasites and other disease-causing organisms. These efforts promise to bring advances in fighting diseases still rampant in the developing world. The World Health Organization has named a handful of "target diseases" in its tropical disease research program. They include the parasitic diseases malaria, schistosomiasis, trypanosomiasis, and leishmaniasis that collectively endanger some 500 million people and kill nearly 2 million people each year. The Institute for Childhood and Neglected Diseases plans to build on the work of a number of TSRI scientists in such areas as schistosomiasis and malaria and will focus its efforts on understanding the mechanisms of action in major parasitic diseases.

The new institute will include state-of-the-art research laboratories in a facility to be constructed on TSRI's campus on the east side of North Torrey Pines Road. The project architects are Todd Williams and Billie Tsien, who designed The Neurosciences Institute.

These are, indeed, exciting times in science, and we at TSRI feel extremely fortunate to have the opportunity to use the vast outpouring of new knowledge in our particular areas of expertise. We fully expect the new Institute for Childhood and Neglected Diseases to yield extraordinary new discoveries in the years ahead.

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Senior Vice President's Overview

William H. Beers, Ph.D.

Scientific discoveries continued to flourish this year at The Scripps Research Institute while a number of construction projects proceeded on schedule in an effort to accommodate the aggressive rate of growth that we have come to expect as the norm at TSRI. In addition, we were fortunate to receive a number of major philanthropic contributions that have helped us to fund important new initiatives. Of course, we are most appreciative of John and Becky Moores' unique contribution of 26 rare, collectible automobiles to TSRI, providing the lead gift for development of the innovative Institute for Childhood and Neglected Diseases. Also, we are extremely grateful to Helen Dorris for her extraordinary generosity in establishing the Harold L. Dorris Neurological Research Center this year.

TSRI scientists contributed to the body of scientific literature this year with a number of significant research achievements. For example, Chi-Huey Wong and his colleagues designed small-molecule mimics of the tetrasaccharide sialyl Lewis X that are more active and easier to synthesize than the natural ligand. In fact, the compounds are the most potent sialyl Lewis X mimics known to date and are potential drug candidates for the treatment of reperfusion injury and other inflammatory disorders. Dr. Wong continues the work by studying the binding mechanisms of the designed mimics in the hope of achieving even greater potency.

David Cheresh's group not only has uncovered a mechanism to help explain angiogenesis activity but also developed a recombinant form of a protein fragment that blocks angiogenesis and tumor growth in an in vivo experimental model. This research may provide a potentially novel therapeutic approach for diseases associated with neovascularization, including cancer, diabetic retinopathy, macular degeneration, and arthritis. The enzyme fragment, known as PEX, may act as an on-off switch for the development of blood vessels or as a control mechanism that establishes appropriate blood vessel structure. Thus, the appearance of PEX at sites of neovascularization not only may control normal angiogenesis, but when administered in sufficient quantities, may provide a naturally occurring therapeutic inhibitor of diseases associated with angiogenesis.

Elizabeth Getzoff and John Tainer, together with scientists at the Cleveland Clinic, have determined the molecular structures of the complete active site of the enzyme responsible for generating nitric oxide. Knowledge of these structures advances understanding of how the essential intercellular signal and protective cytotoxin nitric oxide is produced and regulated. Additionally, this structural information will provide important information and enable rational drug design for the potential control of many processes in humans that depend on nitric oxide, including blood pressure regulation, digestion, muscular contraction, the immune response, learning, and memory.

James Hoch and his collaborators at the R.W. Johnson Pharmaceutical Research Institute have developed a series of new antibacterial compounds designed to target the biological mechanisms by which bacteria establish an infection in the host. With resistance to antibiotics an increasing public health threat, the compounds offer the potential to provide protection against Staphylococcus aureus, or staphylococcal infection, vancomycin-resistant enterococci, and penicillin-resistant Staphylococcus pneumoniae. The scientists are hopeful that these inhibitors targeting the signal transduction mechanisms will be useful new tools for treatment of infectious disease.

