The Scripps Research Institute

Series: Molecular Medicine Institutions

William H. Beers, Ph.D., Senior Vice President

The Scripps Research Institute (TSRI), the coun- In 1977 the multiple research programs that try's largest private, non-profit research organi- had developed were formally drawn together zation, has always stood at the forefront of basic into the Research Institute of Scripps Clinic and biomedical science. Headed by President Richard by the mid- 1980s laboratory space had grown to A. Lerner, M.D., in just three decades the Insti- some 300,000 square feet. Major programs in cell tute has become internationally recognized for and molecular biology, synthetic and bioorganic its work in immunology, molecular and cellular chemistry, and the neurosciences had developed, biology, chemistry, neurosciences, autoimmune in addition to efforts in immunology and clini- diseases, cardiovascular diseases and synthetic cally oriented investigations. vaccine development. Particularly significant is As the faculty roster has grown, so naturally the study of the basic structure and design of have the focus and number of areas of research. biological molecules; in this arena TSRI is among Today, TSRI scientists are actively investigating a handful of the world's leading centers. biological and chemical aspects of more than 40 diseases, including AIDS, alcoholism, allergy, Alzheimer's disease, cancer, cardiovascular dis- HISTORY ease, dementia, depression, diabetes, genetic dis- While its roots go back to the founding of the eases, hepatitis, infectious diseases, multiple scle- Scripps Metabolic Clinic in 1924 by philanthropist rosis, renal disease, scleroderma, Sjogren's Ellen Browning Scripps, TSRI's modem beginnings syndrome, sleep disorders, and diseases involv- date to the 1955 establishment of Scripps Clinic ing neural and muscular degeneration. Among and Research Foundation, when a major portion of other areas of research that cross specific disease the Clinic's limited reserves were committed to the lines are those that involve numerous investiga- construction of a new research facility and to the tions into the structure and function of proteins; recruitment of exceptional biomedical scientists. biocatalysis and protein design; the factors, pro- In 1961, the institution recruited pioneering cesses, and regulation of inflammation; bioor- immunologist Frank Dixon and four of his col- ganic chemistry and molecular design; natural leagues from the University of Pittsburgh, re- product synthesis; prebiotic chemistry; and the searchers who were then contributing insightful form and function of animal and plant cells. observations on the causes and progression of In 1991, when Scripps Clinic and Research autoimmune disease, to establish a Department Foundation and Scripps Memorial Hospitals reaf- of Experimental Pathology in La Jolla. Their filiated, the Institute became a separate corporation work attracted others and the research program under the parent organization, Scripps Institutions flourished and diversified into biochemistry, mi- of Medicine and Science. With that change its crobiology, virology, studies of blood coagula- name became The Scripps Research Institute. tion, and cancer research. From the outset, the guiding philosophy of the research focused on PHILOSOPHY clinical and basic investigations of the pathogen- TSRI's philosophy emphasizes the compilation of esis of human disease. basic knowledge in the biosciences for the appli- cation of medical discoveries; the pursuit of fun- Address correspondence and reprint requests to: Robin B. damental scientific advances through interdiscipli- Goldsmith, The Scripps Research Institute, 10550 North nary programs and collaborations; and the Torrey Pines Road, La Jolla, CA 92037, U.S.A. Tel: 619- 784-8134; Fax: 619-784-8118; E-mail: education and training of researchers preparing to [email protected] meet the scientific challenges of the next century.

