Molecular Genetics and Metabolism 100 (2010) S92–S96

Contents lists available at ScienceDirect

Molecular Genetics and Metabolism

journal homepage: www.elsevier .com/locate /ymgme

Future drug discovery and development

Orest Hurko *

Translational Medicine Research Collaboration, TMRC Building, James Arrott Drive, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom

a r t i c l e i n f o

Article history:Received 16 December 2009Received in revised form 9 January 2010Accepted 9 January 2010Available online 29 January 2010

Keywords:Target-based drug discoveryTranslational medicineTarget validationCommon disordersMendelian disorders

1096-7192/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.ymgme.2010.01.010

* Present address: Wyeth Research S2322, 500 A19426, USA. Fax: +1 484 865 9402.

E-mail addresses: o.hurko@dundee.ac.uk, hurkoo@

a b s t r a c t

Drug discovery and development has evolved significantly over the last century. Extrapolation from cur-rent practice invites speculation about the future in four areas of particular interest. These include therange of therapeutic modalities; the methods for selection of drug targets; the interjection of transla-tional medicine in between the traditional discovery and development phases; and the relationshipsbetween institutions. A major focus for the latter three developments is the shortcomings of current tar-get validation. This personal view will be given from perspectives gained in large integrated pharmaceu-tical companies that are primarily focused on common disorders. Where appropriate, comparisons willbe made to the development of treatments for rare Mendelian disorders.

� 2010 Elsevier Inc. All rights reserved.

Introduction

Most of our current pharmacopeia was developed by pharma-ceutical companies that focus on common diseases. This will bethe perspective of this essay. Before speculating about the future,I will summarize relevant history and current practice. The empha-sis will be on the consequences of a shift from an empirical ap-proach based on incremental improvements of remedies knownto be effective in human disease to the current, theoretical ap-proach of target-based drug discovery. A major consequence of thisshift is a significant delay in target validation. This forum brings tomind further questions, not in my original remit: ‘‘What can ex-perts in rare disorders and those of common disorders learn fromeach other?” and ‘‘Are our respective enterprises fundamentallydistinct or are there opportunities for mutually beneficial coopera-tion?” Can the unrivalled target validation inherent in Mendeliandisorders be brought to bear on common diseases?

Early days of the pharmaceutical industry focused on investiga-tion and refinement of proven remedies. Many of these were her-bal preparations, the efficacy of which had been established bymillennia of empirical trial and error in human disease. Notableexamples include narcotics from opium poppies, digitalis from fox-glove, salicylates from willow bark, quinine from the bark of thecinchona tree, and cocaine from the leaves of the coca plant [1].

The first major change occurred in the 19th century. Develop-ment of organic chemistry by the German coal tar industry, pri-

ll rights reserved.

rcola Road, Collegeville PA

wyeth.com

marily for the development of dyes and pigments, providedanother source of pharmaceuticals [2]. Some early efforts were di-rected to the identification and synthesis of the active principle ofestablished herbal folk remedies. Other efforts included synthesisof novel compounds such as sulfonamides, the utility of whichwas surmised by trial and error in human disease.

Serendipitous observations of efficacy gave rise to furtherexplorations. A notable example of a chance finding is providedby chlorpromazine. This putative antimalarial agent was testedin an era when inmates of psychiatric asyla were convenient sub-jects for clinical trials. The unexpected observation of decreaseddelusions and hallucinations provided empiric proof for its efficacyas an antipsychotic. Later investigations of this interesting clinicalphenomenon culminated in the dopamine theory of schizophrenia[3]. However, just as for traditional herbal remedies, the startingpoint for further pharmacological investigations remained empiricobservation of efficacy and tolerability. Theory followed observa-tions in human disease.

Not all such observations were performed carefully. In the ab-sence of systematic study, the efficacy of many purported remedieshad been assumed incorrectly. This was addressed by a second ma-jor change that occurred in 1962 with passage of the Kefauver–Harris amendments to the United States Food, Drug and CosmeticAct. These mandated rigorous demonstration of utility, as well assafety, of candidate pharmaceuticals in prespecified diseases [4–8]. This ushered in the current era of sequential clinical trials:Phase 1 (pharmacokinetic analysis and estimation of a maximum tol-erated dose in several dozen healthy volunteers), Phase 2 (proof ofconcept trials demonstrating efficacy in carefully selected and moni-tored groups of hundreds of subjects), and Phase 3 (pivotal trials in

O. Hurko / Molecular Genetics and Metabolism 100 (2010) S92–S96 S93

larger populations, typically thousands of individuals, representativeof those for which the registration label is sought). After registration,Phase 4 surveillance monitors safety in the tens or hundreds ofthousands of patients to whom the drug was prescribed. Althoughnot strictly required, a double-blind placebo controlled format forthe Phase 2 and Phase 3 was widely adopted as a safeguard againstbias [9].

