The Genom of Homo sapiens.pdf

GENOME RESEARCH: THE NEXT GENERATION 51Identify All Proteins in the Cell andTheir Interactions; Develop a ComputationalModel of the CellAll of the technological quantum leaps set forth inNHGRI’s vision for genomics research can be consideredambitious and audacious, but two are even bolder than therest. The ultimate challenges—and ultimate payoffs—interms of advancing biological understanding are developmentof a technology or technologies for determining theabundance and modification state of all proteins in a singlecell in a single experiment, and then coupling suchexperimental data with other data sets and the power ofbioinformatics to create a computational model of thecell.GENOMICS TO HEALTHThe consensus is that the time is now right to move genomicsin an intentional way toward the translational applicationsthat have motivated the Human Genome Projectfrom the very beginning and have inspired great hopefor medical benefits among both the general public andthe biomedical research community. Bearing in mind thatthe road from genomics to health is likely to contain manyunexpected twists and turns, we should not expect thesebenefits overnight. But the stage is now set for a majorpush toward defining the causes and potential cure or preventionof a long list of human diseases.Identify Genetic and Environmental RiskFactors for All Common DiseasesOnce the human HapMap is constructed and this communityresource is made freely available to researchersworldwide, it will be possible to conduct whole-genomeassociation studies of nearly all diseases in all populations,thereby helping to decipher the complicated interplayof multiple genes and multiple nongenetic factors inmany common diseases. In addition, new computationaland experimental methods will need to be devised to allowthe better detection of gene–gene and gene–environmentinteractions in these often complex disorders.Develop Sentinel Systems for Disease Detection;Develop a Molecular Taxonomy of IllnessGenomic technologies possess enormous potential forestablishing new approaches to the prediction and preventionof disease. Testing or screening asymptomatic orpresymptomatic individuals for gene expression patternsassociated with increased disease risk could be used todetect diseases far earlier than is now possible and/or todevelop individual preventive medicine strategies. In addition,clinicians could use the detection of gene variantsthat correlate with drug response to better tailor prescribingpatterns to the individual patient. Much remainsto be done, however, before such strategies are widelyimplemented in the clinic. For example, the cost ofgenome analysis needs to be lowered, and greater caremust be taken to ensure the clinical validity of genetictests.The field of genomics also stands poised to revolutionizeclinical medicine’s current taxonomy of diseasestates, which until now has been based largely on empiricalclassification schemes. Armed with systematicanalyses of DNA sequence, somatic mutations, epigeneticmodifications, gene expression, protein expression,and protein modification, we should begin the processof using detailed molecular characterizations tounderstand, and to potentially reclassify, all human illnesses.A molecular taxonomy of disease will provide amore precise, scientific approach to the diagnosis andprevention of disease, as well as predicting response totreatment.Develop and Deploy High-throughputRobotic Screening of Small Moleculesfor Academic ResearchOur current toolbox for studying translation of the humangenome is woefully understocked. Among the manycommunity resources that needed to be built or expandedare full-length cDNA collections, siRNA collections, collectionsof knockout mice, and transcriptome referencedata sets.However, we believe there is another tool that will offeran unprecedented opportunity to establish a newparadigm for academic biological research: a publiclyavailable library of small, organic drug-like moleculesand the capacity to screen this library against any highthroughputassay (Austin 2003). Although small organicmolecules have a good track record of modulating genefunction and have been the target of intense efforts by thepharmaceutical industry, biologists in academia and thepublic sector have not had easy access to large libraries ofthese compounds and therefore have not taken full advantageof the tremendous power of small molecules toserve as probes to advance our understanding of biology.Further underscoring the need for a public smallmoleculelibrary is the fact that those libraries that existwithin the pharmaceutical industry represent a veryskewed distribution of genomic targets. More than 40%of small-molecule drugs now on the market target G-protein-coupledreceptors, while vast areas of the genomeexist for which no small-molecule probes have been identifiedat all.Providing public-sector scientists with easy access tosmall-molecule tools on the scale now available to thepharmaceutical industry will greatly broaden the scope ofbiological inquiry and have a transformative effect on basicbiomedical research, speeding functional studies ofthe genome and the development of novel therapeutics.This area of genomics research, often referred to as chemicalgenomics, will open the door to a new type of forward/reverseapproach to understanding biological pathwaysin which small-molecule probes can be used toelucidate gene function by studying either the chemical’s