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Experience has shown many times over that information derived from studies of the biology of model organisms is essential to interpreting data obtained in studies of humans and in understanding human biology. Research involving microbial, animal, and plant models will continue to provide a basis for analyzing normal gene regulation, genetic diseases, and evolutionary processes. For this reason, the human genome program will support mapping and sequencing of the genomes of a select number of non-human organisms.

Research projects that use model organisms will also be valuable to technology development. Since the genomes of these organisms are smaller and simpler than that of the human, they represent excellent systems for the development and testing of procedures needed for the much more complex human genome.

A number of organisms have already been identified as particularly useful models for comparative genetic analyses because a large amount of information about their genetics and molecular biology has already been accumulated. These organisms are bacteria (Escherichia coli), yeast (Saccharomyces cerevisiae), the fruit fly Drosophila melanogaster, the worm Caenorhabditis elegans and the laboratory mouse. However, it is fully expected that research projects involving other model organisms will also contribute significantly to the Human Genome Initiative.

Complete physical maps, both long-range restriction maps and an overlapping clone set, are already available for E. coli. Long range restriction maps are available for several other bacteria, and overlapping clone sets are being assembled. Extensive overlapping clone sets have also been assembled for both S. cerevisiae and C. elegans. Projects to sequence E. coli DNA have been initiated in both the United States and Japan. Sequencing of the DNA of another bacterium,B. subtilis, has begun in a consortium of European laboratories. Another European consortium and an American-Japanese collaborative project have each begun to sequence one of the chromosomes ofS. cerevisiae. Finally, a collaborative project, involving a laboratory in the United States and one in the United Kingdom, is planned to begin the sequencing of C. elegans DNA.

While the mouse genome is not simpler than that of man, it is particularly useful for comparisons because of the many biological similarities between the mouse and man. The genetic map of the mouse, based on morphological markers, has already led to many insights into human genetics. There is every reason to believe that a physical map of the mouse genome will be equally useful. In order to prepare a physical map of the mouse, a genetic map based on DNA markers will need to be created. This will then lead to the development of a physical map that can be directly compared with the human physical map.

The general methodology used in studying model organisms will be similar to that described under the previous sections on mapping and sequencing. The need to achieve long range continuity in physical mapping and sequencing projects also applies to model organisms, as do the requirements for reducing costs.

5 YEAR GOAL:

Prepare a genetic map of the mouse genome based on DNA markers. Start physical mapping on one or two chromosomes.

Sequence an aggregate of about 20 million base pairs of DNA from a variety of model organisms, focusing on stretches that are 1 million base pairs long, in the course of the development and validation of new and/or improved DNA-sequencing technology.

The direct product of the Human Genome Initiative will be genome maps and DNA sequences. For maximum utility, it will be critical to develop appropriate computer tools and information systems for the collection, storage, and distribution of the immense amounts of mapping and sequencing data that will be generated in the course of the program.

At present, it is not clear whether the most useful product of the Human Genome Initiative will be a single large database or a distributed set of smaller, networked databases. It is also unclear how genome databases will be structured in the future and whether existing databases can be adapted to meet the overall, long-term needs of the Human Genome Initiative, or whether new systems will have to be developed. However, it is certain that genome databases will need to be comprehensive and up to date, and, if there are several databases, it will be imperative that they effectively link with one another.

In addition to database development, it will be vital to develop new methods and tools for the analysis and interpretation of genome maps and DNA sequences. Successfully addressing both of these areas of genome informatics will require the development of a coordinated national program to make the information and analysis tools from this project readily available to the widest possible range of scientists and physicians in the most useful, timely, and cost-effective manner.

While it is currently possible to describe the informatics goals of the Human Genome Initiative in broad terms, considerable refinement will be necessary as this program develops and informatics technology improves over time. A Joint Informatics Task Force (JITF) has been established by the NIH and the DOE to help the agencies develop detailed informatics programs. The report recommending the establishment of the JITF is included as Appendix 6.

The responsibilities of the JITF will include identification of the uses to which the data will be put and establishment of priorities for both technical objectives and policy areas. Specific issues to be addressed will include: genome database structures, management, and services; development of algorithms, software, and hardware for organization and analysis of data; data exchange standards; electronic networks for collection and distribution of genome information; training and education of informatics personnel; and coordination of genome informatics activities among laboratories and agencies. The JITF will also serve as a national focus for interaction with international activities related to genome informatics.

