A Bold but Logical Step

The biosciences research community is now embarked on a program whose boldness, even audacity, has prompted comparisons with such visionary efforts as the Apollo space program and the Manhattan project. That life scientists should conceive such an ambitious project is not remarkable; what is surprising -- at least at first blush -- is that the project should trace its roots to the Department of Energy.

For close to a half-century, the DOE and its governmental predecessors have been charged with pursuing a deeper understanding of the potential health risks posed by energy use and by energy-production technologies -- with special interest focused on the effects of radiation on humans. Indeed, it is fair to say that most of what we know today about radiological health hazards stems from studies supported by these government agencies. Among these investigations are long-standing studies of the survivors of the atomic bombings of Hiroshima and Nagasaki, as well as any number of experimental studies using animals, cells in culture, and nonliving systems. Much has been learned, especially about the consequences of exposure to high doses of radiation. On the other hand, many questions remain unanswered; in particular, we have much to learn about how low doses produce their insidious effects. When present merely in low but significant amounts, toxic agents such as radiation or mutagenic chemicals work their mischief in the most subtle ways, altering only slightly the genetic instructions in our cells. The consequences can be heritable mutations too slight to produce discernible effects in a generation or two but, in their persistence and irreversibility, deeply troublesome nonetheless.

Until recently, science offered little hope for detecting at first hand these tiny changes to the DNA that encodes our genetic program. Needed was a tool that could detect a change in one "word" of the program, among perhaps a hundred million. Then, in 1984, at a meeting convened jointly by the DOE and the International Commission for Protection Against Environmental Mutagens and Carcinogens, the question was first seriously asked: Can we, should we, sequence the human genome? That is, can we develop the technology to obtain a word-by-word copy of the entire genetic script for an "average" human being, and thus to establish a benchmark for detecting the elusive mutagenic effects of radiation and cancer-causing toxins? Answering such a question was not simple. Workshops were convened in 1985 and 1986; the issue was studied by a DOE advisory group, by the Congressional Office of Technology Assessment, and by the National Academy of Sciences; and the matter was debated publicly and privately among biologists themselves. In the end, however, a consensus emerged that we should make a start.

Adding impetus to the DOE's earliest interest in the human genome was the Department's stewardship of the national laboratories, with their demonstrated ability to conduct large multidisciplinary projects -- just the sort of effort that would be needed to develop and implement the technological know-how needed for the Human Genome Project. Biological research programs already in place at the national labs benefited from the contributions of engineers, physicists, chemists, computer scientists, and mathematicians, working together in teams. Thus, with the infrastructure in place and with a particular interest in the ultimate results, the Department of Energy, in 1986, was the first federal agency to announce and to fund an initiative to pursue a detailed understanding of the human genome.

Of course, interest was not restricted to the DOE. Workshops had also been sponsored by the National Institutes of Health, the Cold Spring Harbor Laboratory, and the Howard Hughes Medical Institute. In 1988 the NIH joined in the pursuit, and in the fall of that year, the DOE and the NIH signed a memorandum of understanding that laid the foundation for a concerted interagency effort. The basis for this community-wide excitement is not hard to comprehend. The first impulse behind the DOE's commitment was only one of many reasons for coveting a deeper insight into the human genetic script. Defective genes directly account for an estimated 4000 hereditary human diseases -- maladies such as Huntington disease and cystic fibrosis. In some such cases, a single misplaced letter among three billion can have lethal consequences. For most of us, though, even greater interest focuses on the far more common ailments in which altered genes influence but do not prescribe. Heart disease, many cancers, and some psychiatric disorders, for example, can emerge from complicated interplays of environmental factors and genetic misinformation.

The first steps in the Human Genome Project are to develop the needed technologies, then to "map" and "sequence" the genome. But in a sense, these well-publicized efforts aim only to provide the raw material for the next, longer strides. The ultimate goal is to exploit those resources for a truly profound molecular-level understanding of how we develop from embryo to adult, what makes us work, and what causes things to go wrong. The benefits to be reaped stretch the imagination. In the offing is a new era of molecular medicine characterized not by treating symptoms, but rather by looking to the deepest causes of disease. Rapid and more accurate diagnostic tests will make possible earlier treatment for countless maladies. Even more promising, insights into genetic susceptibilities to disease and to environmental insults, coupled with preventive therapies, will thwart some diseases altogether. New, highly targeted pharmaceuticals, not just for heritable diseases, but for communicable ailments as well, will attack diseases at their molecular foundations. And even gene therapy will become possible, in some cases actually "fixing" genetic errors. All of this in addition to a new intellectual perspective on who we are and where we came from.

The Department of Energy is proud to be playing a central role in propelling us toward these noble goals.

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.