Research Realizing the Promise of Genomics in Biomedical

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)

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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 representative 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- andI 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]).

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. Failing to mount a US-based cohort study New technologies must also integrate with older ones. For in the near future will compromise US scientists as well as instance, it is incorrect to assume that genetic testing will the ability to understand and improve health for US citi- soon relegate that old standby of genetics, the family his- zens. tory, to the dustbin. Instead, optimal patient care will use a combination of the old and new, as exemplified by inter- New Technologies pretation of BRCA1 testing, in which the risk that a woman New technologies, and new applications of those already es- who tests positive for a BRCA1 mutation will actually de- tablished, will enable and shape much of the future of ge- velop breast cancer is most precisely calculated based on nomics. An obvious example is genome sequencing. Over knowledge of her family history.24 Indeed, an important step the past decade, technological advances have lowered the in preparing patients and health professionals for the on- cost of sequencing at a fairly constant rate, halving it ap- slaught of new genomics-based clinical tools is to make the proximately every 22 months. Currently, sequencing 1000 use of the family history more efficient, effective, and ubiq- high-quality bases of DNA costs less than $1 (J. Peterson, uitous in health care.25 PhD, and K. Wetterstrand, MS, written communication, Au- The broad impact of genomics on health in the near fu- gust 1, 2005). It appears that refinements of the current gel- ture should come from its applications to diagnostics, phar- based sequencing methods will allow this trend to con- macogenomics, and drug development. Some genomic medi- tinue for another few years. Moreover, within a few years cine has already started to move from promise to reality. An new “disruptive” technologies, many based on single- example in diagnostics is the use of multigene analysis to

Downloaded from www.jama.com at Johns Hopkins University on February 16, 2009 COMMENTARIES predict the need for chemotherapy in certain breast can- society about genomics remains a vital challenge. Society cers.26 In pharmacogenomics, knowledge of a patient’s ge- will deal effectively with the complex issues unveiled by genetic makeup can sometimes help avoid adverse drug re- nomics only if a broad array of its members are sufficiently actions, as a study earlier this year showed for warfarin.27 knowledgeable and comfortable about the science in- In drug development, genomics can already salvage a drug volved to engage actively in societal discussion and deci- that might otherwise be abandoned, as demonstrated by ge- sion making. The societal impact of genomics also makes it fitinib, which has little benefit for the majority of those with imperative that genomics researchers reflect the society from lung cancer but may prove lifesaving in the sizable minor- which they come; otherwise, society’s interests in the re- ity with a specific genotype.28,29 search questions asked and how they are answered will be Successfully integrating genomics into health care will re- only incompletely represented. quire more than simply an understanding of how genetic One societal concern raised by new genetics technolo- factors influence health and drug response. Health profes- gies, ie, potential discrimination in health insurance or em- sionals will need to become genomically literate. New cur- ployment based on results of genetic testing, has been ap- ricula and educational models must be developed to achieve parent for several years and requires a national legislative that goal, an effort that the National Coalition for Health solution. Data show that, because of this concern, much of Professional Education in Genetics is spearheading.30,31 Be- the US public hesitates, or even refuses, to participate in ge- havioral science research will