FIG. 1. The Scripps Research Institute

The bulk of the Institute's funding is from * Demonstrated that rheumatoid factor is a the National Institutes of Health and other Fed- product of an antibody gene that has main- eral agencies. In addition, collaborative industrial tained its 'germlike" arrangement, explain- partnerships with leading pharmaceutical com- ing why so many rheumatoid factors are so panies provide additional funding in several ar- similar. eas key to the organization's research objectives. * Developed a new and efficient method to Private philanthropy also continues to be an im- produce monoclonal antibodies. portant source of funding for the Institute. * Determined the complete, three-dimensional, Currently housed in multiple laboratory atomic structure of the poliovirus. buildings with more than 700,000 square feet of * Pioneered the concept that small, synthetic space overlooking the Pacific, the Institute's staff peptides could replace larger peptide chains includes more than 230 principal scientific inves- of bacteria and viruses for the purpose of tigators, 600 postdoctoral fellows and more than making vaccines. 1,500 laboratory, administrative, and support * Cloned the gene for the enzyme that is defi- services personnel. In addition, more than 100 cient in people with Gaucher's disease and de- students enrolled in TSRI's graduate program are veloped a method to predict the severity of the working toward their doctoral degrees. disease. Rather than isolating faculty members and * Purified the antihemophilic Factor VIII, a co- laboratories into separate and distinct disciplines, agulation protein lacking in people with he- the generally prescribed university model, the mophilia A. Monoclate, the purified concen- cooperative, collaborative spirit is encouraged trate of Factor VIII, enables hemophiliacs to and embraced. Technicians, postdoctoral fellows, receive blood plasma that is free of contami- and administrative support staff all are given the nation with viruses from blood donors. latitude and responsibility to accomplish their * Synthesized surfactant, a lung material that tasks so as to serve the best interests of science. keeps air sacs open and prevents respiratory distress syndrome. * Pioneered the development of catalytic anti- MAJOR SCIENTIFIC bodies, opening new possibilities for protein synthesis and the rational design of new ACHIEVEMENTS drugs. * Developed and successfully tested the anti- * Mapped the prohormone for somatostatin in leukemia drug 2-Chlorodeoxyadenosine (2- the brain and associated it with the primary CdA, trade name: Leustatin). neuropathic signs of Alzheimer's disease. W. H. Beers: Molecular Medicine Institutions 795

* Discovered a cell receptor for allergy-induc- field. An initiative in RNA chemistry and biology ing IgE antibodies on lymphocytes, a finding is emerging; the intent is to develop structural that redirected research on the control of and functional understanding of these key mol- allergic diseases. ecules of life that can ultimately lead to new * Designed and synthesized a new class of therapeutic agents. In addition, cohesive efforts molecules, known as enediynes, that repre- in drug design bring the Institute's structural and sent some of the most potent anti-cancer computational facilities for proteins and nucleic agents ever tested and demonstrate unusual acids together with the expertise in organic syn- selectivity in their ability to destroy cancer thesis and combinatorial chemistry. cells while leaving healthy cells intact. Opportunities in newly emerging fields that * Solved the three-dimensional structure of blend chemistry with biology currently are being the enzyme superoxide dismutase (SOD), explored. These include biomaterial science, as thereby establishing a direct link between well as the opportunities created by the sequenc- mutations in the gene for SOD that lead to ing of the human genome with the enormous an unstable, less active enzyme and can array of small molecules being made through cause amyotrophic lateral sclerosis (Lou Geh- combinatorial chemistry. These disciplines will rig's disease). meet at the appropriate therapeutic target-the * Completed the total chemical synthesis of proteins, receptors, or nucleic acids associated the anti-cancer drug, Taxol, approved by the with a particular disease. Food and Drug Administration for the treatment of ovarian cancer. * Developed novel approach to inducing tumor regression by turning off neovascularization Cell Biology of the tumor, thereby setting the stage for the development of a new type of angiogen- Because of the importance of cell biology in elu- esis inhibitor. cidating the basic mechanisms of health and dis- * Determined the three-dimensional structure ease, the Department of Cell Biology (Norton B. of the T-cell receptor, as well as its orienta- Gilula, Ph.D., Chairman) was established as an tion bound to a major histocompatibility extension of TSRI's unique strength in integrat- complex (MHC) molecule. ing cell and molecular biology with molecular structure and chemical determinations. The department's efforts are focused in a number of SCIENTIFIC DEPARTMENTS areas related to the broad range of cellular functions and processes, including cell-cell commu- The