THE HUMAN GENOME PROJECT
The Human Genome Project (HGP) was one of the great feats of exploration in history - an inward voyage of discovery rather than an outward exploration of the planet or the cosmos; an international research effort to sequence and map all of the genes - together known as the genome - of members of our species, Homo sapiens. Completed in April 2003, the HGP gave us the ability to, for the first time, to read nature's complete genetic blueprint for building a human being.
A Brief History
The Human Genome Project (HGP) was the international, collaborative research program whose goal was the complete mapping and understanding of all the genes of human beings. All our genes together are known as our "genome."
The HGP was the natural culmination of the history of genetics research. In 1911, Alfred Sturtevant, then an undergraduate researcher in the laboratory of Thomas Hunt Morgan, realized that he could - and had to, in order to manage his data - map the locations of the fruit fly (Drosophila melanogaster) genes whose mutations the Morgan laboratory was tracking over generations. Sturtevant's very first gene map can be likened to the Wright brothers' first flight at Kitty Hawk. In turn, the Human Genome Project can be compared to the Apollo program bringing humanity to the moon.
The hereditary material of all multi-cellular organisms is the famous double helix of deoxyribonucleic acid (DNA), which contains all of our genes. DNA, in turn, is made up of four chemical bases, pairs of which form the "rungs" of the twisted, ladder-shaped DNA molecules. All genes are made up of stretches of these four bases, arranged in different ways and in different lengths. HGP researchers have deciphered the human genome in three major ways: determining the order, or "sequence," of all the bases in our genome's DNA; making maps that show the locations of genes for major sections of all our chromosomes; and producing what are called linkage maps, complex versions of the type originated in early Drosophila research, through which inherited traits (such as those for genetic disease) can be tracked over generations.
The HGP has revealed that there are probably somewhere between 30,000 and 40,000 human genes. The completed human sequence can now identify their locations. This ultimate product of the HGP has given the world a resource of detailed information about the structure, organization and function of the complete set of human genes. This information can be thought of as the basic set of inheritable "instructions" for the development and function of a human being.
The International Human Genome Sequencing Consortium published the first draft of the human genome in the journal Nature in February 2001 with the sequence of the entire genome's three billion base pairs some 90 percent complete. A startling finding of this first draft was that the number of human genes appeared to be significantly fewer than previous estimates, which ranged from 50,000 genes to as many as 140,000.The full sequence was completed and published in April 2003.
Upon publication of the majority of the genome in February 2001, Francis Collins, the director of NHGRI, noted that the genome could be thought of in terms of a book with multiple uses: "It's a history book - a narrative of the journey of our species through time. It's a shop manual, with an incredibly detailed blueprint for building every human cell. And it's a transformative textbook of medicine, with insights that will give health care providers immense new powers to treat, prevent and cure disease."
The tools created through the HGP also continue to inform efforts to characterize the entire genomes of several other organisms used extensively in biological research, such as mice, fruit flies and flatworms. These efforts support each other, because most organisms have many similar, or "homologous," genes with similar functions. Therefore, the identification of the sequence or function of a gene in a model organism, for example, the roundworm C. elegans, has the potential to explain a homologous gene in human beings, or in one of the other model organisms. These ambitious goals required and will continue to demand a variety of new technologies that have made it possible to relatively rapidly construct a first draft of the human genome and to continue to refine that draft.
Of course, information is only as good as the ability to use it. Therefore, advanced methods for widely disseminating the information generated by the HGP to scientists, physicians and others, is necessary in order to ensure the most rapid application of research results for the benefit of humanity. Biomedical technology and research are particular beneficiaries of the HGP.
However, the momentous implications for individuals and society for possessing the detailed genetic information made possible by the HGP were recognized from the outset. Another major component of the HGP - and an ongoing component of NHGRI - is therefore devoted to the analysis of the ethical, legal and social implications (ELSI) of our newfound genetic knowledge, and the subsequent development of policy options for public consideration.
<< Back to Visions
A Vision for the Future
The completion of a high-quality, comprehensive sequence of the human genome is a landmark event. The genomic era is now a reality.
In contemplating a vision for the future of genomics research, it is appropriate to consider the remarkable path that has brought us here. Recognition of DNA as the hereditary material2, determination of its structure3, elucidation of the genetic code4, development of recombinant DNA technologies5, 6, and establishment of increasingly automatable methods for DNA sequencing7, 8, 9, 10 set the stage for the Human Genome Project (HGP) to begin in 1990.
Thanks to the vision of the original planners, and the creativity and determination of a legion of talented scientists who decided to make this project their overarching focus, all of the initial objectives of the HGP have now been achieved at least two years ahead of expectation, and a revolution in biological research has begun.
The project's new research strategies and experimental technologies have generated a steady stream of ever-larger and more complex genomic data sets that have poured into public databases and have transformed the study of virtually all life processes. The genomic approach of technology development and large-scale generation of community resource data sets has introduced an important new dimension into biological and biomedical research. Interwoven advances in genetics, comparative genomics, high-throughput biochemistry and bioinformatics are providing biologists with a markedly improved repertoire of research tools that will allow the functioning of organisms in health and disease to be analysed and comprehended at an unprecedented level of molecular detail. Genome sequences, the bounded sets of information that guide biological development and function, lie at the heart of this revolution. In short, genomics has become a central and cohesive discipline of biomedical research.
The practical consequences of the emergence of this new field are widely apparent. Identification of the genes responsible for human mendelian diseases, once a herculean task requiring large research teams, many years of hard work, and an uncertain outcome, can now be routinely accomplished in a few weeks by a single graduate student with access to DNA samples and associated phenotypes, an Internet connection to the public genome databases, a thermal cycler and a DNA-sequencing machine. With the recent publication of a draft sequence of the mouse genome11, identification of the mutations underlying a vast number of interesting mouse phenotypes has similarly been greatly simplified. Comparison of the human and mouse sequences shows that the proportion of the mammalian genome under evolutionary selection is more than twice that previously assumed.
