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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, hasalways stood at the forefront ofbasic biomedical science. HeadedbyPresidentRichard A. Lerner, M.D., in justthree decades the Insti-tute has become internationally recognized for its work in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune

diseases, cardiovascular diseases and synthetic

vaccine development. Particularly significant is the study of the basic structure and design of

biological molecules; inthis arena TSRI is among ahandful of the world's leading centers.

HISTORY

While its roots go back to the founding of the Scripps Metabolic Clinicin 1924by philanthropist EllenBrowning Scripps, TSRI's modembeginnings

date to the 1955 establishment of Scripps Clinic andResearchFoundation,whenamajor portionof the Clinic's limited reserveswerecommittedtothe construction of a new research facility and to the recruitment ofexceptionalbiomedical scientists.

In 1961, the institution recruitedpioneering immunologist Frank Dixon and four of his col-leagues from the University of Pittsburgh, re-searchers who were then contributing insightful

observations on the causes and progression of autoimmune disease, to establish a Department of Experimental Pathology in La Jolla. Their work attracted others and the research program flourished and diversified into biochemistry,

mi-crobiology, virology, studies of blood

coagula-tion, and cancer research. From the outset, the

guiding philosophy of the research focused on clinical and basicinvestigations of the

pathogen-esis of human disease.

Addresscorrespondence andreprintrequests to:RobinB. Goldsmith, The ScrippsResearchInstitute, 10550North TorreyPinesRoad,LaJolla,CA92037,U.S.A.Tel:

619-784-8134; Fax:619-784-8118;E-mail: rgoldsmi@scripps.edu

1997,THEPICOWER INSTITUTE PRESS.Allrights reserved. MolecularMedicine, Volume 3, Number 12, December 1997 793-798

In 1977 themultiple researchprograms that

had developed were formally drawn together

into the Research Institute of Scripps Clinicand by the mid- 1980slaboratory space had grown to some 300,000 squarefeet.Major programs in cell and molecular biology, syntheticandbioorganic chemistry, andthe neurosciences haddeveloped,

in addition to efforts in immunology and clini-cally oriented investigations.

As thefacultyrosterhasgrown, sonaturally

have the focus and number of areas of research. Today, TSRI scientists are actively investigating

biological and chemical aspects of morethan40

diseases, including AIDS, alcoholism, allergy,

Alzheimer's disease, cancer, cardiovascular dis-ease, dementia, depression, diabetes, genetic dis-eases,hepatitis, infectiousdiseases, multiple scle-rosis, renal disease, scleroderma, Sjogren's

syndrome, sleep disorders, and diseases involv-ing neural and muscular degeneration. Among other areas of research that crossspecificdisease lines arethose that involve numerous investiga-tions into thestructureandfunctionof proteins;

biocatalysis and protein design; the factors, pro-cesses, and regulation of inflammation;

bioor-ganic chemistry and molecular design; natural

product synthesis; prebiotic chemistry; and the form and function of animal and plant cells.

In 1991, when Scripps Clinic and Research Foundation and Scripps Memorial Hospitals

reaf-filiated,the Institute became a separate corporation under the parent organization, Scripps Institutions of Medicine and Science. With that change its namebecame The Scripps Research Institute.

PHILOSOPHY

TSRI'sphilosophy emphasizes the compilation of basicknowledgeinthe biosciences for the appli-cation of medicaldiscoveries; the pursuit of fun-damental scientific advances through interdiscipli-nary programs and collaborations; and the education and training of researcherspreparingto meetthe scientificchallengesof the next century.

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FIG. 1. TheScripps ResearchInstitute

The bulk of the Institute's funding is from the National Institutes of Health and other Fed-eralagencies. Inaddition, collaborative industrial partnerships with leading pharmaceutical com-panies provide additional funding in several

ar-eas keytothe organization's research objectives. Private philanthropy also continues to be an im-portant source of funding for the Institute.

Currently housed in multiple laboratory buildings with more than 700,000 square feet of space overlooking thePacific, the Institute's staff includes more than 230 principal scientific inves-tigators, 600 postdoctoral fellows andmore than

1,500 laboratory, administrative, and support

services personnel. In addition, more than 100

students enrolledin TSRI'sgraduate programare

working toward their doctoral degrees.