Despite this significant change, the overall trajectory of drugdiscovery and development remained the same. One usuallystarted with something that was known to work and then asked‘‘Why does it work?” and ‘‘How can it be made to work better?”Incremental improvements were the order of the day in the eraof ‘‘me-too” pharmacology. The net result was a pharmacopeia thatcan be traced to less than 500 targets [2].

About a decade ago there was a third major change. Target-based drug discovery arose as a consequence of three technologicaladvances that occurred within several years of each other: thesequencing of human and other genomes [10], the systematic gen-eration of extensive compound libraries through combinatorialchemistry [11], and the development of high-throughput screening[12]. Output of drug discovery organizations soared. The list of po-tential drug targets expanded from less than five-hundred to tensof thousands. The vast majority of these potential targets still havenever been pharmacologically proven in human disease. In thepursuit of these novel targets, theory precedes empirical validationin human disease by more than a decade.

Macromolecular drug targets are chosen on the basis of a pre-vailing theory of a disease with an unmet medical need of suffi-cient magnitude to warrant investment. Putative drug targets areusually proteins implicated in pathophysiology. Unlike the casefor Mendelian disorders, the inference of the primary trigger formost common diseases is hypothetical. The structure and distribu-tion of putative drug targets are deduced from gene sequences andquantitative transcriptional profiles of multiple tissues, or relatedtechniques. Selection of a drug target initiates a several year se-quence of empirical observations, first in test tubes, later in ani-mals, and only much later in human disease. The hypothesis isnot tested definitively in its intended application for at least a dec-ade after selection of a novel target.

First, the chosen target is expressed in vitro and in vivo. Robustassays are devised to either quantify the binding of ligands to theexpressed target or the modification of its biochemical/physiolog-ical activity. These assays are then used to score the results of ahigh-throughput screen in which the target is exposed to each ofseveral hundred thousand different compounds. Compounds thatsignificantly alter the assay signal generated by the target at micro-molar concentrations are considered ‘‘hits,” worthy of furtherexploration. Spurious results are minimized by selection of onlythose compounds that demonstrate a dose-response relationship.

Typically most high-throughput screens yield one or several‘‘hits” at a cost of several hundred thousand dollars, a year of prep-aration, and several months of execution and analysis. But this isonly the beginning of a more expensive and time-consuming pro-cess of chemical modification of the original hit into a series ofcompounds with (1) higher affinity; (2) pharmacological proper-ties that allow absorption into the body and distribution to the tar-get organ; (3) cost-effective manufacture; and (4) suitable stabilityon the shelf and in the body. This is accomplished by an iterativeprocess in which teams of chemists make structural variants whichare subsequently tested by biologists in vitro and then in animalmodels. The most successful chemical variants are sent for anotherround of modification. Unsuccessful variants signal a dead-end. Allthese contribute to a ‘‘structure–activity” model. Over the course ofseveral years, there can be about half a dozen iterations or morebefore success is achieved with identification of a compound withnanomolar affinity and suitable pharmacological properties. Other-

wise the project is abandoned. However, many of the compoundsthat satisfy these criteria subsequently fail because of preclinicaltoxicity, usually unpredictable, detected by another team of scien-tists that join the project at a later stage.

Only those compounds proven safe and effective in animals areconsidered for clinical trials, in some variant of the Phase 1, 2, 3 se-quence described previously. Since adoption of target-based drugdiscovery, there has been a steady decline in the rate of clinicalsuccess. Currently, less than 10% of compounds entering Phase 1trials become marketed drugs [13]. Success rates vary by therapeu-tic area. Only 2–5% of candidates for treatment of neuropsychiatricdiseases succeed. Over the last decade, technological advanceshave shifted the peak failure rate from Phase 1 studies to Phase2, the initial test of efficacy in human disease. Jurgen Drews hasestimated that of 7,000,000 compounds considered, only one re-sults in a drug registered for use in the clinic [2]. On average, thisprocess requires 8–12 years and expenditure of $1.2 billion dollars,including costs incurred for those compounds lost to attrition.

