The human genome project: misguided science policy

TIBS 1 6 - DECEMBER .~991

DISCUSSION FORI THE DECISIONto map and sequence the human genome (The Human Genome Project or HGP) raises a number of important issues. These include ethical questions over the use of genetic information, the scientific merit of the project, whether such big scientific initiatives or smaller projects generate technological breakthroughs, and the relative influence of scientists, politicians and the media in setting scientific priorities and science policy. This critique of the HGP focuses on two issues: is it good science policy? and is it good science? I will draw examples from the American HGP but similar arguments will apply to similar national and international initiatives ~.z. Genome projects have also been proposed for an expanding list of model organisms, including dogsa and rice4.

Odjns of the HGP in their accompanying articles, Yager and Hood suggest that major discoveries in genetics and molecular biology made the undertaking of the HGP possible and perhaps even inevitable. However, other areas of biochemistry have experienced similar technological breakthroughs. For example, our understanding of protein structure is based on major developments in peptide chemistry, X-ray crystallography and nuclear magnetic resonance. Nevertheless, ! would hesitate to argue that these advances in physical biochemistry justify spending three billion dollars on solving the structures of randomly selected human proteins. The political involvement in the origins of the HGP is unique for an undertaking in the biological sciences. The HGP did not rise from a broad consensus among scientists or physicians that the information was badly needed. Rather, the project was initiated within the US Department of Energy by Charles De Lisi from the Los Alamos Laboratory, New Mexicos. A bill to fund the HGP was subsequently introduced by New Mexico Senator DomeniciT. A strong case can be made that the pro-

Genome mapping and sequencing projects are inappropriate and wasteful expenditures of precious research funds. By focusing on the acquisition of nucleotide sequence;, the various genome projects emphasize the products of 3cience over the process of science. It is doubtful that much of the resulting information will provide insights into human diseases or fundamental biological processes. The routine nature of genome sequencing makes it ill-suited for training young scientists. Such projects may also hamper the education of future investigators by diverting research support from universities to genome centers and commercial firms.

ject owes its existence to this powerful US Senator, who remains the project's major political advocate s.

The HGPand sciencepolicy A major objection to policy aspects of the HGP centers on the important question: who should formulate science policy? I do not believe that scientists have an inherent right to government support. Society must decide how much of its wealth is devoted to scientific research. However, once that decision has been made, there should be justifiable scientific or medical reasons for allocating those funds. Prior to the HGP initiative, the genes for cystic fibrosis, muscular dystrophy and numerous cancers had been located by traditional mapping procedures supported by traditional funding mechanisms of the US National Institutes of Health (NIH). Indeed, the NIH was spending $300 million per year on mapping efforts well before the HGP surfaced 7. The addition of the genome project brings this amount to a staggering half billion dollars annually. As argued above, this money was added through the efforts of politicians and not scientists. The HGP is poorly formulated policy for other reasons. It has created a deep rift within the US biological community. The past several years have been extremely lean for US scientists, es-

M. C. Rechstelneris at the Departmentof Biochemistry,Universityof UtahSchoolof Medicine,Salt LakeCity, UT84132, USA. © 1991,ElsevierSciencePublishers. 0JK) 0376-5067/91/$02.00

pecially those funded by NIH. At a time when less than one grant in eight received funding, when annual budgets of existing grants were cut by 10--20%,and when many newly appointed assistant professors could not obtain support to begin their research careers, we saw the disbursal of enormous sums of money to a handful of genome researchers. Is it surprising that such a policy created significant resentment? Awarding mega-grants to a few established senior scientists while struggling young investigators went unsupported was certain to be demoralizing. Many who witnessed the plight of our young colleagues were dismayed and remain angry to this day. The HGP diverts funding from university laboratories to centers, thus having a negative impact on training future scientists. The US genome project eventually plans to spend $200 million annually, which translates into more than I000 research grants from the NIH - or about seven grants for each major research university in the US. Each grant would support a diverse collection of undergraduates, graduate students and post-doctoral fellows, thus providing tremendous educational benefit in addition to the new knowledge gained. By contrast, the diversion of funds to genome centers may result in