The challenge will be not only to design databases to meet the growing needs for access and for increasingly sophisticated search capabilities, but also to keep up with the voluminous amount of information that will be produced at ever faster rates. A number of research efforts are in progress to improve database design, software for database access, and data entry procedures.

Recently, the National Center for Biotechnology Information (NCBI) was established at the National Library of Medicine to create automated systems for knowledge about molecular biology, biochemistry and genetics, and to pursue research in biological information handling, particularly with respect to human molecular biology. Thus, the mission of the NCBI supports, in part, that of the Human Genome Initiative. Consequently, the efforts of the NCBI will be closely coordinated with the human genome program through the JITF and by frequent staff interactions with the NIH and the DOE.

5 YEAR GOAL:

Develop effective software and database designs to support large-scale mapping and sequencing projects.

Create database tools that provide easy access to up-to-date physical mapping, genetic mapping, chromosome mapping, and sequencing information and allow ready comparison of the data in these several data sets.

Develop algorithms and analytical tools to interpret genomic information.

The plan to map and sequence the entire human genome is predicated on the belief that humankind will benefit immensely from attendant advances in medicine, biological research, and biotechnology. Yet, as with any new technology, controversial usage of the information and capabilities that will flow from the Human Genome Initiative also may emerge. Ethical, legal, and social issues arise in regard to ways of ensuring that this information is used in the most responsible manner.

Some of the questions that must be considered concern individual privacy and confidentiality. Should information about an individual's genetic makeup become available to others without that person's knowledge and permission? How can we assure that genetic information does not lead to stigmatization or to discrimination in areas such as insurance or employment?

Concerns also arise in connection with the medical applications resulting from the genome program, such as the anticipated ability to predict a person's future health. Initially, at least, there will be a time lapse--in many cases of years--between the ability to diagnose certain genetic disorders and the ability to treat them. How will an individual cope with a devastating diagnosis when no treatment is available? What issues does such a situation raise?

These questions are not new. Physicians and counselors are facing them today when treating patients with genetic and other diseases. However, the greatly increased flow of information about human genetics will make the need to deal with these issues more compelling. The NIH and DOE human genome programs will support studies that investigate concerns such as these. About 3 percent of the genome budget will be available for activities that address ethical, social, and legal issues related to the project.

A series of specific recommendations for the research agenda and related activities in the ethics component of the human genome program has been developed by a joint DOE-NIH working group on ethics. These recommendations will guide the program over the next five years and will continue to be refined as the program proceeds. A complete report of the ethics working group is attached (Appendix 7).

The purpose of the ethics component of the human genome program is to:

• address and anticipate the implications for individuals and society of mapping and sequencing the human genome;
• examine the ethical, legal and social sequelae of mapping and sequencing the human genome;
• stimulate public discussion of the issues;
• develop policy options to assure that the information is used for the benefit of the individual and society.

• stimulate research on the issues through grants;
• refine the research agenda through workshops, commissioned papers, and invited lectures on specific topics selected by the working group on ethics;
• solicit public testimony from the community at large through town meetings;
• support the development of educational materials for all levels;
• encourage international collaboration in this area.

5 YEAR GOAL:

Develop programs addressed at understanding the ethical, legal and social implications of the human genome project.

Identify and define the major issues and develop initial policy options to address them.

The Human Genome Initiative is creating the need for a considerable number of scientists and other trained personnel who have the skills to pursue the research goals and apply the information generated by the program. The ability of the U.S. research establishment and industry to take advantage of the products of the human genome project will require highly trained individuals.

Scientists with diverse expertise are required: geneticists and molecular biologists, as well as investigators from fields such as physics, chemistry, engineering, mathematics, and computer science. Critically needed are scientists with interdisciplinary skills--those who understand the biological problem at hand and can find solutions by applying skills from other disciplines. Many more technicians also will be required to operate the large amount of technology that the genome program will employ.

The NIH Ad Hoc Program Advisory Committee on Complex Genomes recommended that research training be an integral part of the human genome program. This recommendation has been reinforced by the current Program Advisory Committee on the Human Genome. In response to these recommendations, the following initiatives have been put in place:

Pre-doctoral training grants in genome research will support training of scientists with the skills needed to carry out basic and applied research related to the goals of the Human Genome Initiative and to apply that knowledge to solve important biomedical research problems. The focus of this training will be interdisciplinary, intended to give students a deeper understanding of how the methods and principles of one or more of the non-biological sciences can interact with those of biology to address research problems related to genomic analysis.