need to establish how best to netics research or to avail themselves of potentially helpful use genomic information to affect health behaviors, and out- clinical genetic testing.37 Fortunately, this year the US Sen- comes research will need to validate which applications of ate unanimously passed legislation, the Genetic Informa- genomics to health care are cost-effective. tion Nondiscrimination Act of 2005,38 that protects against Another challenge will be to apply the benefits of ge- such discrimination, and the president has indicated that nomic medicine to the developing world.32 It would be in- he would sign this bill. The bill has been introduced in the correct to assume that genomic approaches are irrelevant House of Representatives and is assigned to 3 committees, to the health needs of resource-poor nations. For example, but no hearings have yet been scheduled. the genome sequences of the Anopheles gambiae mos- It is also evident that genomics will alter views of race quito33 and the malaria parasite34 are both in hand, and and ethnicity. Much has been made about the facts made knowledge of genetic factors that influence host response clear by genomics that any 2 individuals share about 99.9% to malaria and its treatments is increasing.35 With such ad- of their DNA, that variation in the DNA sequence is greater vances, it is easy to foresee genomics contributing to more within population groups than between them, and that few, effective treatment and prevention for malaria, as well as if any, common DNA sequence variants occur only within many other leading causes of morbidity and mortality in the a single population group. Nonetheless, it is also clear that, resource-poor world. largely for geographic and historical reasons, some DNA variants differ significantly in frequency in different groups. Genomics and Society Among such variants will be those that help create the sur- Genomics will have a paradigm-altering impact, not only face physical features that many people use to identify, and on current understanding of biology and on health, but also some to define, racial and ethnic groups. How will identi- on other aspects of society. The ability to prepare for and fication of those variants affect concepts of race and eth- manage that societal impact will determine whether genom- nicity? Will it reify race as a biological concept or empha- ics lives up to its promise, as much as will the ability to use size the meaninglessness of using features influenced (and genomics effectively in biology and health. For instance, ge- not even fully determined) by only a small number of genes nomics will help unravel not only those complex gene- to define populations? Panels of variants, because of their environment interactions that lead to health and disease but population frequencies, are already being used to link in- also those that lead to many human traits; eg, genomics tools dividuals to certain ancestral populations.39 But the preci- will identify inherited factors that play a role in atheroscle- sion of such estimates is likely overstated by many com- rotic disease and diabetes but will also identify inherited fac- mercial suppliers. What happens when these “scientific” tors that play a role in traits such as height, nicotine depen- population assignments differ from those previously ap- dence, and intelligence. plied to individuals—either by themselves or by others? Will The wisdom of the traditional watchwords primum non this affect how health professionals approach individual pa- nocere applies to the societal implications of genomics at least tients and, for public health purposes, populations? Ge- as much as to its health implications. Recognition of this is nomics will force facing these sorts of questions. one reason for the financial and intellectual investment that the field of genomics has historically made in consider- Conclusions ation of ethical, legal, and social implications (ELSI) is- While the claims for the immediate impact of genomics have sues36—an investment unparalleled in biomedical re- sometimes been overstated, the ultimate consequences of search. It is also a reason that education of a broad array of the integration of genomics into medical research and medi-