This model is difficult for common diseases; prohibitive for rareMendelian disorders.

These considerations, as well as observations of nascent initia-tives, prompt me to speculate that the near future may see changesin four areas: (1) a greater utilization of protein-based therapeu-tics; (2) greater use of quantitative systems-biological modelingto guide target selection; (3) insertion of translational medicinestudies in humans to select compounds likely to succeed in laterregistration trials; (4) more risk-sharing at early stages in precom-petitive consortia. A major driver for the latter three endeavors isthe need for earlier validation of drug targets.

Therapeutic modalities

The first future shift to consider, one already very much in pro-gress, is in the nature of therapeutic modalities. Approaches as di-verse as gene therapy, RNA and stem cells are being considered,but most are still quite exploratory. Their utility will be tested far-ther into the future than I care to speculate in this essay. In thenear future, small organic molecules will remain the mainstay ofthe pharmaceutical industry, but protein-based therapeutics arelikely to account for a larger share of development portfolios. Orig-inally, protein-based therapeutics were limited to replacement fordeficient protein hormones, chiefly insulin and growth hormoneharvested from animals or human cadavers, and on xenogenic anti-toxins harvested from immunized animals. Enzyme replacementfor Gaucher’s disease and clotting factors for hemophilia are estab-lished examples for rare Mendelian disorders [14]. The productionof protein therapeutics for these indications has benefited fromseveral methodological advances. With the development of molec-ular biological techniques, replacement proteins came to be syn-thesized in bacteria or other cells transfected with human genesencoding these proteins [15–18]. This both eliminated the hazardsof transmission of infectious agents, such as copurified prions thatcause Jakob–Creutzfeld disease, and reduced costs. Xenogenic anti-sera are being replaced by monoclonal antibodies produced in vitroby hybridomas derived by the somatic-cell hybridization tech-nique devised by Kohler and Milstein [19–21].

These methodological advances not only improved productionof protein therapeutics for these standard indications, but nowhold promise for others. In theory any molecular target that is onor outside the cell – such as a cell-surface receptor or secreted pro-tein or peptide – is ‘‘druggable” by a protein. Although such drugtargets have traditionally been approached through the use ofsmall organic molecules, in certain circumstances a protein-basedapproach may be preferable. Targets that interact with other mol-ecules over large surface areas might be particularly suited to pro-

S94 O. Hurko / Molecular Genetics and Metabolism 100 (2010) S92–S96

tein therapy. If target selectivity is an issue, proteins, especiallyantibodies, might be an appropriate strategy since they are veryspecific. Target biology permitting, there is increasing explorationby both small molecule and protein approaches, often in parallel.

Molecular techniques were then married to those of somatic-cell hybridization. After selection of mouse hybridomas secretingmonoclonal antibodies with the desired specificity, the sequenceof the gene encoding the antibody is analyzed to identify murineresidues not found in the human repertoire. Codons thus selectedare mutagenized to yield a ‘‘humanized” product that retains thespecificity of the original murine monoclonal [20,21].

An alternate procedure of ‘‘antibody phage display” is supplant-ing the somatic cell approach [22–24]. Antibody-encoding genesfrom several dozen unrelated human donors are used to generatea library of some 1011 recombinant phage. Bacteria transfectedwith such a phage library are subjected to 2–3 selection cycles thatstart with binding of secreted antibodies to the chosen moleculartarget. This is followed by washing, elution, and further amplifica-tion. Newer technological advances enable development of high-affinity protein therapeutics through the choice of scaffolds basedon smaller engineered or naturally occurring proteins. Among theformer are SMIPs (small modular immunopharmaceuticals)[25,26]. Among the latter are IgNARs (heavy-chain, homodimericimmunoglobulins called new antigen receptors) from sharks orcamellids [27–29]. Though still in the exploratory stages, thesenew scaffolds promise enhanced stability, the ability to crossblood–brain and mucosal barriers, as well as enhanced penetrationinto target tissues. Another attractive feature is a significantly re-duced cycle time for optimization and perhaps greater protectionsfrom ‘‘biosimilars” produced by competitors. The extent to whichthese promises are realized will determine their future utility.

