The Human Genome Project

The human genome project: a false dawn?

R L Zimmern, director. 

Public Health Genetics Unit, Strangeways Research Laboratory, Cambridge CB1 4RN

The promise of the human genome project to transform biology and medicine is alluring. To document the sequence of bases, three billion in total, that make up the building blocks of human DNA is a formidable task requiring not only the knowledge and skills of the biochemist, geneticist, and molecular biologist but also the technological expertise of engineers and information scientists. Detailed genetic maps have already been constructed to resolutions of 1-2 centimorgans (cM),¹ and physical mapping has resulted in the integration into the genetic map of over 30 000 genes.² Similar efforts have led to the complete sequencing of smaller organisms, such as the bacterium Escherichia coli, the yeast Saccharomyces cerevisiae, and the worm Caenorhabditis elegans, many parts of which are homologues of sequences in the human genome.

New goals for the US Human Genome Project were defined in October 1998.³ These have included a commitment to complete a third of the human sequence and a "working draft" to cover 90% of the genome by 2001. The whole genome will be sequenced by 2003, two years in advance on the original target date. Sequencing technology will be improved and speeded up, and costs of sequencing each base pair will be reduced from current levels of $0.50 to an expected $0.25 within the next five years. There will be a drive to identify sequence variation, particularly single base pair differences (known as single nucleotide polymorphisms, SNPs), and to develop technologies for their rapid, large scale identification in populations. An SNP map of at least 100 000 markers will be created. The Wellcome Trust, with 10 of the world's leading drug companies and five of the world's leading genome laboratories, has also announced a collaborative effort costing $45 million to identify 300 000 SNPs, mapping half of them for use in epidemiological studies.⁴ The hope is that variations may be detected and that associations with common diseases may be made. Other goals of the human genome project relate to the development of functional genomics, the science of how genes and the environment interact to give rise to the cellular mechanisms that underlie biological processes; a study of comparative genomics; the ethical, legal, and social implications of the human genome project; bioinformatics and computational biology; and training.

	Benefits

Top Benefits Problems A synthesis References

But to what end "the burden and the heat"? Many physicians and scientists are confident of future benefits: of intellectual gains due to a greater understanding of disease mechanisms, and of an improved scope for therapeutic developments. ^{5 6} Yet, it is also claimed that the application of a taxonomy of disease, based on biochemical and molecular mechanisms, will transform the practice of clinical medicine, moving from a paradigm of diagnosis and treatment to one of prediction and prevention.

We can now distinguish not only the well known monogenic diseases such as cystic fibrosis but also subgroups of complex diseases such as cancer, osteoporosis, Alzheimer's disease, schizophrenia, diabetes, and asthma, in which the genetic contribution is a single gene mutation, from those where the causal mechanisms are truly polygenic and multifactorial. New epidemiological methodologies have also been developed to dissect out the exact size of the genetic component and to analyse the respective contribution of gene and environment and the influence of other modifying genes. ^{7 8} The ability to identify subtypes of breast cancer ^{9 10} and colorectal cancer ^{11 12} and to direct preventive strategies at people with high risk mutations have often been cited as examples of genetic mechanisms in complex, multifactorial disordersin reality these are but examples of subgroups with rare single gene mutations. Nevertheless, in day to day practice, cancer genetics has led to an increase in the workload of the medical geneticist.

An understanding of genetic risk factors and their interaction with the environment will allow diseases to be predicted and prevented, at both individual and population levels, by using environmental or behavioural interventions directed at genotypically susceptible individuals rather than by altering the genome itself.^13-15 Individuals may be identified because of family history or by genetic testing. Those susceptible will be offered diagnostic interventions such as colonoscopy, chemoprevention such as tamoxifen, or the removal of target organs, such as colectomy or mastectomy.

In time, the stratification of patients by reference to pharmacogenetic considerations will allow more appropriate, effective, and safer drug treatments, and may also permit doctors to determine risk and susceptibility to disease. Examples include hypertension¹⁶; cancer,¹⁷ where prognostic genetic markers will make more specific the use of adjuvant chemotherapeutic agents; and Alzheimer's disease,¹⁸ where the apolipoprotein E profile may also give prognostic, although as yet not diagnostic, information. Gene therapy provides another approach; currently it has limited practical value, but it has engendered much research interest.¹⁹

View larger version (31K): [in this window] [in a new window]   A model of disease prevention. Boxes on the left show some of the interventions which influence genetic risk; boxes on the right show factors which influence environmental risk

From a public health perspective, opportunities for interventions at a population level provide scope for optimism in the longer term. The use of screening programmes to identify subpopulations at increased risk of disease may lead to more specifically directed health promotion programmes and behavioural interventions. As yet, the only important examples have been in identiying rare high penetrance genes with low population prevalences, such as BRCA1 and BRCA2, but research is now directed at finding common polymorphisms of low prevalence which confer susceptibility and interact with environmental factors such as tobacco or nutrition. In the field of occupational medicine, considerations of increased susceptibility to chemical and other agents have prompted discussion of pre-employment screening and its ethical implications. Environmental toxicology provides an example of how pollutants and toxic substances may interact to produce disease at higher rates in genetically susceptible individuals. ^{20 21} A model of prevention based on these considerations is shown in the figure.

