NAS Report: Full Speed Ahead On Human Gene Sequencing

Editor’s note: February was a key month for the proposed project to map and sequence the human genome. The National Research Council of the National Academy of Sciences issued its report “Mapping and Sequencing the Human Genome,” which sounds a strong call for an immediate, largescale program. Meanwhile, David Baltimorebiologist, devoted part of his keynote address at the annual meeting of the American Association for the Advancement of Science to a cautionary note regarding the project. Here are excerpts from the report and from Baltimore’s address. Acquiring a map, a sequence, and an increased understanding of the human genome merits a special effort that should be organized and funded specifically for this purpose. Such a special effort in the next two decades will greatly enhance progress in human biology and medicine. "The technical problems associated with mapping and sequencing the human and other genomes are sufficiently great that a scientifically sound program should begin with a diversified, sustained effort to improve our ability to analyze complex DNA molecules. Although the needed capabilities do not yet exist, the broad outlines of how they could be developed are clear. Prospects are therefore good that the required advanced DNA technologies would emerge from a focused effort that emphasizes pilot projects and technological development. Once established, these technologies would not only make the complete analysis of the human and other genomes feasible, but would also revolutionize many other areas of basic biology and biotechnology. "Important early goals of the effort should be to acquire a high-resolution genetic linkage map of the human genome, a collection of ordered DNA clones, and a series of complementary physical maps of increasing resolution. The ultimate goal would be to obtain the complete nucleotide sequence of the human genome, starting from the materials in the ordered DNA clone collection. Attaining this goal would require major (but achievable) advances in DNA handling and sequencing technologies. "A comparative genetic approach is essential for interpreting the information in the human genome. Therefore, intensive studies of those organisms that provide particularly useful models for understanding human gene structure and function and evolution must be carried out in parallel. "The mapping and sequencing effort should begin primarily as a series of competing, peer-reviewed programs emphasizing technology development. Funding should include both grants to individuals and grants to medium-sized multidisciplinary groups of scientists and engineers. Because the technology required to meet most of the project’s goals needs major improvement, the committee specifically recommends against establishing one or a few large sequencing centers at present. "The human genome project should differ from present ongoing research inasmuch as the component subprojects should have the potential to improve by 5- to 10-fold increments the scale or efficiency of mapping, sequencing, analyzing, or interpreting the biological significance of the information in the human genome. "Progress toward all the above goals will require the establishment of well-funded centralized facilities, including a stock center for the cloned DNA fragments, generated in the mapping and sequencing effort and a data center for the computer-based collection and distribution of large amounts of DNA sequence information. The committee suggests that the groups supplying these services be selected through open competition. The committee recommends the following: "In view of the importance and magnitude of the task, a rapid scale-up to $200 million of additional funding per year is recommended. These additional funds should not be diverted from the current federal research budget for biomedical sciences. A majority of the committee recommends: "A single federal agency serves as the lead agency for the project. This agency would receive and administer the funds for the project and would be responsible for the operation of the stock center and data center, as well as administer the peer-review system utilized in determining the recipients of funds. It should work closely with a Scientific Advisory Board in developing and implementing a high standard of peer review. The Scientific Advisory Board, composed primarily of scientists knowledgeable in relevant fields, would provide advice not only on peer review, but also on quality control, international cooperation, coordination of efforts of the laboratories in the project, and the stock and data centers. The two main types of human genome maps are genetic linkage maps and physical maps. Genetic linkage maps are made mainly by studying families and measuring the frequency with which two different traits are inherited together, or linked. Physical maps are derived mainly from chemical measurements made on the DNA molecules that form the human genome.... Full-scale mapping, both genetic linkage and physical, should begin immediately.... The committee believes that most support should go to groups that are attempting to map large genomes.... First, pilot projects should be conducted with a goal of sequencing approximately 1 million continuous nucleotides (which is 5 to 10 times as large as the largest continuous regions that have been sequenced to date). Second, improvements in existing sequencing technology and the development of entirely new technologies should be vigorously encouraged. This would include applications of automation and robotics at all steps in sequencing. To derive the major benefits from the human genome sequence, it will be necessary to have an extensive data base of DNA sequences from the mouse (whose genome is the same size as that of the human) and from simpler organisms with much smaller genomes, such as bacteria, yeast, Drosophila melanogaster. . . and Caenorhabditis elegans.... Information and Materials handling This project will... require an unprecedented sharing of materials among the laboratories involved...access to all sequences and materials generated by these publicly funded projects should and even must be made freely available.... The committee examined the cost of the project and concluded that an annual budget of $200 million over the next 15 years would not be excessive when compared with the value of the results that would be produced. A project of this type need not threaten the existing biological research community for several reasons. First, the money ought not be provided at the expense of currently funded biological research. Second, it ought to be distributed by peer re- view. Third, by including selected other organisms required for the interpretation of the human genome map and sequence, the project ought not mislead the public into placing a false emphasis on the uniqueness of human materials for understanding ourselves. Fourth, this project ought to include work by both small research laboratories and large multidisciplinary centers formed by juxtaposing several small research groups having different expertise. Since individual investigators working in small groups have been the source of nearly all the major methodological breakthroughs that have driven the modern revolution in biology, the proposed organization ensures that our extraordinarily successful pattern of doing biology will be preserved. For the human genome project to be of maximum value, the committee believes that it needs to be well-organized and coordinated. The committee feels that the project should be sited within one of three federal agencies, the National Institutes of Health, the Department of Energy, or the National Science Foundation.

NAS Report: Full Speed Ahead On Human Gene Sequencing

The Scientist Staff

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