Target selection

A second area in which a future change appears likely is thatof selection of drug targets. This is particularly difficult for com-mon diseases. With the exception of infections, the primary causeof such diseases is poorly understood. What understanding we dohave is usually based on extrapolation from later stages in thepathophysiological cascade, themselves poorly understood, andthe actions of proven remedies, most of which had been discov-ered serendipitously. Choices of novel drug targets are oftenrather speculative, based on molecular observations not groundedthoroughly in considerations of complex physiological pathwaysor quantitative physiology. An empiric work-around for thesegaps is the use of animal disease models. However, as describedin the introduction, most compounds that have proven safe andeffective in animal models fail in the clinic [13]. Some, thoughnot all, of these failures may result from inappropriate choice ofdrug target [30]. It must be remembered that the majority ofputative targets discovered by molecular biologists did not evenhave a name ten years ago, much less the decades of study re-quired for a thorough understanding of their biology, much lesstheir role in human disease. Furthermore, metabolic pathwaysimportant in some species may be minor or redundant in others.Finally, animal models rarely capture more than a few relevantaspects of the human disease for which they are intended. Bettervalidation of drug targets would be most welcome in the currentparadigm.

Two approaches are worthy of mention. Both are based onshortcuts to a more thorough understanding of authentic humandisease. Systems Biology proposes network analysis from dense ar-rays of ‘‘-omic” data – genomic, proteomic, lipidomic, etc. – gath-ered from comparisons of sampled human tissue and/or bodilyfluids from affected patients with those of controls [31–33]. Pro-

posed analyses of such networks seek to identify quantitativelyimportant nodes of intersecting metabolic pathways as potentialdrug targets. To date, the proven utility of ‘‘-omics” in drug discov-ery and development is thus far limited to oncology [34–36]. Anal-yses of transcriptional profiles or patterns of phosphoactivatedsignaling pathways have in some instances successfully distin-guished a subgroup of individuals that respond to a particular tar-geted therapy from the majority of patients with a histologicallyidentical tumor that do not. Extensions of this approach are beingused to guide the initial selection of drug targets for other tumors.However, attempts to extend this approach to other, non-clonaldiseases have been hampered by a variety of technical and concep-tual hurdles. Chief among these are identification of, or access to,the tissue relevant to the disease at an appropriate time in itscourse.

The other approach to better understanding of human disease isbetter known to participants in this symposium: thorough charac-terization of an extreme phenotype with a known cause [37]. Chiefamong these are Mendelian disorders [38]. In contrast to mostcommon diseases in which the root cause(s) is a matter of specu-lation, the root cause of most Mendelian disorders is known.Whereas treatment effects in common disorders are often modest,sometimes difficult to distinguish from the noise in the variance ofclinical course of individual subjects, in Mendelian disorders ef-fects of treatment can be quite dramatic, permitting smaller trials.These are significant advantages, even acknowledging complica-tions resulting from environmental and epigenetic factors. Suchcomplications are occur in both common and Mendelian disorders.A major obstacle is posed by the rarity of Mendelian disorders andthe consequent limitation of the scarce resources apportioned totheir study. In some circumstances, justification for such expendi-ture could come from lessons applicable to common disorders thathave a larger impact on public health.

A prime example comes from the study of rare Mendelian dis-orders of lipid metabolism associated with atherosclerosis [39].The detailed study of rare high-density pedigrees segregatinghypercholesterolemia resulted in the identification of cholesterolas a culprit in a rare form of atherosclerosis which proved general-izable to the more common disease that is a leading cause of deathin industrialized societies. This enabled identification of the targetof the statins, currently the most commercially successful drugs inthe market. It is currently hoped, but not proven, that a similargeneralization from rare Mendelian disorders associating amyloiddeposition in presenile dementias to what has come to be knownas Alzheimer disease in the general population will prove valid.Finding meaningful mechanistic links between rare Mendelian dis-orders to those of more prevalent human disorders may provideopportunities for meaningful collaborations mutually beneficialto students of both.

Furthermore, demonstration of efficacy in a monogenic disordermay be a cost-effective translational step before testing in a morecommon but more heterogeneous disease [37]. This, and other as-pects of translational medicine, will be discussed in the nextsection.

