PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. The Future of Human Genomics by Juergen K. V. Reichardt, Ph.D Juergen K. V. Reichardt Plunkett Chair of Molecular Biology (Medicine) The University of Sydney Medical Foundation Building (K25), room 135 92 - 94 Parramatta Road Camperdown NSW 2006 Australia Tel: +61 2 9036 3356 FAX: +61 2 9036 3357 Email: jreichardt@med.usyd.edu.au The sequencing of the human genome at the dawn of this century by two groups [1, 2] was justifiably heralded as a breakthrough. It promised seven years ago and still promises today major new advances in understanding ourselves as humans as well as the molecular etiology of diseases and their rational prevention, improved diagnosis and personalized treatment. However, I believe that at least three fundamental questions [3] must be answered to take full advantage of the promise of the full sequence of the human genome. 1. What is the molecular basis of complex diseases, such as cancer, diabetes, heart diseases and mental illness? 2. What is the function of ~1/3 of the human genome or some 10,000 “unknown” genes? 3. What is the functional significance of tens of millions of genetic variants in humans? Recently [3, 4], I proposed a set of interrelated research and educational approaches aimed at improving our understanding of the human genome. A two-pronged, long-term educational strategy is required to address the three issues in the human genome we raised above: (I) train an interdisciplinary research work force focused on complex diseases and genomes; and (II) train physician scientists (e.g. M.D. Ph.D.s) who can carefully dissect complex phenotypes into subcategories. The dawn of the golden age of molecular genetics and especially bacteriophage molecular biology in the last century saw an influx of physicists who brought their own ideas and intellectual approaches to create a completely new field of research [e.g. 5]. I propose that a similar interdisciplinary approach with new talent from within and from outside of biological research will rejuvenate and significantly advance human genomics and hence human health over the next decade or two [3, 4]. To address the issues raised by the etiology of complex phenotypes and the function of the many unknown human genes and genetic variants, more basic researchers and fundamental research are needed which will have to be inspired by new ideas (perhaps from within and from outside of current biological research). A broad interdisciplinary approach with new talent from within and from outside of biological research, including biochemists, bioinformaticians, cell biologists, chemists, epidemiologists, along with geneticists and genomic experts, will rejuvenate and significantly advance human genomics and hence human health in the coming years. An increase in the number of researchers who are inspired by new ideas (perhaps emerging from outside of current biological research and medicine) will help address the research priorities outlined above. The analysis of genes with currently unknown (or tenuously inferred) functions along with the analysis of the tens of millions of gene variants will certainly require researchers with an informatics background. However, in addition, we will almost certainly have to engage in traditional biochemistry and molecular biology again to unravel the function of the ~10,000 unknown human genes along with the tens of millions of genetic variants in the human genome [e.g. 1, 2, 3]. I note that some of the more traditional biochemical and molecular analyses may be considered outdated today but I firmly believe that they are essential for making substantive progress in the next 10-15 years [3]. These investigations may well lead to another golden age in biochemistry and molecular biology, reinvigorating these traditional disciplines in both current research activities and the contemporary training of young investigators [3, 4]. Furthermore, I suspect that many complex phenotypes currently are probably a rather heterogeneous collection of various entities with distinct etiologies [4]. In other words, most complex diseases currently involve multiple pathogenetic pathways because the current categorizations of phenotypes, such as atherosclerosis, diabetes and most cancers are probably way too broad. They presumably rather represent a heterogenous collection of really diverse phenotypes with a myriad of underlying mechanisms. Therefore, M.D.s and -- perhaps more importantly -- M.D. Ph.D.s with proper medical and rigorous scientific training must be educated by our universities [e.g. 4]. The physician scientists can then use their clinical insights, intuition, metrics and molecular tools to subclassify currently all-too-broad diseases into well-defined sub-phenotypes likely to have a single etiology. In summary, I propose that a renewed interest in the many unanswered and often ignored questions posed by the sequencing of the human genome be tackled now [1, 2, 3]. This comprehensive approach [4] will bring the full potential of the sequenced human genome to fruition for our own understanding as a species and the improvement of human health. I believe that we must address at least three basic questions over the next decade or two: i) the molecular basis of common complex diseases, such as cancer, diabetes, heart diseases and mental illness, ii) the function of ~1/3 of the human genome or some 10,000 “unknown” genes, and iii) the functional significance of tens of millions of human genetic variants. Synergistically the answer to these three big questions will improve human health allowing for rational disease prevention, better diagnosis and personalized treatment of disease. To this end, I suggest we reinvigorate basic and clinical research. In particular, physician scientists and scientifically inclined and trained physicians should attempt to carefully subclassify all complex disease phenotypes into precisely defined sub-phenotypes likely to be caused by a single mechanism using their clinical intuition along with all available molecular tools. This in turn will allow for more accurate molecular analyses to unravel the underlying molecular mechanisms of complex diseases without the probably devastating confounding of multiple etiologies. Furthermore, human geneticists and model organism geneticists along with other basic scientists such as biochemists, bioinformaticians and molecular biologists from within and outside of the biological sciences should comprehensively delve into the function of “unknown” genes and the many human genetic variants we all carry. In the long run, the proposed path consisting of scientific and educational approaches I advocate will fulfill the enormous promise of the sequence of the human genome. We will then grasp its full potential in not only understanding ourselves better but also understanding human diseases mechanistically. Therefore, many diseases may ultimately become preventable by rational, targeted approaches directed at one’s personal background, diseases will be diagnosed earlier and more accurately for better treatment, and treatment itself will be targeted accurately to the underlying mechanism and it will be personally based on someone's individual genetic background. Acknowledgements JKVR is a Medical Foundation Fellow at the University of Sydney. Work in his laboratory is also supported in part by NCI grant P01 CA108964 (project 1 to JKVR). References 1. Lander, ES et al. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15; 409(6822):860-921 2. Venter, JC et al. The sequence of the human genome. Science. 2001 Feb 16; 291(5507):1304-51 3. Reichardt, JK. Quo vadis, genoma? A call to pipettes for biochemists. Trends Biochem Sci. 2007 Dec; 32(12):529-30 4. Reichardt, JK. Realizing the Potential of the Sequenced Human Genome, Trends Genet. 2008 in press 5. Alberts, B et al. Molecular Biology of the Cell. 2002, 4th ed., Garland Science ### << Previous Next >> [ View All Perspectives ] |
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