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Table I. Agenda and schedule of the HGP

DECEMBER 1991

subtilis (a Gram-positive bacterium) and two species of mycobacteria (causPeriod O~e~ives ing leprosy and tuberculosis, respectively). Mapping and sequencing the Improve technologies for mapping, sequencing and informatics 1990-1995 genomes of this evolutionarily diverse Create low-resolution genetic (2-5 cM) and physical (STS) maps of the human genome Create high-resolution genetic (1-2 cM) and low-resolution physical maps of mouse set of model organisms will allow infergenome ences to be drawn about the evolution Complete the genetic and physical maps of simple model genomes of genes and their regulatory elements. Complete several 1-5 Mb pilot sequencing projects (specific NIH/DOE goals are 10 Mb of human sequence, and 20 Mb of sequence from model genomes) In addition, it will aid in determining the function of genes that are found in 1995-2000 Continue to improve genome technologies the human genome. (The function of a Refine the human genetic map (to a resolution of 1-2 cM) gene can readily be assessed in a model Refine the physical map of the human genome (<1 Mb spacing of STSs) Finish the mapping and sequencing of simple model genomes organism by a combination of studies Attempt several pilot sequencing projects that are significantly larger than those of the involving ablation ~7, complementationTM, first phase (each ~1% or more of the human genome) site-directed mutagenesis s2 and a s s a y for the stage- and tissue-specificity of Sequence last 95% of human genome (excluding tandemly repeated DNA) 2000-2005 Sequence regions of the mouse genome that correspond to biomedically important expression19.) regions of the human genome Technology development. Methods for Study important human polymorphisms (e.g. HI_A) oligonucleotide synthesis, genetic and Create working version of integrated database (to contain genetic, physical and sequence maps of human and model genomes) physical mapping and DNA sequencing must be substantially improved before Broader issues that will receive both immediate and long-term study a complete analysis of large genomes • Development of format of database for the genetic, physical and sequence maps will be feasible. As a first step, existing • Systematic study of gene function (ablation, ccmplementation, expression studies) methods (such as the Sanger dideoxy• Definition of (tissue- and stage-specific) mRNA expression patterns method for sequencing DNA) will be • Definition of transcriptional control networks in development • Mapping and sequencing the genomes of additional model organisms streamlined, automated and made • Study of social, ethical and legal issues of genome research more sensitive. (For example, the detection of dideoxy- sequencing ladders may be greatly enhanced through continued from page 454 specific cDNAs). Multiple sequence use of resonance ionization specdeterminations will be made at some troscopy or mass spectrometry2°.) A more ambitious goal is to develop (3) Overlapping clones in a library can loci in the human genome, to a s s e s s be rapidly identified by screening with the prevalence and importance of entirely new technologies for DNA STSs ~3,~4. This should allow the con- mutations and polymorphisms ~5. sequencing, that are 100-1000 times struction of 'contigs' (sets of contigu- Because of the low information content faster and cheaper than existing methous overlapping clones) for much of and severe technical difficulties, most ods. Thus investigations are underway the human gennme in a variety of of the tandemly repeated DNA (cen- on the possibility of sequencing DNA cloning vectors (e.g. YAC, P1 and cos- tromeric and telomeric satellite se- by single-molecule digestion, hybridizmid vectors). (4) Finally, polymorphic quences) in the human genome will not ation to oligonucleotide libraries or scanning-tunneling microscopy2° STSs can be used as points of corre- be sequenced. Computational tools. N e w t y p e s of c o m spondence between genetic and physiModel organisms. Genetic, physical and cal maps ~2,~4. nucleotide sequence maps will also be p u t a t i o n a l hardware and software must DNA sequence. Over the course of the obtained from the genomes of two cat- be developed to manage the day-to-day HGP, the nucleotide sequence of a sub- egories of model organisms. (1) One operatiom of large-scale mapping and stantial portion of the human genome category is represented by the mouse sequencing projects, to analyse the will be determined. However, the as a mammal closely related to humans complex signals and images generated timetable of this endeavor will be set in terms of developmental pathways, by data-acquisition devices (e.g. the by the rate of evolution of DNA genome size and complexity, and evolu- fluorescent DNA sequencer), and to sequencing technology. Until this tech- tionary homology in the chromosomal extract meaningful information from nology is greatly improved, only small arrangement of genes 16. Because gen- DNA and protein sequences (which, in pilot projects (1-5 Mb each) will be etic crosses between inbred strains and abstract terms, are ordered strings of attempted. Most of these pilot projects subspecies of mice can be prepared alphabetical symbols). In addition, new will focus on sequencing the genomes easily, there should be rapid progress database formats must be explored, so of simple model organisms such a s toward constructing a dense genetic that the information generated by the Escherichia coil, from which the yield of map and localizing important disease HGP can be clearly presented to biolinformation is expected to be high. For genes in the mouse. (2) There is an ogists and physicians. Ultimately, a the human genome, priority will be international commitment to map and database system will be created to given to regions that are biologically or sequence large portions of the present the genetic, physical and medically important, or that have a genomes of Drosophila melanogaster sequence maps of the human and high information content (e.g. major (fruit fly), Caenorhabditis elegans, model genomes, as well as clinical disease genes, dense genomic coding (nematode worm), Arabidopsis thaliana descriptions of genetically determined regions such as the major histocom- (a simple plant), Saccharomyces cere- diseases and traits. This system will patibility or T-cell receptor loci, and visme (baker's yeast), Escherichia coil loci corresponding to tissue- or stage- (a Gram-negative bacterium), Bacillus continued on page 458