Translational medicine

The third change foreseeable in the near future of drug discov-ery and development is that of increased reliance on translationalmedicine as a bridge between preclinical studies and registrationtrials in human subjects. Since popularization of this term, transla-tional medicine has been used by some to refer to the entire enter-prise of medicine: ‘‘From bench to bedside and from bedside tobench.” A stirring anthem, but not very useful in delineating a spe-cific enterprise. In the pharmaceutical industry, a more restricted

O. Hurko / Molecular Genetics and Metabolism 100 (2010) S92–S96 S95

definition has proven useful: determining if a drug candidate thathas proven safe and effective in animals does anything worthwhilewhen given to a human being in a very carefully-engineered set-ting [9,42,43]. Is the target valid? Such translational trials are aprelude, but not a substitute for, standard Phase 2 clinical trialsundertaken as part of a registration package in preparation forPhase 3 studies. Phase 2 trials are used as the initial test of efficacyin humans, as determined through quantified effects on prespeci-fied clinical endpoints when the drug is given to patients withina diagnostic category that is broadly enough defined to warrant acommercially justifiable label. In contrast, the goal of a transla-tional trial is to give a drug candidate every possible chance of suc-ceeding without immediate concern for the practical realities ofthe clinic or the marketplace.

In practical terms, this involves the use of biomarkers and mod-el systems in human subjects to optimize (1) enrollment of onlythose subjects most likely to respond favorably; (2) dosing regi-mens that result in adequate receptor occupancy, as dictated bythe interplay of pharmacokinetics and pharmacodynamics and(3) sensitive detection of salutary effects on the pathophysiologicalcascade underlying the disease [40–41]. Success in such an artifi-cially contrived experiment does not guarantee success in a morecommercially viable, broader population that needs to be selectedand dosed more practicably, albeit less precisely. However, itwould be prudent to reserve the more substantial resources re-quired for the conduct of subsequent Phase 2 studies to those com-pounds that proved successful in the translational trial. Such earlyvalidation in humans is the ideal. Judicious use of translationalprinciples, so defined, promises to reduce the most common pre-ventable causes of costly failures in registration trials [44,45]: (1)inappropriate dosing regimens; (2) enrollment of nonrespondersinto clinical trials; (3) inability to detect a disease-modifying effectfor chronic or intermittent diseases and (4) induction of unaccept-able side-effects in a subset of subjects.

As discussed in the previous section, the fifth cause of Phase 2failures, namely, an inappropriate choice of an invalid drug target,could to some extent be minimized preclinically. Failure in an opti-mally designed translational trial in human subjects would allow acompound that had proven itself safe and effective in animals, tobe abandoned confidently without the costs of a registration trial.

Institutional considerations

The fourth prediction for the future of drug discovery and devel-opment has to do with institutional arrangements. The over-whelming majority of drugs in our current pharmacopeia werediscovered and developed by the pharmaceutical industry, muchof it by publicly-traded companies. However, these discoverieswere usually made by building on the rich biological and patho-physiological understanding developed by academic researcherswho are supported by grants from the government and disease-re-lated charities. These funding institutions are tolerant of the longlead times and the high failure rates associated with the ground-breaking fundamental research required for thorough understand-ing of biology and disease.

In contrast, attraction of shareholders, who provide the supportfor most large pharmaceutical companies, requires the promise ofhigh returns in a reasonable time period. In the pharmaceuticalindustry, these returns occur only after a lead time of the decadeelapsing between selection of a target and the registration ap-proval required to bring a drug to market. Such high risks and longlead times are comparable only to those of the petroleum industry.In both industries, shareholders require high rates of return if theyare to be lured away from safer short-term investments. Becausethe cost of goods is only a minor portion of a drug’s market value,

most of it resides in the intellectual property invested in the drug.The vigilance with which this intellectual property is guarded – ini-tially with secrecy, later with patent protection – is critical not onlyto the recovery of the costs associated with drug discovery anddevelopment, but also by the profits required by shareholders.All other things being equal, there is a demonstrable premium incoming into the market as quickly as possible.

However, there is now a major competing consideration. In theprevious era, when there were only 500 or so drug targets to con-sider, this goal was most easily achieved by the conduct of all re-search behind closed doors. Hiring all of the individuals with theexpertise required for the prosecution of a limited number ofwell-validated targets was a tractable undertaking. Most of thesedrug targets had been validated by pharmacological experiencein human disease. This is no longer the case. The number of poten-tial targets number in the tens of thousands. The vast majority ofthese have not been validated in human disease. No one pharma-ceutical company has the breadth and depth of internal resourceto exploit the full range of possibilities. Doing without external col-laborators is no longer an option.