Rather than isolating faculty members and laboratories intoseparateanddistinctdisciplines, the generally prescribed university model, the cooperative, collaborative spirit is encouraged andembraced.Technicians, postdoctoralfellows, andadministrative support staff all aregiven the latitude and responsibility to accomplish their tasks so as toserve the bestinterests of science.

MAJOR SCIENTIFIC

ACHIEVEMENTS

* Developed and successfully tested the

anti-leukemia drug 2-Chlorodeoxyadenosine

(2-CdA, trade name: Leustatin).

* Demonstrated that rheumatoid factoris a

product of an antibody gene that has main-tained its 'germlike" arrangement, explain-ing why so many rheumatoid factors are so similar.

* Developed a new and efficient method to

produce monoclonal antibodies.

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

* Pioneered the concept that small, synthetic peptides could replace larger peptide chains

ofbacteria and viruses for the purpose of

making vaccines.

* Cloned the genefor the enzyme that is defi-cient inpeople with Gaucher's disease and

de-velopeda method topredict the severity ofthe

disease.

* 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 to receive blood plasma that isfree of contami-nationwith viruses from blood donors.

* Synthesized surfactant, alung material that keeps airsacs open and prevents respiratory distress syndrome.

* Pioneered the development of catalytic

anti-bodies, opening newpossibilities for protein

synthesis and the rational design of new

drugs.

* Mapped the prohormone for somatostatin in

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* Discovered a cell receptorfor allergy-induc-ing IgE antibodies on lymphocytes, afinding

that redirected research on the control of allergic diseases.

* Designed and synthesized a new class of

molecules, known asenediynes, that

repre-sent some of the mostpotent anti-cancer

agents ever tested and demonstrate unusual

selectivity in their ability to destroy cancer cells while leavinghealthy cells intact. * Solved the three-dimensional structure of

the enzyme superoxide dismutase (SOD), thereby establishing a directlink between

mutations inthe gene for SOD that lead to an unstable, less activeenzyme and can cause amyotrophic lateral sclerosis (Lou

Geh-rig's disease).

* Completed the total chemical synthesis of

the anti-cancer drug, Taxol, approved by the

Food and Drug Administration for the

treat-ment of ovariancancer.

* Developed novel approach to inducing tumor

regression by turning off neovascularization of the tumor, thereby setting the stage for

the development ofa new type of

angiogen-esis inhibitor.

* Determined the three-dimensional structure

ofthe T-cell receptor, as well as its

orienta-tion bound to a majorhistocompatibility complex (MHC) molecule.

SCIENTIFIC

DEPARTMENTS

The Skaggs Institute for ChemicalBiology

TheSkaggs Institute for Chemical Biology (Julius

Rebek, Jr., Ph.D., Director) recently has com-pleted its first full year of operation. Established

byanextraordinarycommitment from Aline and L.S. Skaggs, the Institute consists of more than

25 principal investigators with dual appoint-ments infive departments, including Chemistry, Molecular Biology, Cell Biology, Neurobiology andMolecular and Experimental Medicine. The researchers have broad expertise in the structure ofbiological macromolecules, chemical and

an-tibody catalysis, synthetic and combinatorial

chemistry, molecular recognition, and molecular modeling methods.

A hallmark of the new Institute is the syn-ergy that is encouraged between research groups. Four groups now work inmolecular

evo-lution, in areas that relate to the origins of life. The depth of this effort has made The Skaggs Institute the leading edge for research in the

field. Aninitiative in RNA

chemistry

and

biology

is

emerging;

the intent is to

develop

structural and functional understanding ofthese key mol-ecules of life that can ultimately lead to new therapeutic agents. In addition, cohesive efforts

in

drug design bring

theInstitute's structural and

computational

facilities for proteins and nucleic acidstogetherwith the expertisein organic

syn-thesis and combinatorial chemistry.

Opportunities in newly emerging fields that blendchemistrywithbiology currentlyare

being

explored.

These include biomaterial science, as

wellastheopportunities createdbythe

sequenc-ing of the human genome with the enormous array of small molecules being made through

combinatorial chemistry. These disciplines will

meet at the appropriate therapeutic target-the

proteins, receptors, or nucleic acids associated with aparticular disease.

Cell

Biology

Becauseof the importance ofcellbiologyin

elu-cidatingthebasicmechanisms of health and

dis-ease, the Department of Cell Biology (Norton B.