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armies of technicians skilled only at obtaining DNA sequences and entering the results into computer data bases. Even the most ardent HGP proponents admit ~r that sequencing is tedious work. And, according to a recent news account 9, there is clear disagreement among those supervising initial phases of the project as to whether the job is suitable for scientists with doctorates. Walter Gilbert, an HGP advocate and recipient of a genome project grant to sequence the Mycoplasma capricolum genome, will use production-line technicians for the task9. I firmly believe that our brightest students will not wish to be involved in large-scale sequencing. In this regard, Gilbert is almost certainly correct to choose technicians over postdoctoral fellows. Because the long-term health of biomedical research depends upon vigorous training programs, it is bad science policy to fund technicians at the expense of university laboratories. The HGP is also an unreasonable medical undertaking. A rational health policy first seeks cures for the major diseases prevalent in society. The HGP diffuses the focus from principal killers (in the US these are cardiac disease, cancer and substance abuse) to all genetic diseases no matter how many or how few individuals may be afflicted. The proportion of genes that are directly implicated in causing disease may, in fact, be quite small. Moreover, there is no assurance that the gene sequences, once known, will make major contributions to effective therapies. For this reason the HGP is poor medical policy. Advocates of the HGP often emphasize the development of new sequencing technologies as a justification for the undertaking 5,]°. Surely, improving

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sequencing speed at lower cost would be better left to commercial firms, such as ABI or Milligen. After all, they would realize immediate profits by such improvements. Furthermore, DNA sequencing is rarely rate-limiting in the solution of biological or medical problems.

Is the HGP good science? I admit that knowing the entire human genome sequence would provide some useful information, but only some. Good biological approaches might be defined by the insight gained into biological structure and function relative to the effort expended. Using this criterion, the HGP is mediocre science. Consider, for example, the question 'how useful is a cDNA sequence?' The sequence of the important human oncogene p53 has been available for

almost a decade H, yet we still have little insight into the function of the p53 protein. Another example is provided by a second major contributor to human cancer. Who would have guessed from the sequence of Ha-Ras that the protein's carboxyl terminus is modified by farnesylation, palmitylation, methylation and proteolysis and that these posttranslational modifications are necessary for oncogenicity]2? l contend that sequencing a diseasecausing gene will provide medical insight only in proportion to how much basic biochemistry or physiology is already known. In the absence of prior studies on function, new cDNA sequences will often be of limited value. As for the >95% of the human genome that exists as pseudogenes, continued on page 459

