Realizing the Promise of Genomics in Biomedical Research Alan E. Guttmacher; Francis S. Collins Online article and related content current as of February 16, 2009. JAMA. 2005;294(11):1399-1402 (doi:10.1001/jama.294.11.1399) http://jama.ama-assn.org/cgi/content/full/294/11/1399 Correction Contact me if this article is corrected. Citations This article has been cited 31 times. Contact me when this article is cited. Topic collections Statistics and Research Methods; Genetics; Genetic Counseling/ Testing/ Therapy Contact me when new articles are published in these topic areas. Subscribe Email Alerts http://jama.com/subscribe http://jamaarchives.com/alerts Permissions Reprints/E-prints [email protected] [email protected] http://pubs.ama-assn.org/misc/permissions.dtl Downloaded from www.jama.com at Johns Hopkins University on February 16, 2009 COMMENTARIES Realizing the Promise of Genomics in Biomedical Research Alan E. Guttmacher, MD Another current initiative is the Encyclopedia of DNA El- ements project,16 which seeks to completely identify the bio- Francis S. Collins, MD, PhD logical mechanisms active in a carefully chosen represen- tative selection (about 1%) of the human genome. This effort N APRIL 2003, THE HUMAN GENOME PROJECT ACHIEVED has become increasingly important as evidence has mounted all of its original goals, including production of a fin- that not only the small portion of human DNA that codes ished sequence of the human genome.1 With that his- for proteins has biological importance. In fact, evolution- toric achievement, the Human Genome Project ended ary comparisons between multiple mammalian genome se- Iand the “genome era” began. Especially because this tran- quences indicate that about two thirds of the most strongly sition occurred only days before the 50th anniversary of Wat- conserved elements of the human genome fall outside of these son and Crick’s article describing the DNA double helix,2 it protein-coding regions.17 The “junk” in “junk DNA” de- led to much discussion regarding the future of genetics and scribes the current level of understanding of this part of the genomics and how they would affect biological explora- genome, not its biological significance. tion, health, and even society.3-8 Now, 2 years into the ge- Another ongoing effort that will help realize the promise nome era, is biomedical research any closer to that future, of genomics is in the area of “chemical genomics.” The goal and, if so, what does it look like? of this application of genomics is to expand the universe of small molecules that can be used as probes for understand- Current and Future Genome Initiatives ing biological pathways. While the human genome appears Several current genome initiatives afford a look at the fu- to contain more than 20 000 genes, the entire current phar- ture even as they bring it closer. One is an international ef- macopoeia targets only about 500 genes and their prod- fort to create a haplotype map (HapMap) to explore varia- ucts.18 In the past decade, advances in combinatorial chem- tion within the human genome.9,10 Now rapidly approaching istry have allowed the generation of libraries that contain completion, the HapMap Project11 has already provided les- hundreds of thousands of compounds, representing a broad sons about geographic distribution of human genome varia- diversity of chemical shapes. Improved methods of high- tion and has contributed convincing evidence that the varia- throughput screening have made it possible to screen these tion in the human genome is organized into local libraries with assays for particular targets, generating ago- neighborhoods, or haplotypes.12 Because of this structure, nists and antagonists for particular proteins, pathways, or cel- knowledge of which base is located in a particular variable lular phenotypes. However, most of this activity has occurred position of an individual’s genome sequence allows very good in the private sector, where only a minority of targets have prediction of the variants present nearby, a phenomenon been pursued as being “druggable.” As part of the Roadmap referred to as linkage disequilibrium. These regions of dis- process,19 the National Institutes of Health has recently estab- equilibrium operate over variable distances, but often stretch lished a network of chemical genomics centers available to across 10 to 30 kilobases. The HapMap project is defining all researchers, as well as a new database, PubChem,20 that the boundaries of these segments of linkage disequilib- makes much of the resultant data freely accessible. Availabil- rium across the whole genome. This now allows research- ity of these tools will enable academic researchers to broaden ers to choose a panel of a few hundred thousand single- the diversity of targets for chemical genomics. While most of nucleotide polymorphisms (SNPs) that ably represent the compounds identified in this way will be limited to use variation across the whole genome and, by genotyping only as research probes, a small percentage may even go forward this panel, to achieve an excellent