Gilula, Ph.D., Chairman) was established as an

extension of TSRI's unique strength in

integrat-ing cell and molecular biology with molecular

structure and chemical determinations. The de-partment's efforts are focused in a number of

areasrelatedtothebroadrangeofcellular func-tions and processes, including cell-cell

commu-nications; membrane receptor binding and

sig-naling; the initiation and regulation of the cell

cycle and mitosis; receptor-mediated

endocyto-sis; intracellular trafficking; the structure and

function of the nuclear envelope; genetics and

genome analysis; the structure and function of the cytoskeleton; extracellular matrix-cell

sur-face interactions; and growth factor regulatory mechanisms.

Scientists in the Division of Plant Biology within the department areutilizing the

molecu-lar biological techniques that have been

devel-oped in studies of animal systems and applying

themtothebiology of plants. Studies inprogress range frombasic investigations, such as the

ge-netic control ofphotosynthesisand the structure

andfunction of plant cellmembranes and trans-port mechanisms, to more applied research

in-cluding the use of plants to produce abundant

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Chemistry

The mission of the Department of Chemistry

(K.C.Nicolaou, Ph.D., Chairman)is threefold: to generate basic knowledge in the chemical and biologicalsciences onwhichapplicationsto med-icine, new materials and related areas may be founded; to connect fundamental discoveries through interdisciplinaryprograms and collabo-rations to biomedical and related applications; andto educate andtrain scientists in the chem-ical and biologchem-ical sciences.

The department offers a broad scope of ac-tivitiesthatblendssophisticated synthetic chem-istry, molecular design and biocatalysis, and bioorganic chemistry. Organic synthesis is

pur-suedas anadvancingscience.Bothdiscoveryand invention of new reactions and target-oriented totalsynthesisareinvestigated. Intheareaofnew

synthetic technology, research focuses on asym-metriccatalysis, newcatalyst design, bond-forming

reactionsandnovelring constructions. Intotal

syn-thesis,complex biologicallyactivenaturalproducts

and other challenging molecules are targeted for

synthesis.

The power of synthetic organic chemistry combined with chemical principles is utilizedin moleculardesign, chemicalsynthesisand

biolog-ical investigations of molecules with specific bi-ological actions such as enzyme inhibitors, nu-cleic acid-cleaving molecules, and anti-tumor agents, as well as powerful chemical catalysts. Biological concepts and tools are used to design

and produce large molecules such as enzymes and catalytic antibodies, and exploit their value in mechanistic and molecular recognition stud-ies. Another primary area of focus is the

under-standing, improvement, and mimicking of en-zymes. These effortscombinechemistrywith the cuttingedgetoolsof molecularbiology,genetics, andimmunology.

Immunology

Beginning in the 1960s, research in the Depart-ment of Immunology (Richard Ulevitch, Ph.D.,

Chairman) wasfocusedprimarily onthe under-lying biology of autoimmune and immunologic diseases. These initial studies developed a

con-ceptual framework to explain how normal but inappropriate immune reactions can give rise to both local and systemic diseases.

During the past decade, the department has broadened itsresearch base to include studies of the molecular basis of the immune response,

including virus-induced immunodeficiencies, and the role of the cells of the vascular and inflammatory systems in human disease. Basic

studies of theimmunesystemincludethe genet-ics of the antibody response; T-cell immunity,

includingantigenpresentation, thymic selection, and receptor signaling; tolerance induction and

autoimmunity; and the stimulation, control, and biochemistry ofinflammation.

Techniquesthathave beendevelopedto iso-late and screenvirtuallythe entireantibody rep-ertoire of humans or other mammals are being used to produce and recover scientifically and therapeutically useful antibodies that have

po-tential against viruses and the mechanisms of

autoimmune disease. Research in vascular biol-ogy and inflammation has led to a new

under-standing ofthe role of adhesionproteins in

reg-ulating tumorcellgrowth, thevascularization of tissues in diseases such as cancer, and the

mo-lecular mechanisms ofblood coagulation.

Molecular Biology

The Department of Molecular Biology (Peter

Wright, Ph.D., Chairman) takes an

interdiscipli-nary approachto the study of the structure and

functionunderlyingnormaland abnormalcellular

processes. TSRI researchers are making contribu-tions inthe field through collaborative studies

in-volvingmolecular genetics, molecular biology, pro-teinengineering, and structuralbiology.

