At the end of the road in Little Cottonwood Canyon, near Salt Lake City, Alta is a place of near-mythic renown among skiers. In time it may well assume similar status among molecular geneticists. In December 1984, a conference there, co-sponsored by the U.S. Department of Energy, pondered a single question: Does modern DNA research offer a way of detecting tiny genetic mutations -- and, in particular, of observing any increase in the mutation rate among the survivors of the Hiroshima and Nagasaki bombings and their descendants? In short the answer was, Not yet. But in an atmosphere of rare intellectual fertility, the seeds were sown for a project that would make such detection possible in the future -- the Human Genome Project.

In the months that followed, much deliberation and debate ensued. But in 1986, the DOE took a bold and unilateral step by announcing its Human Genome Initiative, convinced that its mission would be well served by a comprehensive picture of the human genome. The immediate response was considerable skepticism -- skepticism about the scientific community's technological wherewithal for sequencing the genome at a reasonable cost and about the value of the result, even if it could be obtained economically.

Things have changed. Today, a decade later, a worldwide effort is under way to develop and apply the technologies needed to completely map and sequence the human genome, as well as the genomes of several model organisms. Technological progress has been rapid, and it is now generally agreed that this international project will produce the complete sequence of the human genome by the year 2005.

And what is more important, the value of the project also appears beyond doubt. Genome research is revolutionizing biology and biotechnology, and providing a vital thrust to the increasingly broad scope of the biological sciences. The impact that will be felt in medicine and health care alone, once we identify all human genes, is inestimable. The project has already stimulated signifi-cant investment by large corporations and prompted the creation of new companies hoping to capitalize on its profound implications.

But the DOE's early, catalytic decision deserves further comment. The organizers of the DOE's genome initiative recognized that the information the project would generate -- both technological and genetic -- would contribute not only to a new understanding of human biology, but also to a host of practical applications in the biotechnology industry and in the arenas of agriculture and environmental protection. A 1987 report by a DOE advisory committee provided some examples. The committee foresaw that the project could ultimately lead to the efficient production of biomass for fuel, to improvements in the resistence of plants to environmental stress, and to the practical use of genetically engineered microbes to neutralize toxic wastes. The Department thus saw far more to the genome project than a promised tool for assessing mutation rates. For example, understanding the human genome will have an enormous impact on our ability to assess, individual by individual, the risk posed by environmental exposures to toxic agents. We know that genetic differences make some of us more susceptible, and others more resistant, to such agents. Far more work must be done before we understand the genetic basis of such variability, but this knowledge will directly address the DOE's long-term mission to understand the effects of low-level exposures to radiation and other energy-related agents -- especially the effects of such exposure on cancer risk. And the genome project is a long stride toward such knowledge.

The Human Genome Project has other implications for the DOE as well. In 1994, taking advantage of new capabilities developed by the genome project, the DOE formulated the Microbial Genome Initiative to sequence the genomes of bacteria of likely interest in the areas of energy production and use, environmental remediation and waste reduction, and industrial processing. As a result of this initiative, we already have complete sequences for two microbes that live under extreme conditions of temperature and pressure. Structural studies are under way to learn what is unique about the proteins of these organisms -- the aim being ultimately to engineer these microbes and their enzymes for such practical purposes as waste control and environmental cleanup. (DOE-funded genetic engineering of a thermostable DNA polymerase has already produced an enzyme that has captured a large share of the several-hundred-million-dollar DNA polymerase market.)

And other little-studied microbes hint at even more intriguing possibilities. For instance, Deinococcus radiodurans is a species that prospers even when exposed to huge doses of ionizing radiation. This microbe has an amazing ability to repair radiation-induced damage to its DNA. Its genome is currently being sequenced with DOE support, with the hope of understanding and ultimately taking practical advantage of its unusual capabilities. For example, it might be possible to insert foreign DNA into this microbe that allows it to digest toxic organic components found in highly radioactive waste, thus simplifying the task of further cleanup. Another approach might be to introduce metal-binding proteins onto the microbe's surface that would scavenge highly radioactive isotopes out of solution.

Biotechnology, fueled in part by insights reaped from the genome project, will also play a significant role in improving the use of fossil-based resources. Increased energy demands, projected over the next 50 years, require strategies to circumvent the many problems associated with today's dominant energy systems. Biotechnology promises to help address these needs by upgrading the fuel value of our current energy resources and by providing new means for the bioconversion of raw materials to refined products -- not to mention offering the possibility of entirely new biomass-based energy sources.

We have thus seen only the dawn of a biological revolution. The practical and economic applications of biology are destined for dramatic growth. Health-related biotechnology is already a multibillion-dollar success story -- and is still far from reaching its potential. Other applications of biotechnology are likely to beget similar successes in the coming decades. Among these applications are several of great importance to the DOE. We can look to improvements in waste control and an exciting era of environmental bioremediation; we will see new approaches to improving energy efficiency; and we can even hope for dramatic strides toward meeting the fuel demands of the future. The insights, the technologies, and the infrastructure that are already emerging from the genome project, together with advances in fields such as computational and structural biology, are among our most important tools in addressing these national needs.

Aristides A. N. Patrinos
Director, Human Genome Project
U.S. Department of Energy

To Know Ourselves was prepared at the request of the U.S. Department of Energy, Office of Health and Environmental Research, as an overview of the Human Genome Project.