Skaggs Institute for Chemical Biology nications; membrane receptor binding and sig- The Skaggs Institute for Chemical Biology (Julius naling; the initiation and regulation of the cell Rebek, Jr., Ph.D., Director) recently has com- cycle and mitosis; receptor-mediated endocyto- pleted its first full year of operation. Established sis; intracellular trafficking; the structure and by an extraordinary commitment from Aline and function of the nuclear envelope; genetics and L.S. Skaggs, the Institute consists of more than genome analysis; the structure and function of 25 principal investigators with dual appoint- the cytoskeleton; extracellular matrix-cell sur- ments in five departments, including Chemistry, face interactions; and growth factor regulatory Molecular Biology, Cell Biology, Neurobiology mechanisms. and Molecular and Experimental Medicine. The Scientists in the Division of Plant Biology researchers have broad expertise in the structure within the department are utilizing the molecu- of biological macromolecules, chemical and an- lar biological techniques that have been devel- tibody catalysis, synthetic and combinatorial oped in studies of animal systems and applying chemistry, molecular recognition, and molecular them to the biology of plants. Studies in progress modeling methods. range from basic investigations, such as the ge- A hallmark of the new Institute is the syn- netic control of photosynthesis and the structure ergy that is encouraged between research and function of plant cell membranes and trans- groups. Four groups now work in molecular evo- port mechanisms, to more applied research in- lution, in areas that relate to the origins of life. cluding the use of plants to produce abundant The depth of this effort has made The Skaggs quantities of antibodies and other mammalian Institute the leading edge for research in the proteins, and viral pathogenesis. 796 Molecular Medicine, Volume 3, Number 12, December 1997

Chemistry including virus-induced immunodeficiencies, The mission of the Department of Chemistry and the role of the cells of the vascular and (K.C. Nicolaou, Ph.D., Chairman) is threefold: to inflammatory systems in human disease. Basic generate basic knowledge in the chemical and studies of the immune system include the genet- biological sciences on which applications to med- ics of the antibody response; T-cell immunity, icine, new materials and related areas may be including antigen presentation, thymic selection, founded; to connect fundamental discoveries and receptor signaling; tolerance induction and through interdisciplinary programs and collabo- autoimmunity; and the stimulation, control, and rations to biomedical and related applications; biochemistry of inflammation. and to educate and train scientists in the chem- Techniques that have been developed to iso- ical and biological sciences. late and screen virtually the entire antibody rep- The department offers a broad scope of ac- ertoire of humans or other mammals are being tivities that blends sophisticated synthetic chem- used to produce and recover scientifically and istry, molecular design and biocatalysis, and therapeutically useful antibodies that have po- bioorganic chemistry. Organic synthesis is pur- tential against viruses and the mechanisms of sued as an advancing science. Both discovery and autoimmune disease. Research in vascular biol- invention of new reactions and target-oriented ogy and inflammation has led to a new under- total synthesis are investigated. In the area of new standing of the role of adhesion proteins in reg- synthetic technology, research focuses on asym- ulating tumor cell growth, the vascularization of metric catalysis, new catalyst design, bond-forming tissues in diseases such as cancer, and the mo- reactions and novel ring constructions. In total syn- lecular mechanisms of blood coagulation. thesis, complex biologically active natural products and other challenging molecules are targeted for Molecular Biology synthesis. The power of synthetic organic chemistry The Department of Molecular Biology (Peter combined with chemical principles is utilized in Wright, Ph.D., Chairman) takes an interdiscipli- molecular design, chemical synthesis and biolog- nary approach to the study of the structure and ical investigations of molecules with specific bi- function underlying normal and abnormal cellular ological actions such as enzyme inhibitors, nu- processes. TSRI researchers are making contribu- cleic acid-cleaving molecules, and anti-tumor tions in the field through collaborative studies in- agents, as well as powerful chemical catalysts. volving molecular genetics, molecular biology, pro- Biological concepts and tools are used to design tein engineering, and structural biology. and produce large molecules such as enzymes TSRI is one of the world's largest centers for and catalytic antibodies, and exploit their value structural biology and has achieved a number of in mechanistic and molecular recognition stud- scientific "firsts" in this area, including the first ies. Another primary area of focus is the under- three-dimensional structure determination for a standing, improvement, and mimicking of en- protein involved in cell-cycle regulation, the zymes. These efforts combine chemistry with