Series: Molecular Medicine Institutions

The Scripps Research Institute

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

The Scripps Research Institute (TSRI), the coun-try's largest private, non-profit research organi-zation, has always stood at the forefront of basicbiomedical science. Headed by President RichardA. Lerner, M.D., in just three decades the Insti-tute has become internationally recognized forits work in immunology, molecular and cellularbiology, chemistry, neurosciences, autoimmunediseases, cardiovascular diseases and syntheticvaccine development. Particularly significant isthe study of the basic structure and design ofbiological molecules; in this arena TSRI is amonga handful of the world's leading centers.

HISTORYWhile its roots go back to the founding of theScripps Metabolic Clinic in 1924 by philanthropistEllen Browning Scripps, TSRI's modem beginningsdate to the 1955 establishment of Scripps Clinicand Research Foundation, when a major portion ofthe Clinic's limited reserves were committed to theconstruction of a new research facility and to therecruitment of exceptional biomedical scientists.

In 1961, the institution recruited pioneeringimmunologist Frank Dixon and four of his col-leagues from the University of Pittsburgh, re-searchers who were then contributing insightfulobservations on the causes and progression ofautoimmune disease, to establish a Departmentof Experimental Pathology in La Jolla. Theirwork attracted others and the research programflourished and diversified into biochemistry, mi-crobiology, virology, studies of blood coagula-tion, and cancer research. From the outset, theguiding philosophy of the research focused onclinical and basic investigations of the pathogen-esis of human disease.

Address correspondence and reprint requests to: Robin B.Goldsmith, The Scripps Research Institute, 10550 NorthTorrey Pines Road, La Jolla, CA 92037, U.S.A. Tel: 619-784-8134; Fax: 619-784-8118; E-mail:rgoldsmi@scripps.edu

1997, THE PICOWER INSTITUTE PRESS. All rights reserved.Molecular Medicine, Volume 3, Number 12, December 1997 793-798

In 1977 the multiple research programs thathad developed were formally drawn togetherinto the Research Institute of Scripps Clinic andby the mid- 1980s laboratory space had grown tosome 300,000 square feet. Major programs in celland molecular biology, synthetic and bioorganicchemistry, and the neurosciences had developed,in addition to efforts in immunology and clini-cally oriented investigations.

As the faculty roster has grown, so naturallyhave the focus and number of areas of research.Today, TSRI scientists are actively investigatingbiological and chemical aspects of more than 40diseases, including AIDS, alcoholism, allergy,Alzheimer's disease, cancer, cardiovascular dis-ease, dementia, depression, diabetes, genetic dis-eases, hepatitis, infectious diseases, multiple scle-rosis, renal disease, scleroderma, Sjogren'ssyndrome, sleep disorders, and diseases involv-ing neural and muscular degeneration. Amongother areas of research that cross specific diseaselines are those that involve numerous investiga-tions into the structure and function of proteins;biocatalysis and protein design; the factors, pro-cesses, and regulation of inflammation; bioor-ganic chemistry and molecular design; naturalproduct synthesis; prebiotic chemistry; and theform and function of animal and plant cells.

In 1991, when Scripps Clinic and ResearchFoundation and Scripps Memorial Hospitals reaf-filiated, the Institute became a separate corporationunder the parent organization, Scripps Institutionsof Medicine and Science. With that change itsname became The Scripps Research Institute.

PHILOSOPHYTSRI's philosophy emphasizes the compilation ofbasic knowledge in the biosciences for the appli-cation of medical discoveries; the pursuit of fun-damental scientific advances through interdiscipli-nary programs and collaborations; and theeducation and training of researchers preparing tomeet the scientific challenges of the next century.

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FIG. 1. The Scripps Research Institute

The bulk of the Institute's funding is fromthe National Institutes of Health and other Fed-eral agencies. In addition, collaborative industrialpartnerships with leading pharmaceutical com-panies provide additional funding in several ar-eas key to the organization's research objectives.Private philanthropy also continues to be an im-portant source of funding for the Institute.

Currently housed in multiple laboratorybuildings with more than 700,000 square feet ofspace overlooking the Pacific, the Institute's staffincludes more than 230 principal scientific inves-tigators, 600 postdoctoral fellows and more than1,500 laboratory, administrative, and supportservices personnel. In addition, more than 100students enrolled in TSRI's graduate program areworking toward their doctoral degrees.