(Credit: NHGRI)

The ability to localise and sequence the genes responsible for the classic monogenic disorders has enabled doctors to be much more precise about the use of genetic tests. Relatives of patients with monogenic disease will be able to have their risk assessed accurately before symptoms develop and will have the opportunity to use newer reproductive technologies, such as pre-implantation genetic diagnosis, to prevent the births of children with disabling genetic disorders. Though these techniques avoid the abortion of an affected fetus, they still rely on the destruction of early embryonic cells.

	Problems

Top Benefits Problems A synthesis References

Will these benefits come about? Will "the hours of light return" to enable us to "discern ... all we have built"? Some are here already, particularly those related to prenatal testing and the prevention of monogenic disorders. But the promise and the optimism are not universally shared. Scepticism presents itself in different forms and guises. At a scientific level, there is now ready acknowledgment that the ascertainment of the genomic sequence is but the first of many complex steps in the understanding of disease processes. Within the genome, little is known of non-coding DNA sequences; of the mechanisms responsible for replication, RNA splicing, and control of gene expression; or of the role of structures such as centromeres and telomeres. The functional significance of DNA and RNA and the biological processes of the cell that are ultimately determined by gene action are to a large extent unanswered, or only answered in the most imperfect way, and will require many years of dedicated basic research. To the most pessimistic sceptics, the complexities of biological phenomena may be such that even with the most advanced computing technologies, the multitudinous interactions of gene with gene and gene with environment may defy analysis.

This complexity could well prevent the correlation of genotype with clinical phenomena. Variable expressivity and incomplete penetrance are already seen in the relatively simple monogenic disorders. Similar phenotypes may result from genetic heterogeneity, whether in the form of allelic heterogeneity (different mutations at the same locus) or locus heterogeneity (where mutations occur at different loci). By contrast, different mutations in the same gene may give rise to separate clinical effects, such as in the RET proto-oncogene, where certain activating mutations result in multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid cancer, and other inactivating mutations in Hirschsprung disease.²² Phenocopies, where environmental factors alone imitate genetic traits, may also confuse. The technical identification of the mutations themselves is fraught with difficulty and subject to error, resulting in tests of imperfect sensitivity and specificity. ^{23 24} As a consequence, the validity and predictive value of genetic testing may in many instances be poor and of little clinical use.

The uncertainties of genotype-phenotype correlations are moreover compounded by questions of preventability and of the psychological and social implications of greater genetic knowledge.²⁵ Even if genetic testing could determine with some degree of certainty that particular individuals were susceptible to certain environmental factors, it is far from certain that their behaviour would change to avoid the factor in question. Would they undertake the test at all, and if they did would their anxiety be increased? What would be the impact on society as a whole, and would widespread knowledge of population genetic traits lead to genetic discrimination? These factors could dampen the great promise that some people see for genetic testing, and for the importance of genomic research in general, although some optimism may be derived from evidence that people are more likely to respond positively to tests for physical diseases for which preventive interventions are available.

These attitudes are reinforced by what some see as a general ambivalence to the scientific method in our society²⁶; by a suspicion of technological developments; by an abhorrence of things judged to be "unnatural" (of which genetically modified foods are now bearing the brunt of public displeasure); by an antipathy to animal research and transgenic animals; by viewing the gene as an icon of scientific determinism, of the corporate power of the pharmaceutical industry, and of discriminatory practices²⁷; and by the legacy of the eugenics movement.²⁸ These representations oversimplify public attitudes, which are in reality more complex and able to distinguish subtly between what is perceived as acceptable or unacceptable. But the general suspicion remains and does much to dampen widespread enthusiasm for genetic and reproductive technologies.

Ethical considerations, such as the implications for insurance, employment, privacy, and confidentiality, also pose a thorny problem. Moreover, governments everywhere are attempting to contain health service costs, and evidence based medicine and economic considerations require detailed evidence that new technologies are both effective and efficient. These social factors, which determine the context in which science is practised and technologies are disseminated and accepted, cannot be ignored. As much as the science, they will influence the scope and pace of development.

	A synthesis

Top Benefits Problems A synthesis References

The paradigm of the new genetics and the human genome project is exemplified by huge tensionsbetween those who embrace the technology and science with fervent enthusiasm, and those whose suspicions and ethical concerns betray an antipathy directed at its most striking successes. In view of the complex ethical and social implications posed by the new genetics, the checks and balances which arise from the tensions may serve some useful purpose.

The funding of basic research in the fields of genetics and molecular biology by government, research councils, charities, and the pharmaceutical industry is not inconsiderable, and it shows an appreciation of the importance and potential of the subject. In the past two decades reproductive technologies such as in vitro fertilisation have been completely integrated into mainstream medicine, showing that the public is able to embrace scientific developments which it understands and perceives to be of benefit. The value of public consultation and participation is now universally accepted, showing that with information and knowledge the collective wisdom of lay people can do much to support the aspirations of experts and scientists, but equally that failure to involve them may result in rejection of even beneficial technologies.²⁹ The ethical, legal, and social implications programme within the human genome project is sensitive to the need to integrate the ethics and the sociology with the science and shows that lessons have been learnt about the importance of human values in the implementation of technology.