the structure of the poliovirus, the structure of the cutting edge tools of molecular biology, genetics, T-cell receptor, and the structure for SOD. and immunology. Another major effort is in the area of computational molecular biology. Advances include improved methods and new computational ap- proaches that are of fundamental importance for Immunology structure-based drug design. Further advances, Beginning in the 1960s, research in the Depart- using theoretical and experimental methods, ment of Immunology (Richard Ulevitch, Ph.D., have been made in the prediction of protein- Chairman) was focused primarily on the under- folding pathways. lying biology of autoimmune and immunologic In the area of molecular engineering, impor- diseases. These initial studies developed a con- tant progress is being made on several fronts. ceptual framework to explain how normal but New technology has been developed for the syn- inappropriate immune reactions can give rise to thesis of artificial antibodies. Through a test-tube both local and systemic diseases. evolution process developed at TSRI, new ri- During the past decade, the department has bozymes and antibodies with unique binding broadened its research base to include studies of and catalytic activities have been created. the molecular basis of the immune response, One of the department's main goals is to un- W. H. Beers: Molecular Medicine Institutions 797 derstand biological signaling events at the molecu- development that centers on the cell and the gene lar level. A detailed understanding of the processes as fundamental units of development. at the molecular level that result in large changes in Researchers here are addressing this problem biological systems is key to the design of novel by focusing on the brain in the earliest stages of agents that can be used to control disease. development. The role of specific adhesion molecules in regulating cell-cell interactions is being examined in an effort to link knowledge on ge- Molecular and Experimental Medicine netic information to events that direct cell division, movement, and eventual death. The majority of studies in this department These efforts suggest a link between cell ad- (Ernest Beutler, M.D., Chairman) seek to under- hesion molecules (CAMs) that control cell-cell stand the life processes that, when disturbed, binding, and substrate adhesion molecules lead to disease. Thus, the research conducted is and wide-ranging and involves several related fields (SAMs) that affect cell migration transfor- of study, including blood coagulation, the biology mations of cell states. For normal development of and to occur, the expression of CAMs and SAMs is platelets, hemodynamics bleeding disorders, co-regulated by precise genetic signaling. TSRI and the role of thrombosis in cardiovascular and researchers have extended the scope of this work The also in- cerebrovascular diseases. department and identified a promoter and transcription en- cludes a clinical research component in the areas of hancer for the gene encoding L-CAM. It was the biochemistry of anti-cancer drugs, diabetes, and inflammation. then shown that the enhancer region contained A pointed example of the clinical benefits sequences that were regulated by homeobox genes-DNA sequences that play an important that have resulted from work performed in the role in embryonic development. department is the development of Leustatin, an effective anti-leukemia in most Members of the department also study the- agent and, cases, ories of how in a that a cure for cell leuke- the brain functions perception, drug provides hairy work of relevance in understanding memory mia. The drug was originally conceived as an loss, dyslexia, recovery from stroke, and learning agent that could provide a laboratory model for a disabilities. type of immunodeficiency. As the work pro- gressed it became apparent that it might have anti-cancer qualities. Animal studies were un- Neuropharmacology dertaken and subsequently, human trials were in initiated at Scripps. A one-week course of treat- Research this department (Floyd E. Bloom, is ment results in a cure for more than 80 M.D., Chairman) focused on gaining a better percent understanding of infectious, environmental and of patients with none of the side effects associ- inherited ated with anti-cancer Further studies diseases of the brain, and developing drugs. by molecules that can act to reverse the disease Ernest Beutler, M.D. indicate that the drug may or be effective a number of immune disor- process stimulate normal repair mechanisms. against In an effort to understand the mechanisms that ders, including multiple sclerosis. lead to disorders of the brain, investigators have focused their efforts on a select number of problems, including drug and alcohol addiction, Alz- Neurobiology heimer's disease, multiple sclerosis, and AIDS The major scientific focus of the Department of dementia. Neurobiology (Gerald M. Edelman, M.D., Ph.D., Underlying these highly specific studies of Chairman) is on vertebrate development, in par- various forms of brain and behavioral dysfunc- ticular, the development of the nervous system. tion are interactive research efforts into cell-sig- An emphasis is placed on how the brain develops naling molecules and the parallel endeavor into the its "wiring" and function to guide motion, per- nature of neuronal-immune system interactions. ception, and sensation. Another primary area of research involves the bi- The fundamental question of development ology of the largely overlooked supportive, im- asks how the one-dimensional genetic code speci- mune, and inflammatory cells in the brain. The fies the cellular events that result in a three-dimen- decision to reach beyond neuron-to-neuron events sional animal of a given species. The availability of is another factor that sets the department's re- modem cellular and molecular biology tools in research efforts apart from other groups. cent decades has given rise to a view of embryonic These efforts are focused in two directions. 