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T I B S 1 6 - DECEMBER 1991

DNA sequence (e.g. the complete sequences of metazoan chromosomes), incorporate text, graphics and pointers which will provide a direct and immedito other databases and to the scientific ate challenge to this field. Exhaustive and medical literature, and will be analysis of such sequences (which may accessed through a sophisticated contain errors at a low frequency24)will query language 2~'2~. Its availability will not be trivial. Applied sciences. (1) Genetic diagnosis change both the design of experiments in biology and the process of diagnosis in medicine. A dense genetic linkage map will aid in the analysis of diseases and treatment in medicine. The HGP has other goals that do not that are polygenic in origin or that have fit neatly into a single category. These both hereditary and environmental include study of the ethical, legal and components. Medically important exsocial implications of genome research; amples of such diseases include canestablishment of interdisciplinary train- cer, coronary heart disease and certain ing programs; and transfer of genome neurological or psychiatric disorders". technology from research laboratories (2) Animal models. A limiting factor in to the private industrial sector. the study of many human diseases is Concerning the last of these goals, it the lack of an appropriate experimental must be admitted that different nation- model. Mapping and partial sequencing al governments are motivated to fund of the mouse genome will allow mouse the HGP in part because of the 'spin- models to be developed for many offs' they anticipate for their own human diseases. (3) Tissue identifibiotechnology industries. We discuss cation and forensics. The HGP will supsome of these issues further below. port the study of polymorphisms in many regions of the human genome. Creation of scientific opportunities This in turn will lead to the design of During its brief history, the HGP has rapid and sensitive tests to distinguish contributed to science mainly through idiotypes on the basis of DNA sequence the development of new technologies. differences25. (4) Agriculture. It is now However, the addition of genetic, physi- possible to rapidly create high-resolcal and sequence maps to the biologi- ution genetic linkage maps for specific cal and medical 'infrastructure' should organisms, e.g. commercially important stimulate advances in many pure and farm animals and crop plants. The applied scientific fields, as we illustrate existence of such maps will allow the with a few examples. selective breeding of new strains of aniPure sciences. (1) Genomics. This mals and plants that present desirable branch of molecular biology deals with and commercially important multigenic the structure, organization, instabilities traits 2G. and evolution of large genomes 23. Some of the methods required to study large The timetable genomes (e.g. in situ mapping of genes it is hard to predict an accurate in interphase nuclei, cloning in YACs timetable for the HGP because of the and contig construction by fingerprint- rapid evolution of ideas and technology. ing) have come directly from the HGP. Nonetheless, we venture a rough Other methods (e.g. fluorescent DNA prediction in Table !, which may be sequencing, oligonucleotide synthesis) altered by future discoveries or by have been streamlined and automated changes in funding. The HGP is proby the HGP. The field of genomics relies posed to have three five-year phases. heavily on the comparison of DNA The first phase (1990-1995) will focus sequences between species which mainly on technology development. allows the detection of functionally Projected milestones will include the important conserved regions (e.g. pro- construction of low-resolution genetic tein-coding sequences, regulatory el- and physical linkage maps of the ements). Efforts at sequence compari- human genome, and the completion of son will be greatly stimulated by the perhaps ten moderate-scale (1-5 Mb) HGP. (2) Informatics. This field is a pilot sequencing projects (each involvmeeting-ground between mathematics, ing, for example, a yeast chromosome linguistics, cryptography and computer or a major human disease locus). The science. It deals with problems such as second phase (1995-2000) will continue the recognition of inlormative patterns to focus on technology development. in strings of alphabetic symbols (such Projected milestones include the refineas DNA sequences). The HGP will gen- ment of the human genetic and physierate long uninterrupted stretches of cal maps, and completion of a few pilot continued from page 456

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sequencing projects on a scale significantly larger than attempted in phase I. (Each pilot project might, for example, involve sequencing a small human chromosome or the genome of a model organism.) The third phase (2000-2005) will focus mainly on sequencing a substantial portion of the human genome (but only if the technology proves equal to this task, and if a sufficient monetary commitment is made). The bulk of this sequencing effort probably will be subcontracted to firms in the private industrial sector. Projected milestones will include completion of most of the human genome sequence, and full implementation of the database of genetic, physical and sequence maps. Currently the HGP suffers from serious bottlenecks at several levels but we expect that these will be eventually removed by advances in technology. For example, a method has recently been developed for automated typing of alleles at genetic loci, based on the oligonucleotide ligation assay ~4. Currently, this method allows 600 DNA samples to be typed per day. Another example of a technology advance is the development of a computer chip that can scan a sequence database at a rate approaching 107 characters per second, to match an arbitrary input sequencezT. Comparable advances in large-scale DNA sequencing may well occur in the next decade, because substantial resources are now being devoted to this problem 2°.