Downloaded from www.jama.com at Johns Hopkins University on February 16, 2009 COMMENTARIES cal practice are likely to be revolutionary. By providing in- 15. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Comple- ment factor H polymorphism and age-related macular degeneration. Science. 2005; sights into the networks and pathways of biology, genom- 308:421-424. ics has already begun to alter the fundamental understanding 16. National Human Genome Research Institute. The ENCODE Project: ENCy- clopedia of DNA Elements. Available at: http://genome.gov/10005107. Accessi- of health and disease, even for diseases that few would de- bility verified July 27, 2005. scribe as “genetic.” By providing more sophisticated knowl- 17. Waterston RH, Lindblad-Toh K, Birney E, et al; Mouse Genome Sequencing edge of biology at the individual level and of disease typol- Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420:520-562. ogy, genomics has already begun to personalize health care. 18. Drews J. Drug discovery: a historical perspective. Science. 2000;287:1960-1964. By widening the number of potential drug targets and bet- 19. Zerhouni E. Medicine: the NIH Roadmap. Science. 2003;302:63-72. 20. National Center for Biotechnology Information. The PubChem Project. Avail- ter identifying those people a specific drug is likely to ben- able at: http://pubchem.ncbi.nlm.nih.gov/. Accessibility verified July 27, 2005. efit and those it is likely to harm, genomics has already be- 21. Collins FS. The case for a US prospective cohort study of genes and environment. gun to expand the pharmacopoeia. By offering novel Nature. 2004;429:475-477. 22. NCAB Working Group on Biomedical Technology. Report to National Cancer approaches to diseases that haunt the developing world, ge- Advisory Board. 2005. Available at: http://deainfo.nci.nih.gov/Advisory/ncab nomics has already begun to affect global health. By chang- /sub-bt/NCABReport_Feb05.pdf. Accessibility verified July 27, 2005. 23. Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH. Mul- ing societal discussion of race and ethnicity, genomics has tiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004; already begun to change society. 305:869-872. 24. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian Two years into the genome era, we have already begun cancer associated with BRCA1 or BRCA2 mutations detected in case series unse- to realize the promise of genomics—but the best is yet to lected for family history: a combined analysis of 22 studies [published correction come. appears in Am J Hum Genet. 2003;73:709]. Am J Hum Genet. 2003;72:1117-1130. 25. Guttmacher AE, Collins FS, Carmona RH. The family history: more important Financial Disclosures: None reported. than ever. N Engl J Med. 2004;351:2333-2336. 26. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of ta- REFERENCES moxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 27. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on tran- 1. Collins FS, Morgan M, Patrinos A. The Human Genome Project: lessons from scriptional regulation and warfarin dose. N Engl J Med. 2005;352:2285-2293. large-scale biology. Science. 2003;300:286-290. 28. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal 2. Watson JD, Crick FH. Molecular structure of nucleic acids: a structure for de- growth factor receptor underlying responsiveness of non-small-cell lung cancer oxyribose nucleic acid. Nature. 1953;171:737-738. to gefitinib. N Engl J Med. 2004;350:2129-2139. 3. Collins FS, Green ED, Guttmacher AE, Guyer MS. A vision for the future of ge- 29. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation nomics research. Nature. 2003;422:835-847. with clinical response to gefitinib therapy. Science. 2004;304:1497-1500. 4. Service RF. Genetics and medicine: recruiting genes, proteins for a revolution 30. National Coalition for Health Professional Education in Genetics. About NCHPEG. in diagnostics. Science. 2003;300:236-239. Available at: http://www.nchpeg.org/. Accessibility verified July 27, 2005. 5. Collado-Vides J, Medrano-Soto A, Tusie-Luna MT. With the finished human 31. Core Competency Working Group of the National Coalition for Health Pro- genome in hand, what next? Genome Biol. 2003;4:328. fessional Education in Genetics. Recommendations of core competencies in ge- 6. Sulston J. Beyond release: the equitable use of genomic information. Lancet. netics essential for all health professionals. Genet Med. 2001;3:155-159. 2003;362:400-402. 32. World Health Organization. Genomics and World Health: Report of the Ad- 7. Guttmacher AE, Collins FS. Welcome to the genomic era. N Engl J Med. 2003; visory Committee on Health Research. Geneva, Switzerland: World Health Or- 349:996-998. ganization; 2002. 8. Trent RJ, Williamson R, Sutherland GR. The “new genetics” and clinical practice. 33. Holt RA, Subramanian GM, Halpern A, et al. The genome sequence of the Med J Aust. 2003;178:406-409. malaria mosquito Anopheles gambiae. Science. 2002;298:129-149. 9. International HapMap Consortium. The International HapMap Project. Nature. 34. Gardner MJ, Hall N, Fung E, et al. Genome sequence of the human malaria 2003;426:789-796. parasite Plasmodium falciparum. Nature. 2002;419:498-511. 10. International HapMap Consortium. Integrating ethics and science in the In- 35. Coppel RL, Roos DS, Bozdech Z. The genomics of malaria infection. Trends ternational HapMap Project. Nat Rev Genet. 2004;5:467-475. Parasitol. 2004;20:553-557. 11. National Human Genome Research Institute. International HapMap Project. 36. A decade of ELSI research: a celebration of the first ten years of the Ethical, Available at: http://genome.gov/10001688. Accessibility verified July 27, 2005. Legal, and Social Implications (ELSI) programs: January 16-18, 2001 [abstracts]. 12. Crawford DC, Nickerson DA. Definition and clinical importance of haplotypes. J Law Med Ethics. 2001;29(2 suppl):1-65. Annu Rev Med. 2005;56:303-320. 37. Hall MA, Rich SS. Patients’ fear of genetic discrimination by health insurers: 13. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age- the impact of legal protections. Genet Med. 2000;2:214-221. related macular degeneration. Science. 2005;308:385-389. 38. Genetic Information Nondiscrimination Act of 2005, S 306, 109th Cong (2005). 14. Haines JL, Hauser MA, Scmidt S. Complement factor H variant increases the 39. Shriver MD, Kittles RA. Genetic ancestry and the search for personalized ge- risk of age-related macular degeneration. Science. 2005;308:419-421. netic histories. Nat Rev Genet. 2004;5:611-618.

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