How is this fundamental tension between the need for exclusiv-ity and the need for collaboration to be resolved? Many feel thatacademic-industrial partnerships as well as limited syndicates be-tween industrial concerns that focus on the early stages of thepipeline may be advantageous. It is unlikely that the finish line willchange appreciably, but even competitors can agree to advance thestarting line on the race to market. The closer one gets to registra-tion and the market, the greater the need for protection of intellec-tual property. In contrast, there is little competitive advantage tobe gained from exclusivity over high-risk undertakings, most ofwhich are destined to failure.

Current examples of early stage cooperation include many differ-ent types of institutional arrangement. Optimal institutionalarrangements are dictated by considerations of cost and risk. Inser-tion of an independent Translational Medicine department betweenthe two longstanding pillars of Discovery and Development, wouldrepresent an intrainstitutional change. Cooperation with outsideinstitutions can be either precompetitive or competitive. Pride ofplace in the first category is the Alzheimer Disease NeuroimagingInitiative (ADNI) [46,47]. ADNI investigates neuroimaging and otherbiomarker correlates, some of which may eventually become vali-dated to a level that permits their use as surrogate markers by regu-lators. Because it is partly funded by the federal government, ADNImakes its data publicly available to all qualified individuals, whetheror not they contribute financially. The more broadly based NIH Bio-markers consortium [48] is organized along similar lines. A morecomplex arrangement has been adopted by the European Unionfor their Innovative Medicines Initiative [49]. Still another arrange-ment is being taken by P1Vital [50], a closed limited syndicate ofpharmaceutical companies seeking to validate experimental volun-teer models of psychiatric disease in collaboration with British aca-demics [51]. At the other extreme is a competitive externalcollaboration, the Translational Medicine Research Collaboration(TMRC) with Wyeth as the sole commercial partner in a limitedenterprise with the four medical schools in Scotland, the relatedtrusts of the National Health Service, and Scottish enterprise [52].The nature of the questions to be resolved to a large extent dictatesthe optimal institutional arrangement. As a general rule, the earlierthe project and the greater the risk, the greater the value of risk-shar-ing and open collaboration.

Conclusion

Having examined four future possibilities from the perspectiveof a large, for profit-pharmaceutical company, it is appropriate toconsider the relevance of such a future for students of uncommon

S96 O. Hurko / Molecular Genetics and Metabolism 100 (2010) S92–S96

diseases, such as the Mendelian disorders that are the subject ofthis symposium. Some of these technological advances can beadapted to a more resource-constrained environment, whereasothers cannot. Indirect interactions between these sectors, suchas repurposing the existing pharmacopeia, require no formal insti-tutional arrangements. Later phases of drug discovery and devel-opment can be subcontracted out to specialized firms, whereasothers of necessity must remain with the skilled clinical practi-tioner-investigator funded by grants from the government or dis-ease-related charities. Interaction with smaller firms may provideopportunities as orphan or, in most cases, as unlicensed drugs. Per-haps the greatest challenge is to tap into the resources of a large,integrated pharmaceutical company in a mutually beneficial col-laboration. One exemplar is provided by familial hypercholesterol-emia in which features of this rare Mendelian disorder were foundto be common with more prevalent atherosclerosis in the generalpopulation. Finding similar common features in other disorderscould couple the detailed clinical understanding of the rare Mende-lian disorder with the technical resources available for less wellcharacterized disorders affecting the general population. Relevanttranslational studies may prove of benefit to both.

Conflict of interest statement

Orest Hurko is an employee of Pfizer. At the time of the confer-ence presentation, Orest Hurko was an employee of WyethResearch.

Acknowledgments

Thanks to Giora Feuerstein for mentorship and critical readingof this manuscript and to Frank Walsh for his vision and enablingof translational medicine.

References

[1] L. Brunton, J. Lazo, K. Parker, J.S. Lazo, K.L. Parker, Goodman and Gilman’s thePharmacological Basis of Therapeutics, McGraw-Hill, New York, 2005.