first approximation of the into early-stage drug discovery. common variants in an individual’s entire, 3-billion–base Another critical area of current emphasis is to under- pair genome. HapMap-based SNPs already have enabled re- stand the complex interactions of genetic and environmen- search that was impractical, if not unimaginable, only a few years ago. An example is the research published this year Author Affiliations: National Human Genome Research Institute, National Insti- tutes of Health, Bethesda, Md. that identified the complement factor H gene as commonly Corresponding Author: Alan E. Guttmacher, MD, Room 4B09, 31 Center Dr, Na- involved in age-related macular degeneration.13-15 tional Institutes of Health, Bethesda, MD 20892-2152 ([email protected]). ©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, September 21, 2005—Vol 294, No. 11 1399 Downloaded from www.jama.com at Johns Hopkins University on February 16, 2009 COMMENTARIES tal factors in health and disease. Case-control studies have molecule sequencing on solid supports, should accelerate proved valuable in adding to such understanding. In the past, this rapid decrease in sequencing costs. If that proves true, however, such studies have generally been forced to limit the promise of the $1000 genome may be less than a de- their search to candidate genes. Given that the chosen can- cade away. didate genes were generally based on hunches with a high Whether within 10 or 12 (or 8) years, such inexpensive risk of error, such studies have frequently lacked power or sequencing will change both research and clinical care, and have uncovered only weak associations that held up poorly progress does not need to wait even that long. The Na- in replication studies. That is all about to change. The use tional Human Genome Research Institute (NHGRI) plans of new tools, particularly the HapMap, should dramati- to focus a significant portion of the sequencing capacity that cally increase the usefulness and power of case-control stud- it supports on medical sequencing. For instance, the NHGRI ies by making practical a SNP-based methodology that ef- and the National Cancer Institute are actively considering fectively samples the entire human genome. Based on this a Human Cancer Genome Project,22 which would use DNA approach, it is likely that many of the major gene variants sequencing and a host of other genome technologies to gather that contribute to diabetes, heart disease, Alzheimer dis- information about the mutations and functional abnormali- ease, common cancers, mental illness, hypertension, asthma, ties found in multiple samples from many major types of and a host of other common disorders will be discovered cancer. Medical sequencing should also provide important in the next few years. insight into many other diseases. For example, sequencing Despite the usefulness of case-control studies for discov- all exons in X-linked mental retardation syndromes may re- ering gene variants associated with increased disease risk, veal much about their etiology. Sequencing candidate genes they have limits. They often contain significant biases due in the extremes of the distribution of quantitative traits should to case ascertainment methodology, provide little informa- also reveal much of importance about common diseases, such tion about predictive biomarkers, and are flawed with re- as coronary atherosclerosis.23 With further technological ad- spect to determination of environmental risk factors be- vances, other previously unimaginable research ap- cause of recall bias. For these and other methodological and proaches will become real. biological reasons, rigorous quantitative understanding of Similarly, clinical care will change dramatically. In a rela- the role of genes and environment in health and disease can tively few years, when the role of specific genetic factors in come only from large, population-representative, prospec- disease is more fully understood and a human genome can tive cohort studies.21 Several such studies have recently be- be sequenced for less than the cost of a colonoscopy (for gun or entered the planning stage in a number of coun- example), an individual’s sequence will likely become part tries. These will be important resources for understanding of the standard medical record, especially since, unlike the the relationships among genetic and environmental factors colon, an individual’s genome sequence is relatively static. and health and disease. But, no matter how helpful studies Thus, unlike colonoscopy, sequencing will not require fre- in other countries are, they alone cannot meet the needs of quent repetition. Similarly, it will become the standard of the United States. Only a US-based study could adequately care to sequence cancer patients’ tumors and to use that in- sample important US minority populations, gather data about formation to refine prognosis and guide therapy. environmental risk factors characteristic of the United States, and provide US researchers with full access to data and bio- Genomics and Health Care logical specimens.