A Vision for the Future of Genomics Research: A Blueprint for the Genomic Era

Part I

The completion of a high-quality, comprehensive sequence of the human genome, in this fiftieth anniversary year of the discovery of the double-helical structure of DNA, 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. Figure 1 shows a timeline of landmark accomplishments in genetics and genomics, beginning with Gregor Mendel's discovery of the laws of heredity¹ and their rediscovery in the early days of the twentieth century. Recognition of DNA as the hereditary material ², determination of its structure ³, elucidation of the genetic code ⁴, development of recombinant DNA technologies ^{5, 6}, and establishment of increasingly automatable methods for DNA sequencing ^7-10 set the stage for the Human Genome Project (HGP) to begin in 1990 (see also www.nature.com/nature/DNA50). 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 (see www.genome.gov/PolicyEthics).

These accomplishments fulfill the expansive vision articulated in the 1988 report of the National Research Council, Mapping and Sequencing the Human Genome ¹⁴. The successful completion of the HGP this year thus represents an opportunity to look forward and offer a blueprint for the future of genomics research over the next several years.

The vision presented here addresses a different world from that reflected in earlier plans published in 1990, 1993, and 1998 (refs 15-17). Those documents addressed the goals of the 1988 report, defining detailed paths towards the development of genome-analysis technologies, the physical and genetic mapping of genomes, and the sequencing of model organism genomes and, ultimately, the human genome. Now, with the effective completion of these goals, we offer a broader and still more ambitious vision, appropriate for the true dawning of the genomic era. The challenge is to capitalize on the immense potential of the HGP to improve human health and well-being.

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 (NIH, www.nih.gov) 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.

A reader's guide

The vision for genomics research detailed here is the outcome of almost two years of intense discussions with hundreds of scientists and members of the public, in more than a dozen workshops and numerous individual consultations (see www.genome.gov/About/Planning). The vision is formulated into three major themes — genomics to biology, genomics to health, and genomics to society — and six crosscutting elements.

We envisage the themes as three floors of a building, firmly resting on the foundation of the HGP (Figure 2). For each theme, we present a series of grand challenges, in the spirit of the proposals put forward for mathematics by David Hilbert at the turn of the twentieth century ¹⁸. These grand challenges are intended to be bold, ambitious research targets for the scientific community. Some can be planned on specific timescales, others are less amenable to that level of precision. We list the grand challenges in an order that makes logical sense, not representing priority. The challenges are broad in sweep, not parochial — some can be led by the NHGRI alone, whereas others will be best pursued in partnership with other organizations. Below, we clarify areas in which the NHGRI intends to play a leading role.



The six critically important crosscutting elements are relevant to all three thematic areas. They are: resources (Box 1); technology development (Box 2); computational biology (Box 3); training (Box 4); ethical, legal, and social implications (ELSI, Box 5); and education (Box 6). We also stress the critical importance of early, unfettered access to genomic data in achieving maximum public benefit. Finally, we propose a series of "quantum leaps," achievements that would lead to substantial advances in genomics research and its applications to medicine. Some of these may seem overly bold, but no laws of physics need to be violated to achieve them. Such leaps would have profound implications, just as the dreams of the mid-1980s about the complete sequence of the human genome have been realized in the accomplishments now being celebrated.













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Courtesy: National Human Genome Research Institute