[2] J. Drews, In Quest of Tomorrow’s Medicines, Springer, New York, 1998.[3] F.R. Frankenburg, R.J. Baldessarini, Neurosyphilis, malaria, and the discovery of

antipsychotic agents, Harv. Rev. Psychiatry 16 (2008) 299–307.[4] L.E. Hollister, The FDA ten years after the Kefauver–Harris amendments,

Perspect. Biol. Med. 17 (1974) 243–249.[5] S. Peltzman, An evaluation of consumer protection legislation: the 1962 drug

amendments, J. Political Economy 81 (1973) (1962) 1051–1056.[6] W.M. Wardell, History and application of drug safety and efficacy

requirements in the United States, Agents Actions 8 (1978) 420–421.[7] T. Ziporyn, The Food and Drug Administration: how those regulations came to

be, JAMA 254 (1985) 2037–2039. 2043-2046.[8] M.R. Hamrell, The history of the United States Food, Drug and Cosmetic Act and

the development of medicine, Biochem. Med. 33 (1985) 268–270.[9] S. Piantadosi, Clinical Trials: A Methodologic Perspective (Wiley Series in

Probability and Statistics), second ed., John Wiley and Sons, Hoboken, 2005.[10] F.S. Collins, The human genome project and the future of medicine, Ann. N.Y.

Acad. Sci. 882 (1999) 42–55.[11] S.J. Teague, A.M. Davis, P.D. Leeson, The design of leadlike combinatorial

libraries, Angew. Chem. Int. Ed. Engl. 38 (1999) 3743–3748.[12] R. Archer, The drug discovery factory: an inevitable evolutionary consequence

of high-throughput parallel processing, Nat. Biotechnol. 17 (1999) 834.[13] CMR International, Global R&D Performance Metrics Programme: Industry

Success Rates Report, 2005, p. 7.[14] M.J. Gait, Synthetic genes for human insulin, Nature 277 (1979) 429–431.[15] A.D. Riggs, K. Itakura, Synthetic DNA and medicine, Am. J. Hum. Genet. 31

(1979) 531–538.[16] G.A. Grabowski, N.W. Barton, G. Pastores, J.M. Dambrosia, T.K. Banerjee, M.A.

McKee, C. Parker, R. Schiffmann, S.C. Hill, R.O. Brady, Enzyme therapy in type 1Gaucher disease: comparative efficacy of mannose-terminatedglucocerebrosidase from natural and recombinant sources, Ann. Intern. Med.122 (1995) 33–39.

[17] J.M. Lusher, I. Scharrer, Evolution of recombinant factor VIII safety:KOGENATE((R)) and Kogenate ((R)) FS/Bayer, Int. J. Hematol. (2009) [Epubahead of print].

[18] J.E. Wraith, Limitations of enzyme replacement therapy: current and future, J.Inherit. Metab. Dis. 29 (2006) 442–447.

[19] G. Köhler, C. Milstein, Continuous cultures of fused cells secreting antibody ofpredefined specificity, Nature 256 (1975) 495–497.

[20] L.K. Jolliffe, Humanized antibodies: enhancing therapeutic utility throughantibody engineering, Int. Rev. Immunol. 10 (1993) 241–250.

[21] X.Y. Liu, L.M. Pop, E.S. Vitetta, Engineering therapeutic monoclonal antibodies,Immunol. Rev. 222 (2008) 9–27.

[22] T. Bratkovic, Progress in phage display: evolution of the technique and itsapplications, Cell. Mol. Life Sci. (2009) [Epub ahead of print].

[23] P. Nieri, E. Donadio, S. Rossi, B. Adinolfi, A. Podestà, Antibodies for therapeuticuses and the evolution of biotechniques, Curr. Med. Chem. 16 (2009) 753–779.

[24] H. Thie, T. Meyer, T. Schirrmann, M. Hust, S. Dübel, Phage display derivedtherapeutic antibodies, Curr. Pharm. Biotechnol. 9 (2008) 439–446.

[25] T. Robak, P. Robak, P. Smolewski, TRU-016, a humanized anti-CD37 IgG fusionprotein for the potential treatment of B-cell malignancies, Curr. Opin. Invest.Drugs 10 (2009) 1383–1390.

[26] X. Zhao, R. Lapalombella, T. Joshi, C. Cheney, A. Gowda, M.S. Hayden-Ledbetter,P.R. Baum, T.S. Lin, D. Jarjoura, A. Lehman, D. Kussewitt, R.J. Lee, M.A. Caligiuri,S. Tridandapani, N. Muthusamy, J.C. Byrd, Targeting CD37-positive lymphoidmalignancies with a novel engineered small modular immunopharmaceutical,Blood 110 (2007) 2569–2577.

[27] H. Dooley, M.F. Flajnik, A.J. Porter, Selection and characterization of naturallyoccurring single-domain (IgNAR) antibody fragments from immunized sharksby phage display, Mol. Immunol. 40 (2003) 25–33.