The HGP is not 'Big Science' Modern science employs three distinct types of management structure. (1) Most research is conducted by single groups having less than ten members. A principal investigator directs a group's research effort and pursues the necessary funding. (2) Multidisciplinary centers, composed of 10-30 members each, bring together scientists (and occasionally engineers) with diverse but complementary backgrounds. These centers usually focus on problems of a technological nature, and employ a combination of resources and skills that are not common in groups of the first type. An example of a multidisciplinary center is our NSF Center for Molecular Biotechnology at Caltech. This center is developing new automated technologies for purifying and sequencing proteins and DNA, for continued on page 460

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repeated sequences and introns, I believe these serve mainly to space exons or represent junk DNA. Obtaining the sequence of these genomic regions is, in my view, simply a waste of money and effort. The HGP is mediocre science in another way. For me the finest science is characterized by relevant hypotheses tested with elegantly designed and competently performed experiments. The HGP is little more than a massive data-collecting effort. In addition, there is reason to suspect that even the data collection will not be performed with sufficient accuracy. Several groups involved in the early sequencing trials are reported as considering an error rate of one base per thousand adequate. In fact, sequences containing 1-5% error were said by several genomists to be useful for some purposes 9. Frameshifts certainly must have been neglected in such considerations.

I want to touch on one last aspect of the HGP. Defense of the initiative has resulted in some of the most egregious hype in recent memory 13. As Paul Billings, a supporter of the HGP, has stated TM 'Advertising the HGP with slogans equating the complete genetic map to the "grail," the "essence of human life" or a "blueprint" for understanding human biology creates an aura of unbelievability around a concrete task and a potential for a public-political backlash.' On this point I am in wholehearted agreement with Billings. Certainly most would accept the proposition that scientists, like all citizens, have to consider the benefit to society of their activities. They also bear a clear responsibility for offering reasonable predictions of project utility and success. Use of vastly inflated rhetoric to advocate funding will, in the long run, prove harmful to every branch of science. In summary, the HGP represents a series of bad decisions. It was initiated

[or political, not scientific reasons; it offers little opportunity for training the next generation of scientists; it fails to target the major human diseases; it has generated deep division within the US scientific community; and it represents mediocre science. Genome projects should be severely curtailed or, better still, abandoned. The research funds so liberated could be used much more wisely.

References 1 2 3 4 5

Coles, P. (1990) Nature 347,701 Swinbanks, D. (1993.) Nature 351,593 Holden, C. (1991) Science 252, 382 Ferrell, J. (199t) Nature 353, 99 Yager, T. and Hood, L. (1991) Trends Biochem. ScL 16,454-461

6 Merz, B. (1987) J. Am. Med. Assoc. 258, 1131 7 Merz, B. (1988) J. Am. Med. Assoc. 259, 15 8 Roberts, L. (1991) Science 253, 376 9 Roberts, L. (1990) Science 250, 3.336 10 White, R. L and Gesteland, R. F. (1990) FASEBJ. 4, 2942 11 Michalovitz, D., Halevy, O. and Oren, M. (1991) J. Cell. Biochem. 45, 22 12 Touchette, N. (1990) J. NIH Res. 2, 61 13 Martin, R. G. (3.990) New Biol. 2, 747 14 Billings, P. R. (1990) Science 250, 1071