Rather than isolating faculty members andlaboratories into separate and distinct disciplines,the generally prescribed university model, thecooperative, collaborative spirit is encouragedand embraced. Technicians, postdoctoral fellows,and administrative support staff all are given thelatitude and responsibility to accomplish theirtasks so as to serve the best interests of science.

MAJOR SCIENTIFICACHIEVEMENTS* Developed and successfully tested the anti-

leukemia drug 2-Chlorodeoxyadenosine (2-CdA, trade name: Leustatin).

* Demonstrated that rheumatoid factor is aproduct of an antibody gene that has main-tained its 'germlike" arrangement, explain-ing why so many rheumatoid factors are sosimilar.

* Developed a new and efficient method toproduce monoclonal antibodies.

* Determined the complete, three-dimensional,atomic structure of the poliovirus.

* Pioneered the concept that small, syntheticpeptides could replace larger peptide chainsof bacteria and viruses for the purpose ofmaking vaccines.

* Cloned the gene for the enzyme that is defi-cient in people with Gaucher's disease and de-veloped a method to predict the severity of thedisease.

* Purified the antihemophilic Factor VIII, a co-agulation protein lacking in people with he-mophilia A. Monoclate, the purified concen-trate of Factor VIII, enables hemophiliacs toreceive blood plasma that is free of contami-nation with viruses from blood donors.

* Synthesized surfactant, a lung material thatkeeps air sacs open and prevents respiratorydistress syndrome.

* Pioneered the development of catalytic anti-bodies, opening new possibilities for proteinsynthesis and the rational design of newdrugs.

* Mapped the prohormone for somatostatin inthe brain and associated it with the primaryneuropathic signs of Alzheimer's disease.

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* Discovered a cell receptor for allergy-induc-ing IgE antibodies on lymphocytes, a findingthat redirected research on the control ofallergic diseases.

* Designed and synthesized a new class ofmolecules, known as enediynes, that repre-sent some of the most potent anti-canceragents ever tested and demonstrate unusualselectivity in their ability to destroy cancercells while leaving healthy cells intact.

* Solved the three-dimensional structure ofthe enzyme superoxide dismutase (SOD),thereby establishing a direct link betweenmutations in the gene for SOD that lead toan unstable, less active enzyme and cancause amyotrophic lateral sclerosis (Lou Geh-rig's disease).

* Completed the total chemical synthesis ofthe anti-cancer drug, Taxol, approved by theFood and Drug Administration for the treat-ment of ovarian cancer.

* Developed novel approach to inducing tumorregression by turning off neovascularizationof the tumor, thereby setting the stage forthe development of a new type of angiogen-esis inhibitor.

* Determined the three-dimensional structureof the T-cell receptor, as well as its orienta-tion bound to a major histocompatibilitycomplex (MHC) molecule.

SCIENTIFIC DEPARTMENTSThe Skaggs Institute for Chemical BiologyThe Skaggs Institute for Chemical Biology (JuliusRebek, Jr., Ph.D., Director) recently has com-pleted its first full year of operation. Establishedby an extraordinary commitment from Aline andL.S. Skaggs, the Institute consists of more than25 principal investigators with dual appoint-ments in five departments, including Chemistry,Molecular Biology, Cell Biology, Neurobiologyand Molecular and Experimental Medicine. Theresearchers have broad expertise in the structureof biological macromolecules, chemical and an-tibody catalysis, synthetic and combinatorialchemistry, molecular recognition, and molecularmodeling methods.

A hallmark of the new Institute is the syn-ergy that is encouraged between researchgroups. Four groups now work in molecular evo-lution, in areas that relate to the origins of life.The depth of this effort has made The SkaggsInstitute the leading edge for research in the

field. An initiative in RNA chemistry and biologyis emerging; the intent is to develop structuraland functional understanding of these key mol-ecules of life that can ultimately lead to newtherapeutic agents. In addition, cohesive effortsin drug design bring the Institute's structural andcomputational facilities for proteins and nucleicacids together with the expertise in organic syn-thesis and combinatorial chemistry.

Opportunities in newly emerging fields thatblend chemistry with biology currently are beingexplored. These include biomaterial science, aswell as the opportunities created by the sequenc-ing of the human genome with the enormousarray of small molecules being made throughcombinatorial chemistry. These disciplines willmeet at the appropriate therapeutic target-theproteins, receptors, or nucleic acids associatedwith a particular disease.