These trends point to an optimistic future, albeit one whose pace will be modulated by societal concerns. Technology will progress; the checks and balances will remain; the toil will continue; and the scientists "bear the burden and the heat of the long day, and wish t'were done." In time they will discern "all we have built," but the darkness will last a while, and it may be some years before "the hours of light return."

	Footnotes

Funding: The Public Health Genetics Unit is funded by the NHS.

Competing interests: None declared.

	References

Top Benefits Problems A synthesis References

1.	Murray JC, Buetow KH, Weber JL, Ludwigsen S, Shirpbier-Meddem T, Manion F, et al. A comprehensive human linkage map with centimorgan density. Science 1994; 265: 2049-2054[Abstract/Free Full Text].
2.	Deloukas P, Schuler GD, Gyapay G, Beasley EM, Soderlund C, Rodriguez-Tome P, et al. A physical map of 30,000 human genes. Science 1998; 282: 744-746[Abstract/Free Full Text].
3.	Collins FS, Patrinos A, Jordan E, Gesteland R, Walters L, members of DOE and NIH planning groups. New goals for the US Human Genome Project: 1998-2003. Science 1998; 282: 682-689[Abstract/Free Full Text].
4.	Woodman R. Wellcome Trust and drug giants fund marker database. BMJ 1999; 318: 1093[Free Full Text].
5.	Bell J. The new genetics in clinical practice. BMJ 1998; 316: 618-620[Free Full Text].
6.	Beaudet AL. Making genomic medicine a reality. Am J Hum Genet 1999; 64: 1-13[Medline].
7.	Khoury MJ, Beaty TH, Cohen BH. Fundamentals of genetic epidemiology. New York: Oxford University Press; 1993.
8.	Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994; 265: 2037-2048[Abstract/Free Full Text].
9.	Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 1995; 57: 1457-1462[Medline].
10.	Burke W, Daly M, Garber J, Bottain J, Kahn MJ, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. JAMA 1997; 277: 997-1003[Abstract].
11.	Dunlop MG. Science, medicine, and the future. Colorectal cancer. BMJ 1997; 314: 1882-1885[Free Full Text].
12.	Burke W, Petersen G, Lynch P, Bottain J, Daly M, Grauber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. JAMA 1997; 277: 915-919[Abstract].
13.	Khoury MJ, Genetics Working Group. From genes to public health: the applications of genetic technology in disease prevention. Am J Public Health 1996; 86: 1717-1722[Abstract/Free Full Text].
14.	Khoury MJ. Genetic epidemiology and the future of disease prevention and public health. Epidemiology Reviews 1997; 19: 175-180[Abstract/Free Full Text].
15.	Coughlin SJ. The intersection of genetics, public health, and preventive medicine. Am J Prev Med 1999; 16: 89-90[Medline]
16.	Brown MJ. Science, medicine, and the future: hypertension. BMJ 1997; 314: 1258-1261[Abstract/Free Full Text].
17.	Pharoah PDP, Caldas C. Molecular genetics in the assessment of human cancer. Exp Rev in Molec Med (www-ermm.cbcu.cam.ac.uk/99000526a.pdf; accessed 11 March 1999.)
18.	Saunders AM, Hulette C, Welsh-Bohmer KA, Schmechel DE, Crain B, Burke JR, et al. Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease. Lancet 1996; 348: 90-93[Medline].
19.	Russell SJ. Science, medicine, and the future: gene therapy. BMJ 1997; 315: 1289-1292[Free Full Text].
20.	Omenn GS. Genetic susceptibility and the estimation of risk. In: Gordis L, ed. Epidemiology and health risk assessment. New York: Oxford University Press, 1988:92-104.
21.	Khoury MJ, Adams MJ, Flanders WD. An epidemiologic approach to ecogenetics. Am J Hum Genet 1988; 42: 89-95[Medline].
22.	Mak YF, Ponder BA. RET oncogene. Curr Opin Genet Dev 1996; 6: 82-86[Medline].
23.	Holtzman NA. Proceed with caution: predicting genetic risk in the recombinant DNA era. Baltimore. Johns Hopkins University Press, 1989.
24.	Institute of Medicine. Assessing genetic risks: implications for health and social policy. Washington DC: National Academy Press, 1994.
25.	Marteau TM, Croyle RT. The new genetics: psychological responses to genetic testing. BMJ 1998; 316: 693-696[Free Full Text].
26.	Gillott J, Kumar M. Science and the retreat from reason. New York: Merlin Press, 1987.
27.	Hubbard R, Wald E. Exploding the gene myth. Boston: Beacon Press, 1997.
28.	Thom D, Jennings M. Human pedigree and the `best stock': from eugenics to genetics? In: Mateau T, Richards M, eds. The troubled helix. Cambridge: Cambridge University Press, 1996:211-234.
29.	Welsh Institute for Health and Social Care. Report of the citizens' jury on genetic testing for common disorders. Pontypridd: University of Glamorgan, 1997