Genetic Information Genomic Technologies and the

Authors: Thomas F Bumol August M Watanabe

Publish Date: 2001/02/07

Volume: 285, Issue: 5, Pages: 551-555

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Abstract

The completion of the first draft of the human genome has provided an unprecedented opportunity to understand the genetic and molecular basis of disease Parallel developments of new biological technologies such as transcript profiling allow scientists to examine almost any biological system in high molecular resolution Contemporary drug discovery research is now focusing on the identification and validation of pharmaceutical targets in the molecular pathways/systems embedded in this information Novel therapeutic interventions are being developed and evaluated as a result of this research which will be the basis of innovative pharmaceuticals of the futureDespite many advances in medicine disease burdens remain significant in both developed and emerging countries1 Effective drugs for treatment and prevention are needed for many disease areas including cardiovascular disease cancer neurological disorders infectious diseases endocrinology and inflammatory and chronic degenerative diseases Therefore there is excitement about the potential biological revolution that will emerge with understanding the human genome2The various genome initiatives have provided drafts of the chromosomal sequences of humans and other species The enabling technologies for this accomplishment such as transcript profiling now provide new tools to examine complex biological systems at the level of essentially all expressed messenger RNA mRNA and corresponding proteinsThis explosion of biologic information about the proteins and pathways relevant to cellular physiology and disease has stimulated biotechnology and pharmaceutical researchers to assign top priority to identification and validation of key targets known or novel to develop therapies for the many remaining diseases Hypothesisbased biological research is now supplemented with multidisciplinary approaches to systems and circuitbased biology that integrate bioinformatics genomic databases and cellular and molecular biology with the traditional drug discovery disciplines of physiological biochemistry pharmacology and medicinal chemistry As a consequence interventional strategies now include recombinant proteins monoclonal antibodies peptides and small organic molecules as drug candidates The goal is to expedite the testing of novel therapeutic hypotheses in humans and to develop strategies to identify optimal therapy for individual patientsSuccessful drug treatments of today and in the past involve fewer than 500 targets or growth factors as of 19963 whereas the human genome contains 35 000 to 120 000 genes45 At least 5000 of these genes should be important targets or produce therapeutic proteins suggesting that only 10 of potential therapeutic strategies have been identified and exploited to date6 This avalanche of genetic information largely coming from genomic sequences and expressed sequence tag–based sequencing of complementary DNA cDNA libraries initially represents a complete catalogue of component parts of the cell and tissues but does not yet provide insight into how all of the protein products of these genes interact or function within the cellThe challenge for pharmaceutical research is to unravel the pathophysiology of human diseases and thus make it possible to identify targets accessible to drug intervention The new systems or circuit view of biology that has evolved from gene research must be considered in successful drug discovery78 This perspective requires integration of various new technologies into the traditional toolbox of pharmaceutical research This article focuses on this new genomically influenced multidisciplinary approach to contemporary drug discovery by examining genomic information for hypothesis and target generation and the technologies being developed to validate targets for new therapiesBiochemistry pharmacology and medicinal chemistry will continue to play an essential role in identification of pharmacological targets in the posthuman genome era Expertise in preclinical models and human biology is necessary to incorporate genomic information into a molecular systems approach to physiology The traditional drug discovery process will now be supplemented with additional sources of genomic information at the level of chromosomal DNA disease gene associations mRNA transcript profiling of tissues human genetic variance data and animal and developmental models relevant to disease Figure 1For example if the disease target involves the human endothelium genomic information on the target organ system can be mined with bioinformatics for the discovery process910 DNA sequencing of a cDNA library of human endothelial cells or the use of transcriptional arrays can provide a view of gene transcription in normal human endothelium1112 Likewise proteomics or the systematic study of expressed proteins can provide insight into the functional proteins in specific cells1314

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