Post-doctoral fellowships in genome research will provide support for training at the post-graduate level. In addition to the customary training for Ph.D. and M.D. degree holders in molecular biology and other areas relevant to genomics research, there will be an effort to attract individuals who wish to pursue interdisciplinary training. Candidates for these grants who are trained in mathematics, computer science, chemistry, physics, or engineering and who want to augment their skills in those fields with training in biological science to enable them to pursue genome research, will be encouraged. Conversely, biologists who want to acquire research training in biocomputation, instrumentation, biophysics, or other areas related to genome research will be desirable candidates. There also will be fellowship support for individuals interested in the ethical, legal, and social implications of genome research.

Senior fellowships will be available to experienced investigators in physics, mathematics, engineering, and biological, chemical or computer science who want to acquire training and experience in another discipline. It is expected that these senior fellows subsequently will use this additional training to develop and broaden their research interests to include problems related to genome analysis.

Training at National Laboratories will be supported by DOE and will be available for both pre-doctoral and post-doctoral individuals who want to learn techniques of genome research.

Short courses will also be needed to provide in-depth training in a defined area. These courses could address the need of individuals to enhance their skills in molecular techniques, computational sciences, and ethical or legal studies. The NCHGR and the DOE are currently studying the best ways to meet such needs.

5 YEAR GOAL:

Support research training of pre- and post-doctoral fellows starting in FY 1990. Increase the numbers of trainees supported until a steady state of about 600 per year is reached by the fifth year.

Examine the need for other types of research training in the next year.

Although considerable strides have been made in technology development since the publication of the NRC and OTA reports, there is still a need for further innovation to adapt the technology to large scale projects and to bring costs down. During the next five years, there will be an emphasis on technology development in all areas of the program.

Automation, optimization, cost reduction and other improvements will be supported in areas such as cloning technology, robotics, DNA sequencing, gel technology, software tools, and instrument development. Equally important will be the support of completely novel approaches such as the use of scanning tunnelling microscopy or mass spectrometry for sequencing. The technology that ultimately will be used to sequence the human genome may turn out to be a method that is still on the drawing board.

5 YEAR GOAL:

Support innovative and high-risk technological developments as well as improvements in current technology to meet the needs of the genome project as a whole.

Rapid transfer of the technology developed under the human genome program to industries that can develop economically and medically useful applications is a major goal of the project. This will occur in a variety of ways ranging from direct federally funded research at private companies to expedited transfer of new technology into the private sector. The human genome project is certain to spawn and nurture parallel efforts on a host of other plant and animal genomes that are of direct commercial interest. Rapid provision of technology and trained personnel will play a most critical role in driving these efforts.

Industry will benefit directly from the availability of scientists trained by the human genome project and by the availability of databases that provide access to the data generated by the project. These databases will be used in many diverse ways to design products for medical and industrial applications.

In the coming year, a plan will be developed for technology transfer with respect to inventions produced by the genome project. A variety of mechanisms will be explored for facilitating this transfer, for improving information flow, and for identifying potential blocks to efficient transfer. The DOE National Laboratories are already working with private sector interests to establish cooperative ventures. The NIH intramural laboratories have similarly developed a system of cooperative research and development agreements with industry.

The biotechnology industry in the United States is strong and innovative and has very close ties to scientists doing genome research. Indeed, this industry will be a strong participant in all aspects of the project from the beginning. Representatives from industry sit on the advisory committees and industrial scientists have received numerous grants from both NIH and DOE. It is expected that industrial involvement will increase as the project proceeds, especially during the phase of large-scale sequencing.

Transfer of the technology into medical applications will be facilitated where necessary, but will also occur naturally. Many of the scientists supported by the NCHGR human genome program are physicians or work closely with physicians who are involved in patient care.

The various institutes of the NIH all support research on diseases that result from genetic variation and a variety of mechanisms will be used to assure that information is transferred efficiently from the NCHGR to these institutes. A coordinating committee has already been established for this purpose. The NCHGR will be particularly alert to the need to stimulate preparation of reagents for use in the diagnosis and treatment of rare genetic diseases when such reagents may not be commercially viable.

5 YEAR GOAL:

Enhance the already close working relationships with industry.

Encourage and facilitate the transfer of technologies and of medically important information to the medical community.

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File posted April 3, 1995.