Cell BiologyBecause of the importance of cell biology in elu-cidating the basic mechanisms of health and dis-ease, the Department of Cell Biology (Norton B.Gilula, Ph.D., Chairman) was established as anextension of TSRI's unique strength in integrat-ing cell and molecular biology with molecularstructure and chemical determinations. The de-partment's efforts are focused in a number ofareas related to the broad range of cellular func-tions and processes, including cell-cell commu-nications; membrane receptor binding and sig-naling; the initiation and regulation of the cellcycle and mitosis; receptor-mediated endocyto-sis; intracellular trafficking; the structure andfunction of the nuclear envelope; genetics andgenome analysis; the structure and function ofthe cytoskeleton; extracellular matrix-cell sur-face interactions; and growth factor regulatorymechanisms.

Scientists in the Division of Plant Biologywithin the department are utilizing the molecu-lar biological techniques that have been devel-oped in studies of animal systems and applyingthem to the biology of plants. Studies in progressrange from basic investigations, such as the ge-netic control of photosynthesis and the structureand function of plant cell membranes and trans-port mechanisms, to more applied research in-cluding the use of plants to produce abundantquantities of antibodies and other mammalianproteins, and viral pathogenesis.

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ChemistryThe mission of the Department of Chemistry(K.C. Nicolaou, Ph.D., Chairman) is threefold: togenerate basic knowledge in the chemical andbiological sciences on which applications to med-icine, new materials and related areas may befounded; to connect fundamental discoveriesthrough interdisciplinary programs and collabo-rations to biomedical and related applications;and to educate and train scientists in the chem-ical and biological sciences.

The department offers a broad scope of ac-tivities that blends sophisticated synthetic chem-istry, molecular design and biocatalysis, andbioorganic chemistry. Organic synthesis is pur-sued as an advancing science. Both discovery andinvention of new reactions and target-orientedtotal synthesis are investigated. In the area of newsynthetic technology, research focuses on asym-metric catalysis, new catalyst design, bond-formingreactions and novel ring constructions. In total syn-thesis, complex biologically active natural productsand other challenging molecules are targeted forsynthesis.

The power of synthetic organic chemistrycombined with chemical principles is utilized inmolecular design, chemical synthesis and biolog-ical investigations of molecules with specific bi-ological actions such as enzyme inhibitors, nu-cleic acid-cleaving molecules, and anti-tumoragents, as well as powerful chemical catalysts.Biological concepts and tools are used to designand produce large molecules such as enzymesand catalytic antibodies, and exploit their valuein mechanistic and molecular recognition stud-ies. Another primary area of focus is the under-standing, improvement, and mimicking of en-zymes. These efforts combine chemistry with thecutting edge tools of molecular biology, genetics,and immunology.

ImmunologyBeginning in the 1960s, research in the Depart-ment of Immunology (Richard Ulevitch, Ph.D.,Chairman) was focused primarily on the under-lying biology of autoimmune and immunologicdiseases. These initial studies developed a con-ceptual framework to explain how normal butinappropriate immune reactions can give rise toboth local and systemic diseases.

During the past decade, the department hasbroadened its research base to include studies ofthe molecular basis of the immune response,

including virus-induced immunodeficiencies,and the role of the cells of the vascular andinflammatory systems in human disease. Basicstudies of the immune system include the genet-ics of the antibody response; T-cell immunity,including antigen presentation, thymic selection,and receptor signaling; tolerance induction andautoimmunity; and the stimulation, control, andbiochemistry of inflammation.

Techniques that have been developed to iso-late and screen virtually the entire antibody rep-ertoire of humans or other mammals are beingused to produce and recover scientifically andtherapeutically useful antibodies that have po-tential against viruses and the mechanisms ofautoimmune disease. Research in vascular biol-ogy and inflammation has led to a new under-standing of the role of adhesion proteins in reg-ulating tumor cell growth, the vascularization oftissues in diseases such as cancer, and the mo-lecular mechanisms of blood coagulation.

Molecular BiologyThe Department of Molecular Biology (PeterWright, Ph.D., Chairman) takes an interdiscipli-nary approach to the study of the structure andfunction underlying normal and abnormal cellularprocesses. TSRI researchers are making contribu-tions in the field through collaborative studies in-volving molecular genetics, molecular biology, pro-tein engineering, and structural biology.

