conference editorial functional genomics and disease in...

Comparative and Functional GenomicsComp Funct Genom 2003; 4: 516–517.Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/cfg.329

Conference Editorial

Functional genomics and disease in 2003

Michael J. Taussig*Chairman, ESF Programme in Integrated Approaches to Functional Genomics, The Babraham Institute, Cambridge CB2 4AT, UK

*Correspondence to:Michael J. Taussig, ESFProgramme in IntegratedApproaches to FunctionalGenomics, The BabrahamInstitute, Cambridge CB2 4AT,UK.E-mail: [email protected]

Received: 1 August 2003Revised: 4 August 2003Accepted: 5 August 2003 Keywords: functional genomics; proteomics; arrays; disease; diagnosis; prognosis;

sequence variation; ethics

2003 is a highly celebratory year for genomics,with the 50th anniversary of the publication of thedouble helical structure of DNA (April 1953) andthe announcement of the completion of the humangenome sequence (April 2003). The structureof DNA, arguably the most important biologi-cal advance of the 20th century, and the humangenome project have fundamentally affected ourview of biology. The determination of the DNAstructure, in a union of physics, chemistry and biol-ogy, revealed how information is encoded by genesand how those genes are replicated; the completionof the human genome sequence offers the prospectof disease prediction, prevention and cure, as wellas a deeper understanding of our own evolution.

Having determined the informational content ofmany genomes as specified in the DNA, we arenow moving on to elucidating how gene prod-ucts function and how the chemistry of life istranslated into complex cellular organization. Thisis the area covered by functional genomics, theexploration of gene function on a global scale.Functional genomics makes use of revolutionarytechnological advances, characteristically capableof very high sample throughput and producingvast amounts of data, which require computational

processing for interpretation. Array technologieshave proved particularly powerful. DNA arrayscan reveal genetic variation or monitor expres-sion of integrated sets or all of the genes of anorganism at the mRNA level in one experiment,with small samples of tissue; the more recent anti-body arrays can similarly reveal the protein levels,while protein or whole-proteome chips give theopportunity for parallel functional analysis. The‘classical’ proteomics approaches of high resolu-tion two-dimensional gel electrophoresis or liq-uid chromatography, combined with mass spec-trometry, are capable of separating and identifyingthousands of proteins, revealing changes in pro-tein expression and the composition of intracel-lular protein complexes. Protein–protein interac-tions can be analysed in vivo by the yeast two-hybrid approach and its derivatives. Antibodies, themost familiar form of binding molecules, are againproving their immense value in analysing proteinsof unknown function identified from the genomesequence. Elegant knockdown strategies, such asRNAi or mutagenesis approaches, can specificallysilence or alter individual genes, the effects ofwhich can be observed on a global scale in genet-ically amenable ‘model organisms’ such as yeast,

Copyright 2003 John Wiley & Sons, Ltd.

Conference Editorial 517

nematode, fruit fly and mouse, leading to new phe-notypes from which gene function may be deduced.Bioinformatics is a vital growth area without whichthe data cannot be made accessible, organized andunderstood. The application of these technologiesto the understanding and treatment of human dis-ease was the focus of this meeting.

What can we expect the benefits of functionalgenomics research to be for human health? Takingcancer as one example, functional genomics tech-nologies, as exquisitely sensitive high-throughputtools, allow for improved characterization of thevarieties of types and subtypes of tumours. Tran-scriptional and protein profiling reveal an enor-mous number of genes that change activity togetheras part of an interconnected network. One resultof observing the clusters of genes which changein expression has been in improving classifica-tion of cancers, with major clinical significancein assisting earlier diagnosis, prognosis or ther-apy. As regards drug development, the expecta-tion is that the human genome information andfunctional genomics research will lead to curesthrough the identification of altered molecular path-ways, the selection of new tumour-specific targetsand the development of drugs against each tumourtype. The success of the anti-CML drug Gleevec

(and others in the wake of this) suggests thatthe ‘designer drugs’ approach will deliver. How-ever, given the number of cancer varieties, thehuge cost of drug development and many yearsof clinical testing and validation, this cannot typi-cally be expected to occur very quickly. A realis-tic short-term goal for functional genomics, whichwill increase survival, is improved early diagno-sis, currently lacking for many cancers, through thediscovery of protein markers in body fluids, partic-ularly serum. In particular, proteomics technologiesof mass spectrometry and antibody arrays offer thepossibility of screening for early disease. Improveddiagnostic methods for early disease detection areprobably where the promise of functional genomicswill be realized most rapidly.

A major potential benefit of genome informationis prevention of disease by identifying susceptibleindividuals through their genomic profile, correlat-ing DNA sequence variation (SNPs, haplotypes)with disease susceptibility. While the power of pre-diction for single gene disorders conferred by thesequence is very good, it is currently much moremodest for the common, multifactorial diseases,

for which the phenotypes are likely to be causedby combinations of alleles. Functional genomicsapproaches may allow us to understand how theinteractions among gene products ultimately giverise to phenotypes of complex diseases. However,this will be very challenging and many componentswill have to be integrated to understand how thedisease phenotypes are generated.

Genomic research and its implications haveraised a range of issues for ethical and legal consid-eration. Health predictions and early detection areclearly of value where treatment or lifestyle modifi-cation are effective, but where there is little or noth-ing to be done the information may well producemajor stress for the individual and may adverselyimpact life insurance or employment. What shouldbe revealed and how the information is obtainedand used are becoming important considerations.Population-based collections of tissues and medicalhistories are invaluable resources for genomics butraise questions of the rights of the individual and ofthe researchers, as well as the interests of compa-nies keen to utilize the information in drug devel-opment. On the commercial front, there are validconcerns over patenting of genome information andits commercial exploitation. To be of benefit tosociety, the results of genomics research requirecommercial development by biotech and pharma-ceutical companies, and it is clearly in the financialinterests of universities and institutions to facilitatetechnology transfer. The problem is how to recon-cile the academic and industrial ethos — sharingof results versus confidentiality and patent rights.The results of publicly funded research should bemade freely available for the good of society, ashas happened with the human genome project, butthe commercial sector cannot operate in quite thesame way. While academic researchers should notbe restricted in what they can do and publish, atthe same time there has to be an easy transitioninto patenting, commercial application and devel-opment where different rules apply. Problems suchas these will have to be addressed to achieve thewidely anticipated benefits of the understanding ofthe human genome in this 50th anniversary yearof DNA.

Acknowledgements

I am grateful to Gert-Jan van Ommen and Ulf Landegrenfor comments on this article.

Copyright 2003 John Wiley & Sons, Ltd. Comp Funct Genom 2003; 4: 516–517.

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