In a recently published article, Carlos F. Barbas III and his coworkers have added to the 4 letters that make up the simple chemical alphabet of deoxyribonucleic acid (DNA)--the molecule in which the genetic information of all higher forms of life is written. In so doing, Dr. Barbas and his colleagues are attempting to make DNA derivatives that can carry out various chemical processes in the laboratory at once, rather like natural enzymes. To produce more complex DNA enzymes, researchers must increase the number of available DNA components. But the new building blocks also must be suitable for duplication by the polymerase chain reaction, which is designed for naturally occurring genetic material. Dr. Barbas has solved this problem by modifying a natural section of DNA with a variety of short-chain molecules.

As part of our plan to increase TSRI's already prodigious capabilities in the area of nuclear magnetic resonance (NMR) spectroscopy, in August we completed construction of the new Buddy Taub Center for Molecular Structure and Design, a 10,000-square-foot facility located south of the Neurosciences Institute, and TSRI's third stand-alone facility for NMR instrumentation. The NMR facilities here are among the most sophisticated in the world, equipped with several 500- and 600-MHz instruments and one 750-MHz machine. The completion of the new facility allows the installation of 2 additional 600-MHz spectrometers and an 800-MHz instrument, as well as a 900-MHz instrument currently under development. When operational, this new machine will be the most advanced magnet in existence.

Because of the ongoing generosity of the Skaggs family, the Skaggs Scholars in Clinical Science received initial funding of $1 million to identify research-oriented clinicians and to fund collaborative research between clinical scholars and TSRI scientists. The new program is designed to integrate clinical and basic research, refocus basic research discoveries on human conditions, and nurture professional camaraderie between clinicians and basic researchers.

Individually and in the aggregate, TSRI scientists and graduate students this year garnered a number of highly prestigious awards and honors. The latest Science Watch survey, conducted by the Institute for Scientific Information, named TSRI faculty as earning the greatest overall number of citations for "high-impact" articles in chemistry published between 1994 and 1997. In addition to garnering the most total citations, scientists at TSRI accounted for the highest number of high-impact articles, publishing 22 during the 3-year period. K.C. Nicolaou topped the list of authors of high-impact articles, and K. Barry Sharpless and Chi-Huey Wong were in the top 15.

Chemical and Engineering News selected K. Barry Sharpless as one of history's Top 75 Distinguished Contributors to chemical enterprise. In addition, he received the prestigious Harvey Prize from the Technion-Israel Institute of Technology for his outstanding contributions to chemistry.

The research group led by Ian Wilson received the 1996-1997 Newcomb Cleveland Prize of the American Association for the Advancement of Science, awarded to authors of an outstanding article published in Science that includes research data, theories, or syntheses and that makes fundamental contributions to basic knowledge or technical achievements of far-reaching consequences. Jonathan Sprent was elected a fellow of the Royal Society of London. Don Mosier and Peter Wright were named fellows of the American Association for the Advancement of Science. Mark Yeager was among 10 U.S. and Canadian researchers to receive a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund. The awards are intended to foster the productivity of outstanding physician-scientists whose work strengthens the transfer of basic research to patient care.

The following scientists received 1999 national awards administered by the American Chemical Society: Dale Boger, Award for Creative Work in Synthetic Organic Chemistry; M. Reza Ghadiri and Kim Janda, the Arthur C. Cope Scholar Awards; and Chi-Huey Wong, the Claude S. Hudson Award in Carbohydrate Chemistry.

Francis Chisari was honored by the American Liver Foundation for distinguished scientific achievement, Michael Oldstone published Viruses, Plagues and History and received favorable reviews from the New York Times Book Review and The Nation, and Floyd Bloom received an honorary degree from Washington University.

We continue to take great pride in the accomplishments of the scientific staff and the extraordinary abilities of the technical, administrative, and support staffs. After more than a decade at TSRI, while I have come to expect a superior level of achievement, I am humbled by the level of dedication and commitment on the part of the entire TSRI community.

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