Our ability to explore genome function is increasing in specificity as each subsequent genome is sequenced. Microarray technologies have catapulted many laboratories from studying the expression of one or two genes in a month to studying the expression of tens of thousands of genes in a single afternoon12. Clinical opportunities for gene-based pre-symptomatic prediction of illness and adverse drug response are emerging at a rapid pace, and the therapeutic promise of genomics has ushered in an exciting phase of expansion and exploration in the commercial sector13. The investment of the HGP in studying the ethical, legal and social implications of these scientific advances has created a talented cohort of scholars in ethics, law, social science, clinical research, theology and public policy, and has already resulted in substantial increases in public awareness and the introduction of significant (but still incomplete) protections against misuses such as genetic discrimination.
These accomplishments fulfil the expansive vision articulated in the 1988 report of the National Research Council, Mapping and Sequencing the Human Genome14. The successful completion of the HGP in 2003 thus represents an opportunity to look forward and offer a blueprint for the future of genomics research over the next several years.
The articulation of a new vision is an opportunity to explore transformative new approaches to achieve health benefits. Although genome-based analysis methods are rapidly permeating biomedical research, the challenge of establishing robust paths from genomic information to improved human health remains immense. Current efforts to meet this challenge are largely organized around the study of specific diseases, as exemplified by the missions of the disease-oriented institutes at the US National Institutes of Health and numerous national and international governmental and charitable organizations that support medical research. The National Human Genome Research Institute (NHGRI), in budget terms a rather small (less than 2%) component of the NIH, will work closely with all these organizations in exploring and supporting these biomedical research capabilities. In addition, we envision a more direct role for both the extramural and intramural programmes of the NHGRI in bringing a genomic approach to the translation of genomic sequence information into health benefits.
The NHGRI brings two unique assets to this challenge. First, it has close ties to a scientific community whose direct role over the past 13 years in bringing about the genomic revolution provides great familiarity with its potential to transform biomedical research. Second, the NHGRI's long-standing mission, to investigate the broadest possible implications of genomics, allows unique flexibility to explore the whole spectrum of human health and disease from the fresh perspective of genome science. By engaging the energetic and interdisciplinary genomics-research community more directly in health-related research and by exploiting the NHGRI's ability to pursue opportunities across all areas of human biology, the institute seeks to participate directly in translating the promises of the HGP into improved human health.
To fully achieve this goal, the NHGRI must also continue in its vigorous support of another of its vital missions — the coupling of its scientific research programme with research into the social consequences of increased availability of new genetic technologies and information. Translating the success of the HGP into medical advances intensifies the need for proactive efforts to ensure that benefits are maximized and harms minimized in the many dimensions of human experience.
<< Back to Visions
CONCLUSIONS
Preparing a vision for the future of genomics research has been both daunting and exhilarating. The willingness of hundreds of experts to volunteer their boldest and best ideas, to step outside their areas of self-interest and to engage in intense debates about opportunities and priorities, has added a richness and audacity to the outcome that was not fully anticipated when the planning process began.
A final word is appropriate about the breadth of the vision articulated here. A choice had to be made between portraying a broad view of the future of genomics research and focusing more narrowly on the specific role of the NHGRI. Recognizing that researchers and the public are more interested in the promise of the field than about the funding source responsible, we have focused here on the broad landscape of scientific opportunity. We have, however, identified the areas that are particularly appropriate for leadership by the NHGRI throughout this article. These are generally research areas that are not specific to a particular disease or organ system, but have broader biomedical and/or social implications. Yet even in those instances, the word 'partnership' appears numerous times intentionally. We expect to have partnerships not only with other public funding sources, such as the other 26 NIH institutes and centres, but also with many other governmental agencies, private foundations and private-sector organizations. Indeed, public–private partnerships, such as the SNP Consortium, the Mouse Sequencing Consortium and the International HapMap Project, provide powerful new models for the generation of public data sets with immediate and far-reaching value. Thus, many of the most exciting opportunities in genomics research cross traditional boundaries of specific disease definitions, classically defined scientific disciplines, funding sources and public versus private enterprise. The new era will flourish best in an environment where such traditional boundaries become ever more porous.
Although the opportunities described here are thought to be highly achievable, the formal initiation of specific programmes will require more detailed analysis. The relative priorities of each component must be addressed in the light of limited resources to support research. The NHGRI plans to release a revised programme announcement and other grant solicitations later this year, providing more specific guidance to extramural researchers about plans for the implementation of this vision. Furthermore, in genomics research, we have learned to expect the unexpected. From past experience, it would be surprising (and rather disappointing) if biological, medical and social contexts did not change in unpredictable ways. That reality requires that this vision be revisited on a regular basis.
In conclusion, the successful completion of all of the original goals of the HGP emboldens the launch of a new phase for genomics research, to explore the remarkable landscape of opportunity that now opens up before us. Like Shakespeare, we are inclined to say, "what's past is prologue" (The Tempest, Act II, Scene 1). If we, like bold architects, can design and build this unprecedented and noble structure, resting on the firm bedrock foundation of the HGP, then the true promise of genomics research for benefiting humankind can be realized.
"Make no little plans; they have no magic to stir men's blood and probably will themselves not be realized. Make big plans; aim high in hope and work, remembering that a noble, logical diagram once recorded will not die, but long after we are gone will be a living thing, asserting itself with ever- growing insistency".
<< Back to Visions Next Page >>
|
|