798 Molecular Medicine, Volume 3, Number 12, December 1997

The first is to determine the way in which viruses ifornia-licensed clinical laboratory that develops, find and target cells in the nervous system, dis- markets and performs numerous unique, high turbing function, and often leading to cell death. technology, medical diagnostic tests. SRI applies The second area seeks to understand the ways in advanced technology from TSRI to the develop- which glial and immune cells in the brain can ment of clinical diagnostic tests-principally in cause disease. the areas of immunology, coagulation/thrombo- Vascular Biology sis, and molecular pathology-that are utilized by physicians from around the world to detect The goals of the Department of Vascular Biology some of the serious and often rare disorders of (David J. Loskutoff, Ph.D., Chairman) are to de- their patients. It serves as a reference laboratory fine the basic molecular and cellular mechanisms for SmithKline-Beecham Clinical Laboratories in that guarantee the proper expression, function, the United States and for Special Reference Lab- and interaction of proteins and cells of the vas- oratory, Inc., in culature. The Japan. department brings together a co- The division of research and development hesive group of investigators with interests in cell at adhesion mechanisms, thrombosis, hemostasis, SRI is responsible for converting basic research thrombolysis, and other areas of vascular biology discoveries into clinically useful and applicable and medicine. Dominant research themes in- assays with full validation that includes technical clude structure, function, and regulation of the optimization, quality control, standardization, proteins of the coagulation and fibrinolytic sys- clinical relevance, and the capacity to expand tem, as well as the surface receptors on platelets assays to batch sizes that are economically feasi- and endothelial cells. ble. Each year the laboratory continues to de- Emphasis is placed on the development of a velop new assays with applications to clinical greater understanding of the molecular and cel- trials and diagnostics and remains at the fore- lular basis for the formation and dissolution of front of modern diagnostic laboratories. fibrin, the main constituent of blood cells. Stud- ies by TSRI investigators into these areas already have begun to provide insights into the diseases of the vasculature, including arteriosclerosis, EDUCATION thrombosis, stroke, hypertension, and bleeding Education has always been an integral compo- disorders. nent of TSRI's mission. Over the years the Insti- General Clinical Research Center tute's researchers have prepared thousands of postdoctoral fellows and trainees for successful The William H. Black General Clinical Research scientific careers. Because most of the important Center (Francis V. Chisari, M.D., Director) pro- problems in biology and chemistry today re- vides facilities, staff and instrumentation for the quire an performance of interdisciplinary approach to their so- investigator-initiated, peer-re- lutions, in 1989 TSRI viewed research with human subjects. The Cen- established a unique graduate program to ter further provides an environment that pro- help integrate the disci- motes investigative collaborations between plines of cell and molecular biology, structure research scientists and clinicians at Scripps Clinic and chemistry. to facilitate the transfer of basic scientific knowl- The Graduate Program in Macromolecular edge to the clinical arena and evaluation meth- and Cellular Structure and Chemistry is an inno- ods of patient treatment. vative program unlike any other in the United Established in 1974 with a gift from the States. A second doctoral program in chemistry Black Family and financed by a $12 million grant was established in 1981 in an effort to draw upon from the NIH, it is the only one of the 75 simi- the superior capabilities of the TSRI chemistry larly funded centers in the United States not faculty. The program's interactive nature empha- affiliated with a university or medical school. sizes the collaboration of organic and bioorganic chemistry and biology, as well as the connection of fundamental discoveries through interdiscipli- Scripps Reference Laboratory nary activities. These five-year programs provide The Scripps Reference Laboratory (SRI) (David J. an exceptional training opportunity for a select Bylund, M.D., Director) is a fully accredited, Cal- group of intellectually diverse students.