The central challenge for today and thefuture will be to identify chemicals of suffi-cient specificity to exploit modern molecu-lar biological insights.

As paradigms have shifted, the basicdrug discovery process has changed (Fig. 1).Historically, drug discovery programs wereorganized around traditionally defined dis-eases. The first step in the drug discoveryprocess was the creation of an animal modelof disease. A true appreciation of the mech-anism of action of the drug often wasn’tdeveloped until after the chemical haddemonstrated value in the clinic. Currently,drug discovery is focused around moleculartargets thought to be relevant to particulardiseases. Mechanism of action is evaluatedvery early in the discovery process.Advances in genomics will result in furtherchange. To an ever-increasing extent, geno-types associated with pathophysiologicphenotypes will be defined first. This willlead to the identification of potential mole-cular targets for drug discovery at an evenmore rapid rate.

Thus, genomics will increase the pace atwhich traditional definitions of disease arereplaced with molecular biologic defini-tions, and the drug discovery process mustrespond. This is a challenge on which theleadership of the industry is appropriatelyfocused, but success here, in my view, willnot be sufficient to assure the overall suc-cess of a drug discovery and developmentprogram. Far more critical to success are,first, the creation and exploitation of tech-

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As we approach the end of the first century of the modern pharmaceutical industry,advances in sequencing the human andother genomes provide the basis for thenext step in the evolution of the industry:genotypically based drug discovery anddevelopment. Remarkably, the primarysequences of most therapeutically relevantorganisms will be determined and in thepublic domain within the next decade.Thus, the most successful pharmaceuticalcompanies will, in my view, be defined, notby how effectively they sequence genomes,but by how well they integrate genomicinformation into the process of drug dis-covery and development.

The pharmaceutical industry in transitionProfound as it is, the transition induced bygenomics is simply the next step in the revo-lution of the industry and of concepts ofhealth, disease and therapeutics stimulatedby advances in molecular biology. The revo-lution in the pharmaceutical industry beganin earnest around 1980. Before 1980, theindustry was truly chemically driven. Com-panies had enormous capacity to create newchemicals, but relatively little insight intowhat to do with them. Concepts about dis-ease were crude, and there were few molecu-lar targets identified for drug action. Con-sequently, the industry had relatively limitednumbers of organizing hypotheses.

After 1980, the pharmaceutical industryis better described as a biological industryin which chemicals are synthesized toexploit new biological insights. Numerousmolecular targets that may be appropriatefor drug discovery have been identified. Infact, the pace at which new targets are dis-covered has already vastly exceeded theindustry’s ability to exploit them. Thus, theindustry today is target and hypothesis rich.

nologies and approaches that result indrugs of dramatically greater specificityand, second, the establishment of innova-tive drug development methodologies to beused as the characteristics of drugs and thebasic definitions of diseases shift.

The challenges of genotypic drug discoveryTarget validation. The identification of agenotype is a predrug discovery event. Itprovides the opportunity to focus a drugdiscovery program on the molecular targetgenotypically identified. Thus, the firstchallenge is to decide which of the innu-merable potential targets merits a drug dis-covery investment. The term target valida-tion has been coined to describe thisprocess. I would argue that two basic ques-tions need to be answered to validate a mol-ecular target: Is it likely that the moleculartarget contributes to a disease process? Is itlikely that a drug that affects the moleculartarget will have an acceptable therapeuticindex? Of the two questions, the more diffi-cult one is the challenge of understandingthe intrinsic therapeutic index of the target,and what pharmacological side effectswould be induced if a drug absolutely spe-cific to the target were discovered.Answering this question requires tools ofsufficient specificity to avoid confusionabout toxicities unrelated to the pharmaco-logical effects of the drug on the target.

The first step in target validation is toassign a function to the molecular target.This has been the subject of considerablediscussion. Numerous approaches, includ-ing “functional genomics,” have evolved.However, most of the approaches result, atbest, in an answer that is too limited to pro-vide a true sense of the potential intrinsicvalue of the target, and more problematicyet, only a few approaches provide anyinformation bearing on the therapeuticindex of the target.

Functionalization should include infor-mation about what the target does ofcourse. But, equally crucial is information

Optimizing the impact ofgenomics on drug discoveryand developmentThe central challenge is to identify chemicals of sufficient specifity to exploit molecular biological insights.

Stanley T. Crooke

Stanley T. Crooke is chairman and CEOof Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, CA 92008.

Genomics will increase the pace at which tradition-al definitions of disease are replaced with molecularbiologic definitions, and the drug discovery processmust respond.

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that orients the target in the various path-ways in which it may participate. Alsoessential is understanding the target’s posi-tion in the various hierarchies within thecell. Finally, it is necessary to understandthe regulatory processes that control thetarget and the nature of any functionalhomologues of the target.