TSRI is one of the world's largest centers forstructural biology and has achieved a number ofscientific "firsts" in this area, including the firstthree-dimensional structure determination for aprotein involved in cell-cycle regulation, thestructure of the poliovirus, the structure of theT-cell receptor, and the structure for SOD.

Another major effort is in the area of com-putational molecular biology. Advances includeimproved methods and new computational ap-proaches that are of fundamental importance forstructure-based drug design. Further advances,using theoretical and experimental methods,have been made in the prediction of protein-folding pathways.

In the area of molecular engineering, impor-tant progress is being made on several fronts.New technology has been developed for the syn-thesis of artificial antibodies. Through a test-tubeevolution process developed at TSRI, new ri-bozymes and antibodies with unique bindingand catalytic activities have been created.

One of the department's main goals is to un-

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derstand biological signaling events at the molecu-lar level. A detailed understanding of the processesat the molecular level that result in large changes inbiological systems is key to the design of novelagents that can be used to control disease.

Molecular and Experimental MedicineThe majority of studies in this department(Ernest Beutler, M.D., Chairman) seek to under-stand the life processes that, when disturbed,lead to disease. Thus, the research conducted iswide-ranging and involves several related fieldsof study, including blood coagulation, the biologyof platelets, hemodynamics and bleeding disorders,and the role of thrombosis in cardiovascular andcerebrovascular diseases. The department also in-cludes a clinical research component in the areas ofthe biochemistry of anti-cancer drugs, diabetes,and inflammation.

A pointed example of the clinical benefitsthat have resulted from work performed in thedepartment is the development of Leustatin, aneffective anti-leukemia agent and, in most cases,a drug that provides a cure for hairy cell leuke-mia. The drug was originally conceived as anagent that could provide a laboratory model for atype of immunodeficiency. As the work pro-gressed it became apparent that it might haveanti-cancer qualities. Animal studies were un-dertaken and subsequently, human trials wereinitiated at Scripps. A one-week course of treat-ment results in a cure for more than 80 percentof patients with none of the side effects associ-ated with anti-cancer drugs. Further studies byErnest Beutler, M.D. indicate that the drug maybe effective against a number of immune disor-ders, including multiple sclerosis.

NeurobiologyThe major scientific focus of the Department ofNeurobiology (Gerald M. Edelman, M.D., Ph.D.,Chairman) is on vertebrate development, in par-ticular, the development of the nervous system.An emphasis is placed on how the brain developsits "wiring" and function to guide motion, per-ception, and sensation.

The fundamental question of developmentasks how the one-dimensional genetic code speci-fies the cellular events that result in a three-dimen-sional animal of a given species. The availability ofmodem cellular and molecular biology tools in re-cent decades has given rise to a view of embryonic

development that centers on the cell and the geneas fundamental units of development.

Researchers here are addressing this problemby focusing on the brain in the earliest stages ofdevelopment. The role of specific adhesion mol-ecules in regulating cell-cell interactions is beingexamined in an effort to link knowledge on ge-netic information to events that direct cell divi-sion, movement, and eventual death.

These efforts suggest a link between cell ad-hesion molecules (CAMs) that control cell-cellbinding, and substrate adhesion molecules(SAMs) that affect cell migration and transfor-mations of cell states. For normal developmentto occur, the expression of CAMs and SAMs isco-regulated by precise genetic signaling. TSRIresearchers have extended the scope of this workand identified a promoter and transcription en-hancer for the gene encoding L-CAM. It wasthen shown that the enhancer region containedsequences that were regulated by homeoboxgenes-DNA sequences that play an importantrole in embryonic development.

Members of the department also study the-ories of how the brain functions in perception,work of relevance in understanding memoryloss, dyslexia, recovery from stroke, and learningdisabilities.

NeuropharmacologyResearch in this department (Floyd E. Bloom,M.D., Chairman) is focused on gaining a betterunderstanding of infectious, environmental andinherited diseases of the brain, and developingmolecules that can act to reverse the diseaseprocess or stimulate normal repair mechanisms.In an effort to understand the mechanisms thatlead to disorders of the brain, investigators havefocused their efforts on a select number of prob-lems, including drug and alcohol addiction, Alz-heimer's disease, multiple sclerosis, and AIDSdementia.

