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.