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physical mapping of DNA clones, for genetic diagnostics, and for computerized analysis of DNA sequence. (3) 'Big Science' involves the creation of a single, very expensive instrument, and its deployment in one location over a specific time period. Examples of big science in the USA include the Hubble Space Telescope and the Superconducting Supercollider. A big science project depends critically on the proper design and function of a central instrument or facility, and typically involves a strict apportionment of instrument time between a large number of individuals. What type of management structure does the HGP have? Obviously, this project does not depend upon any single instrument, or indeed upon any single conceptual scheme. Rather, it encompasses many different perspectives, strategies and techniques, and involves many individual research groups and dedicated genome centers around the world. Scientific results are obtained incrementally and in a decentralized fashion, and are often confirmed by independent laboratories. Thus the HGP clearly does not fit the historical definition of big science. We believe a more apt comparison can be made to the 'War on Cancer' of the 1970s, which involved many individual research groups and dedicated cancer research centers, and employed a variety of perspectives, strategies and techniques. The HGP will be realized through grants to individual investigators and genome centers. The majority of funding will be given to individual investigators (see below). However, a fiscal commitment has also been made to the genome centers, so that technology development can be addressed with a multidisciplinary perspective. To illustrate the potential for genome centers to make a unique contribution to technology development, consider the problem of large-scale mapping and sequencing. Current methods must be streamlined and automated to become cost-effective and new technologies may be required to speed up the process. To solve these problems, contributions from many different disciplines may be required, which would be hard to bring together in an individual research group. Moreover, it is not usually feasible for a small research group to design and test a prototype for automation, because of the high

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expense and low priority of funding from traditional grant sources. Also the design and testing of prototypes is not immediately profitable, and thus will not be aggressively pursued in the private industrial sector. Thus a special institutional framework with interdisciplinary genome centers seems necessary if large-scale mapping and sequencing are to be made efficient and costeffective.

Multidisciplinary centers and scientific training Some critics argue that the HGP will not stimulate critical thinking skills among our young scientists, but rather will train them to perform repetitive tasks that are more appropriate for technical assistants. We believe, however, that the HGP presents an excellent opportunity to create collaborations and training programs of high quality. If the HGP is to succeed, many challenging technological problems must be solved. This will require an integration of theory and methods from diverse fields including chemistry, computer science, engineering, mathematics, molecular biology, physics and genetics. Some of the genome centers, including our own, have succeeded in recruiting young scientists with diverse but complementary backgrounds, Thus a multidisciplinary approach to problem-solving can be fostered within the HGP. This concept can also be extended to training programs. For example, at Caltech we have established a multidisciplinary PhD program in molecular biotechnology. A candidate is required to have mentors from two different academic disciplines (e.g. biology and computer science), and to choose a thesis topic that relates to a frontier problem in modern biology (such as the HGP). We believe that similar multidisciplinary programs will also arise at other universities that are associated with the HGP.

Analysis of costs and benefits to biomedical research Critics have argued that the HGP will damage the future of biomedical research, because it will be funded at the expense of other research topics studied by individual investigators. We disagree with this argument for the following reasons. (1) The HGP has brought new funds to biomedical research, beyond what

was previously available. In the USA, for example, this has come from the establishment of a National Center for Biotechnology Information21, and from the addition of new funds to the DOE and NIH budgets for the HGP. In France it has come through increased government funding of CEPH and of many genome~related individual research projects. In the UK it has come from a special supplement to the MRC, to create a Human Gene Mapping Resource Centre. We expect the HGP will continue to spur government agencies to release new funds for biomedical research. (2) Funding for dedicated genome centers is, and probably will remain, a minor component of the HGP budget. Most of this budget will be disbursed as grants to individual investigators. For example, in the genome programs of the NIH (USA) and of France, grants to individual investigators are currently favored over grants to genome centers by a ratio of 3:1 in cash terms. (3) Even if the HGP were forced to compete with other biomedical research topics for grant support, it would constitute only a minor drain on the aggregate research budget of this field. Consider that the NIH spent $60 million on the HGP last year in the USA, which amounts to <0.8% of this agency's $8 billion annual budget. Moreover, a significant fraction of HGP funding in the USA came from the Department of Energy, which (apart from its radiation biology program) traditionally has not been a strong supporter of biomedical research. (4) The HGP will have a large 'ripple effect' on funding in the biomedical sciences, because many of its discoveries will stimulate opportunities for new research projects. This ripple effect is clearly illustrated by the events that follow the mapping, isolation, and sequencing of a gene for a major human disease. Investigators gain a new ability to develop animal models for the disease, to study the developmental pattern of expression of the normal gene, to determine the effects of ablating the gene during development (in the animal model), to determine the consequences of mutation on cell physiology (in cultured cells), and even to consider the possibility of gene-replacement therapy for severely affected human individuals. The earliest examples of this ripple effect (from discoveries of the cystic fibrosis and muscular dystrophy genes) occurred before the HGP officially started. However, several thousand