TSRI isone of the world's largest centers for

structuralbiology and hasachievedanumber of

scientific "firsts" in this area, including the first

three-dimensional structure determination for a protein involved in cell-cycle regulation, the structure of the poliovirus, the structure of the T-cell receptor, and the structurefor SOD.

Another major effort is in the area of

com-putational molecular biology. Advances include

improved methods and new computational ap-proaches that are of fundamental importance for structure-based drug design. Further advances,

using theoretical and experimental methods, have been made in the prediction of protein-folding pathways.

Inthe areaof molecularengineering,

impor-tant progress is being made on several fronts.

Newtechnologyhas beendevelopedforthe syn-thesis ofartificial antibodies.Through a test-tube evolution process developed at TSRI, new

ri-bozymes and antibodies with unique binding and catalytic activities have been created.

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un-derstand biologicalsignalingevents atthe molecu-lar level. Adetailedunderstanding of the processes atthemolecular level that result inlarge changesin biological systems is key to the design of novel agents that can be used to control disease.

Molecular and Experimental Medicine The majority of studies in this department (ErnestBeutler, M.D., Chairman) seek to under-stand the life processes that, when disturbed,

lead to disease. Thus, the research conducted is wide-ranging and involves several related fields of study, including blood coagulation, the biology

of platelets,hemodynamics andbleeding disorders,

and the role of thrombosis in cardiovascular and cerebrovascular diseases. The department also in-cludes a clinical researchcomponentinthe areas of the biochemistry of anti-cancer drugs, diabetes,

and inflammation.

A pointed example of the clinical benefits that have resulted from work performed in the

department is the development of Leustatin, an effective anti-leukemiaagentand, inmostcases, a drug that provides a cure for hairy cell leuke-mia. The drug was originally conceived as an agent that couldprovidealaboratorymodel for a type of immunodeficiency. As the work pro-gressed it became apparent that it might have anti-cancer qualities. Animal studies were un-dertaken and subsequently, human trials were

initiated at Scripps. A one-week course of treat-mentresults in a cure formore than 80 percent of patients with none of the side effects

associ-ated with anti-cancer drugs. Further studies by

ErnestBeutler, M.D. indicate that the drug may be effective against a number of immune disor-ders, including multiple sclerosis.

Neurobiology

The major scientific focus of the Department of

Neurobiology (Gerald M. Edelman, M.D., Ph.D., Chairman) is onvertebratedevelopment, in

par-ticular, the development of the nervous system.

Anemphasisisplacedonhowthe braindevelops

its "wiring" and function to guide motion, per-ception, and sensation.

The fundamental question of development

asks how the one-dimensionalgenetic code speci-fies the cellular events that resultina three-dimen-sional animalofagiven species. The

availability

of modem cellular and molecularbiologytoolsin re-centdecades hasgiven rise to aviewofembryonic

development that centers on the cell and the gene asfundamental units ofdevelopment.

Researchers here are addressing this problem by focusing on the brain in the earliest stages of development. The role of specific adhesion mol-ecules inregulating cell-cell interactions is being examined in an effort to linkknowledge on ge-netic information to events thatdirect cell divi-sion, movement, and eventual death.

These efforts suggest a link between cell ad-hesion molecules (CAMs) that control cell-cell

binding, and substrate adhesion molecules (SAMs) that affect cell migration and transfor-mations of cell states. For normal development

to occur, the expression of CAMs and SAMs is co-regulated by precise genetic signaling. TSRI researchers haveextended the scope of this work and identified a promoter and transcription en-hancer for the gene encoding L-CAM. It was then shown that the enhancer region contained sequences that were regulated by homeobox genes-DNA sequences that play an important role in embryonic development.

Members of the department also study the-ories of how the brain functions in perception, work of relevance in understanding memory loss, dyslexia, recovery from stroke, and learning disabilities.

Neuropharmacology

Research in this department (Floyd E. Bloom, M.D., Chairman) is focused on gaining a better

understanding ofinfectious, environmental and inherited diseases of the brain, and developing molecules that can act to reverse the disease process orstimulate normal repair mechanisms. In an effort to understand the mechanisms that lead to disorders of the brain, investigators have focused theirefforts on a select number of prob-lems, including drug and alcohol addiction, Alz-heimer's disease, multiple sclerosis, and AIDS dementia.