Certainly, this is a tall order, and judg-ments about the potential therapeutic valueof molecular targets will have to be madewith incomplete information. Nevertheless,superficial concepts of “target validation”will, in my view, lead to erroneous judg-ments and must be complemented by moresophisticated approaches. Given the com-plexity of target validation, it is clear thatno single approach is likely to provide all ofthe answers.

Integration of genomics into drug discov-ery and development. Genotypic drug dis-covery will require changes in the entiredrug discovery development process. Thequality of judgment concerning the value ofgenomic targets will be defined by howeffectively genomic information is coupledto a broad understanding and experience indrug discovery. New pathways from geno-type to the clinic will need to be created.Traditional in vitro and in vivo models ofdisease will need to be supplemented orreplaced with genotypic models that assessthe effects of alteration of a particular targeton various pathways and physiologic andpathophysiologic processes.

Perhaps more complex will be the effectsof genomics on drug development.Advances in genomics will increase the paceat which traditional definitions of diseasebecome obsolete. Drugs designed to alterthe behavior of a selected genomic targetare unlikely to affect the disease in allpatients with a current endstage diagnosis,as those states certainly result from multiplesecondary events and possibly more thanone initial molecular event.

Consequently, traditional approachesthat focus on broad groups of patients witha diagnosis, such as asthma, may need to bemuch more precisely divided into subsets ofpatients who may have a traditionallydefined disease amenable to treatmentbased on a particular molecular target.Furthermore, we must identify clinical test-ing processes that will support evaluation ofthe role of genomic targets in apparentlyunrelated diseases.

Drugs of sufficient specificity to takeadvantage of genomic insights. The industrymust invest more in technologies andapproaches that can result in chemicalswith sufficient specificity to selectivelyinhibit a single member of a multigene fam-ily. Without that level of specificity, theindustry will be creating sledgehammers

instead of the lasers that are needed. Todate, the industry has responded by invest-ing in approaches that may enhance tradi-tional drug discovery. Rational drug designand combinatorial methods focus primarilyon creating small molecules that can inter-act with their target proteins with greaterspecificity.

While this is a laudable goal, the notionthat such approaches will result in quantumadvances in specificity is not tenable. Thelimiting problem is the amount of chemicalinformation shared between the drug andits target. With traditional small moleculedrugs, there simply isn’t enough informa-tion to assure specific interactions with thetarget protein in the midst of enormousnumbers of closely related proteins. Thus,the industry also has to invest in the tech-nologies that can yield higher informationdrug molecules: monoclonal antibodies,gene therapy, and antisense. Long term,these investments and others focused oninformation-rich molecules and interac-tions must be increased.Setting reasonable expectations. Genomic in-sights affect prediscovery activities. Typ-ically, molecular targets have derived frommolecular biological and molecular phar-macological research in academia. Thisprocess has often taken years and has usual-ly not been even considered when the timeand cost of drug discovery and develop-ment programs have been calculated.Consequently, it is unrealistic to expectgenomics to dramatically reduce the time orcost of drug discovery and development.

It is equally unrealistic to expect to suc-cessfully exploit genomic research unless itis fully integrated into the drug discoveryand development process. What is requiredis informed investment in genomics, cou-pled to the technical, organizational, andconceptual changes in the pharmaceuticaland biotechnology industries necessary toexploit the investment.

ConclusionsGenomic research will support a transitionto genotypic drug discovery and develop-ment. It provides additional support foroptimism that quantum advances in thetherapy of many diseases may be possible.To fully exploit the potential of genomics,the industry must develop integratedapproaches and invest in technologies thatcan result in drugs of dramaticallyimproved selectivity.

AcknowledgmentsThe author wishes to thank Dave Ecker, DanCook, and Frank Bennett for their comments,and Bobbie Harris, Donna Musacchia, andJulie Brunache for excellent typographic andadministrative assistance. ///

Human Disease

Animal Model

Chemicals with Effects inAnimal Models

Disease Focused Leads

Chemicals

Development

Mechanism of ActionStudies

Figure 1. (A) Drug discovery in the past, (B)present, and (C) future.

Molecular Target

Association with PhysiologicalProcesses

Association withPathophysiological Processes

Unmet Medical Needs Asso-ciated with Molecular Target

Chemicals

“Validation” of Target in Models ofDisease

Mechanism-Based Leads

Animal Models - (usually)

Development

Genomic Association ofMolecular Targets with Human

Identification of Molecular Targets

Role in Normal Physiology

Role in Pathophysiology

Chemicals

Characterization of Genetic and Func-tional Relationships of Molecular Target

Validation as a Drug Target

Genotypically Based Leads

Development

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