[28] M.F. Flajnik, H. Dooley, The generation, selection of single-domain, v regionlibraries from nurse sharks, Methods Mol. Biol. 562 (2009) 71–82.

[29] R.L. Stanfield, H. Dooley, P. Verdino, M.F. Flajnik, I.A. Wilson, Maturation ofshark single-domain (IgNAR) antibodies: evidence for induced-fit binding, J.Mol. Biol. 367 (2007) 358–372.

[30] E.E. Schadt, S.A. Monks, S.H. Friend, A new paradigm for drug discovery:integrating clinical genetic, genomic and molecular phenotype data to identifydrug targets, Biochem. Soc. Trans. 31 (2003) 437–443.

[31] E.E. Schadt, S.H. Friend, D.A. Shaywitz, A network view of disease andcompound screening, Nat. Rev. Drug Discov. 8 (2009) 286–295.

[32] R. Dobrin, J. Zhu, C. Molony, C. Argman, M.L. Parrish, S. Carlson, M.F. Allan, D.Pomp, E.E. Schadt, Multi-tissue coexpression networks reveal unexpectedsubnetworks associated with disease, Genome Biol. 10 (2009) R55.

[33] P.Y. Lum, J.M. Derry, E.E. Schadt, Integrative genomics and drug development,Pharmacogenomics 10 (2009) 203–212.

[34] C. Swanton, C. Caldas, Molecular classification of solid tumours: towardspathway-driven therapeutics, Br. J. Cancer 100 (2009) 1517–1522.

[35] J.S. Abramson, M.A. Shipp, Advances in the biology and therapy of diffuse largeB-cell lymphoma: moving toward a molecularly targeted approach, Blood 106(2005) 1164–1174.

[36] E.A. Sausville, S.L. Holbeck, Transcription profiling of gene expression in drugdiscovery and development: the NCI experience, Eur. J. Cancer 40 (2004)2544–2549.

[37] B.H. Littman, S.A. Williams, The ultimate model organism: progress inexperimental medicine, Nat. Rev. Drug Discov. 4 (2005) 631–638.

[38] C.R. Scriver, W.S. Sly, B. Childs, A.L. Beaudet, D. Valle, K.W. Kinzler, B.Vogelstein, The Metabolic and Molecular Bases of Inherited Disease, eighth ed.,McGraw-Hill, Professional, New York, 2000.

[39] J.L. Goldstein, M.S. Brown, Familial hypercholesterolemia: identification of adefect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductaseactivity associated with overproduction of cholesterol, Proc. Natl. Acad. Sci.USA 70 (1973) 2804–2808.

[40] Online Mendelian Inheritance in Man, OMIM (TM), Johns Hopkins University,Baltimore, MD. MIM No.: 104300; 11/30/2009; http://www.ncbi.nlm.nih.gov/omim/.

[41] O. Hurko, F.S. Walsh, Novel drug development for amyotrophic lateralsclerosis, J. Neurol. Sci. 180 (2000) 21–28.

[42] M.N. Pangalos, L.E. Schechter, O. Hurko, Drug development for CNS disorders:strategies for balancing risk and reducing attrition, Nat. Rev. Drug Discov. 6(2007) 521–532.

[43] O. Hurko, J.L. Ryan, Translational research in central nervous system drugdiscovery, NeuroRx 2 (2005) 671–682.

[44] D. Schuster, C. Laggner, T. Langer, Why drugs fail – a study on side effects innew chemical entities, Curr. Pharm. Des. 11 (2005) 3545–3559.

[45] O. Hurko, The use of biomarkers in drug development, Ann. NY Acad. Sci. 1180(2009) 1–10.

[46] S.G. Mueller, M.W. Weiner, L.J. Thal, R.C. Petersen, C.R. Jack, W. Jagust, J.Q.Trojanowski, A.W. Toga, L. Beckett, Ways toward an early diagnosis inAlzheimer’s disease: The Alzheimer’s Disease Neuroimaging Initiative(ADNI), Alzheimers Demen. 1 (2005) 55–66.

[47] http://www.adni-info.org/.[48] http://www.biomarkersconsortium.org/.[49] http://www.imi.europa.eu/.[50] http://www.p1vital.com/.[51] S.W. Chan, R. Norbury, G.M. Goodwin, Risk for depression and neural

responses to fearful facial expressions of emotion, Br. J. Psychiatry 194(2009) 139–145.

[52] http://www.tmrc.co.uk/.