TIBS 16 - DECEMBER1991 other human diseases show mendelian inheritance, and these fall under the purview of the HGP and should have similar effects. Obviously, a ripple effect should also occur whenever a major technological advance is made within the HGP. (5) There is another ripple effect in a broader scientific sense. In pursuing the basic goals outlined earlier, the HGP will give rise to many advances in molecular biotechnology. Both the maps and the new technologies will enable the design of new biological experiments, and will allow more sophisticated medical diagnosis and treatment (see below). Thus the ultimate scientific and medical benefits should far outweigh any short-term fiscal costs that may be incurred.

L0ng-termImplications The HGP will have several long-term positive effects on science and society. (1) It will foster a deeper interaction between biology, medicine and other academic disciplines. For example, the field of informatics will be stimulated by the need for mathematical analysis of patterns in DNA and protein sequence. (2) The technology for genome mapping, sequencing and analysis will be pushed to a much higher level. This technology should eventually diffuse to other branches of biology, medicine and biotechnology, expand the realm of possible experimentation, and ultimately produce commercial spin-offs. (3) As the database of genetic, physical and sequence maps becomes generally accessible, there will be a dramatic effect on the practice of biology. Detailed information on 50000-100000 human genes and their regulatory elements will be available in this database. This will allow a comprehensive description of gene expression networks, in which the timing, location and amplitude of expression of interacting genes in a developing organism is specified. This in turn will facilitate study of some of the most fundamental problems in biology (e.g. cancer, and coordinated gene expression in development. (4) Access to a database of genetic, physical and sequence maps will also fundamentally change the practice of clinical medicine. It will be possible to precisely map the location of the gene(s) responsible for an inherited disease or trait, and to identify the relevant gene product(s). An understanding of genetic predispositions to

complex human diseases will also revolutionize the field of preventive medicine. It will also become possible to design highly specific therapeutic treatments for diseases, perhaps involving the replacement of defective genes 28. Of course, the HGP also has longterm implications that defy a simple analysis of costs and benefits. There is, for example, a potential for misuse of information by groups in society, particularly in the realm of genetic diagnosis ~1,~.We do not presume to answer critics who raise profound questions in the fields of ethics, law and sociology. We note, however, that the HGP is not unique in this respect, since many scientific revolutions have ultimately been catalysts of social change so. The architects of the HGP are well aware of the potential for misuse of information, and have committed significant sums On the USA, 3% of the NIH genome budget) to ongoing studies of social, ethical and legal implications of genome research3L We suspect that our short essay will under-estimate the true magnitude of changes that will come as a consequence of the HGP. We believe a new age in biology and medicine is at hand as we move into the 21st century, and its arrival will be catalysed in part by the HGP.

Acknowledgements We thank K. McCarthy for expert typing. This work was supported in part by NSF, NIH and DOE.

References 1 Watson, J. D. and Cook-Deegan, R. M. (1991) FASEB J. 5, 8-11 2 Suzuki, D. T. and Griffiths, A. J. F. (1976) An Introduction to Genetic Analysis, W. H. Freeman 3 Judson, H. F. (1979) The Eighth Day of Creation: The Makers of the Revolution in Biology, Touchstone 4 Watson, J. D. and Tooze, J. (1981) The DNA Story: A Documentary History of Gene Cloning,

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The January issue of TIBS' sister journal Trends in Biotechnology (TIBTECH) will be a special double issue on Genome Mapping and Sequencing, discussing the innovative technologies being developed to tackle large-scale genome analysis. The organizational and financial aspects of national and international projects, and the potential benefits ensuing from progress on this research horizon are also addressed. For copies of this special issue, please contact our Cambridge, UK address.

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