Underlying these highly specific studies of various forms of brain and behavioral

dysfunc-tion are interactive research efforts into cell-sig-naling molecules and theparallelendeavor into the nature of neuronal-immune system interactions. Anotherprimary area of research involves the bi-ology of the largely overlooked supportive, im-mune, and inflammatory cells in the brain. The decisiontoreachbeyondneuron-to-neuronevents is another factor that sets the department's re-search efforts apart from other groups.

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The first is todetermine the wayinwhichviruses

find and target cells in the nervous system,

dis-turbing function, and oftenleadingto celldeath.

The second area seeks to understand the waysin

which glial and immune cells in the brain can

cause disease.

Vascular Biology

The goals of the Department of Vascular Biology (David J.Loskutoff, Ph.D., Chairman) are to

de-finethe basicmolecular and cellular mechanisms that 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 withinterests incell adhesion mechanisms, thrombosis, hemostasis, thrombolysis,and otherareasof vascularbiology and medicine. Dominant research themes

in-clude structure, function, and regulation of the proteins of the coagulation and fibrinolytic sys-tem, aswell asthe surface receptorsonplatelets and endothelial cells.

Emphasis isplaced onthe development ofa

greater understanding of the molecular and cel-lular basis for the formation and dissolution of

fibrin, the main constituent of blood cells. Stud-iesbyTSRIinvestigators into theseareas already

have begunto provide insights into the diseases of the vasculature, including arteriosclerosis, thrombosis, stroke, hypertension, and bleeding

disorders.

General Clinical Research Center

The William H. Black General Clinical Research

Center (Francis V. Chisari, M.D., Director) pro-vides facilities, staff and instrumentation for the

performance of investigator-initiated, peer-re-viewed research with human subjects. The Cen-ter further provides an environment that

pro-motes investigative collaborations between research scientists and cliniciansat ScrippsClinic

tofacilitate the transfer of basic scientific

knowl-edge to the clinical arena and evaluation meth-ods of patienttreatment.

Established in 1974 with a gift from the BlackFamilyandfinanced bya$12 million grant from the NIH, it is the only one ofthe 75

simi-larly funded centers in the United States not

affiliated witha university ormedical school.

Scripps Reference

Laboratory

The Scripps ReferenceLaboratory (SRI) (DavidJ.

Bylund,M.D., Director) is afully accredited,

Cal-ifornia-licensed clinical laboratory thatdevelops, markets and performs numerous unique, high technology, medical diagnostic tests. SRI applies advanced technology fromTSRI to the

develop-ment of clinical diagnostic tests-principally in the areasofimmunology, coagulation/thrombo-sis, and molecular pathology-that are utilized

by physicians from around the world to detect

some of the serious and often rare disorders of their patients. Itserves as a reference laboratory for SmithKline-Beecham Clinical Laboratories in the United States and for Special Reference

Lab-oratory, Inc., inJapan.

The division of research and developmentat

SRI is responsible for converting basic research discoveries into clinically useful and applicable

assayswith full validation that includestechnical optimization, quality control, standardization, clinical relevance, and the capacity to expand

assays tobatch sizes thatare economically feasi-ble. Each year the laboratory continues to de-velop new assays with applications to clinical trials and diagnostics and remains at the fore-frontof modern diagnostic laboratories.

EDUCATION

Education has always been an integral

compo-nentof TSRI'smission. Over the years the Insti-tute's researchers have prepared thousands of postdoctoral fellows and trainees for successful

scientificcareers. Because mostofthe important problems in biology and chemistry today re-quire an interdisciplinaryapproach to their so-lutions, in 1989 TSRI established a unique graduate program to help integrate the disci-plines of cell and molecular biology, structure

and chemistry.

The Graduate Program in Macromolecular

andCellularStructureandChemistryis an inno-vative program unlike any other in the United

States. A second doctoralprogram in chemistry

wasestablishedin 1981 in aneffort todrawupon the superior capabilities of the TSRI chemistry faculty.Theprogram's interactivenature

empha-sizes thecollaboration of organic and bioorganic chemistryandbiology, aswellasthe connection

offundamentaldiscoveriesthrough interdiscipli-naryactivities. Thesefive-yearprogramsprovide

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