Underlying these highly specific studies ofvarious forms of brain and behavioral dysfunc-tion are interactive research efforts into cell-sig-naling molecules and the parallel endeavor into thenature of neuronal-immune system interactions.Another primary area of research involves the bi-ology of the largely overlooked supportive, im-mune, and inflammatory cells in the brain. Thedecision to reach beyond neuron-to-neuron eventsis another factor that sets the department's re-search efforts apart from other groups.

These efforts are focused in two directions.

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The first is to determine the way in which virusesfind and target cells in the nervous system, dis-turbing function, and often leading to cell death.The second area seeks to understand the ways inwhich glial and immune cells in the brain cancause disease.

Vascular BiologyThe goals of the Department of Vascular Biology(David J. Loskutoff, Ph.D., Chairman) are to de-fine the basic molecular and cellular mechanismsthat guarantee the proper expression, function,and interaction of proteins and cells of the vas-culature. The department brings together a co-hesive group of investigators with interests in celladhesion mechanisms, thrombosis, hemostasis,thrombolysis, and other areas of vascular biologyand medicine. Dominant research themes in-clude structure, function, and regulation of theproteins of the coagulation and fibrinolytic sys-tem, as well as the surface receptors on plateletsand endothelial cells.

Emphasis is placed on the development of agreater understanding of the molecular and cel-lular basis for the formation and dissolution offibrin, the main constituent of blood cells. Stud-ies by TSRI investigators into these areas alreadyhave begun to provide insights into the diseasesof the vasculature, including arteriosclerosis,thrombosis, stroke, hypertension, and bleedingdisorders.

General Clinical Research CenterThe William H. Black General Clinical ResearchCenter (Francis V. Chisari, M.D., Director) pro-vides facilities, staff and instrumentation for theperformance of investigator-initiated, peer-re-viewed research with human subjects. The Cen-ter further provides an environment that pro-motes investigative collaborations betweenresearch scientists and clinicians at Scripps Clinicto facilitate the transfer of basic scientific knowl-edge to the clinical arena and evaluation meth-ods of patient treatment.

Established in 1974 with a gift from theBlack Family and financed by a $12 million grantfrom the NIH, it is the only one of the 75 simi-larly funded centers in the United States notaffiliated with a university or medical school.

Scripps Reference LaboratoryThe Scripps Reference Laboratory (SRI) (David J.Bylund, M.D., Director) is a fully accredited, Cal-

ifornia-licensed clinical laboratory that develops,markets and performs numerous unique, hightechnology, medical diagnostic tests. SRI appliesadvanced technology from TSRI to the develop-ment of clinical diagnostic tests-principally inthe areas of immunology, coagulation/thrombo-sis, and molecular pathology-that are utilizedby physicians from around the world to detectsome of the serious and often rare disorders oftheir patients. It serves as a reference laboratoryfor SmithKline-Beecham Clinical Laboratories inthe United States and for Special Reference Lab-oratory, Inc., in Japan.

The division of research and development atSRI is responsible for converting basic researchdiscoveries into clinically useful and applicableassays with full validation that includes technicaloptimization, quality control, standardization,clinical relevance, and the capacity to expandassays to batch sizes that are economically feasi-ble. Each year the laboratory continues to de-velop new assays with applications to clinicaltrials and diagnostics and remains at the fore-front of modern diagnostic laboratories.

EDUCATIONEducation has always been an integral compo-nent of TSRI's mission. Over the years the Insti-tute's researchers have prepared thousands ofpostdoctoral fellows and trainees for successfulscientific careers. Because most of the importantproblems in biology and chemistry today re-quire an interdisciplinary approach to their so-lutions, in 1989 TSRI established a uniquegraduate program to help integrate the disci-plines of cell and molecular biology, structureand chemistry.

The Graduate Program in Macromolecularand Cellular Structure and Chemistry is an inno-vative program unlike any other in the UnitedStates. A second doctoral program in chemistrywas established in 1981 in an effort to draw uponthe superior capabilities of the TSRI chemistryfaculty. The program's interactive nature empha-sizes the collaboration of organic and bioorganicchemistry and biology, as well as the connectionof fundamental discoveries through interdiscipli-nary activities. These five-year programs providean exceptional training opportunity for a selectgroup of intellectually diverse students.