Predictions of biology as "the science
of the 21st century" have been made by observers as diverse as Microsoft's
Bill Gates and U.S. President Bill Clinton. Already revolutionizing biology,
genome research has spawned a burgeoning biotechnology industry and is
providing a vital thrust to the increasing productivity and pervasiveness
of the life sciences.
Technology and resources promoted
by the Human Genome Project already have had profound impacts on biomedical
research and promise to revolutionize biological research and clinical
medicine. Increasingly detailed genome maps have aided researchers seeking
genes associated with dozens of genetic conditions, including myotonic
dystrophy, fragile X syndrome, neurofibromatosis types 1 and 2, a kind
of inherited colon cancer, Alzheimer's disease, and familial breast cancer.
Current and potential applications
of genome research will address national needs in molecular medicine, waste
control and environmental cleanup, biotechnology, energy sources, and risk
On the horizon is a new era of
molecular medicine characterized less by treating symptoms and more by
looking to the most fundamental causes of disease. Rapid and more specific
diagnostic tests will make possible earlier treatment of countless maladies.
Medical researchers also will be able to devise novel therapeutic regimens
based on new classes of drugs, immunotherapy techniques, avoidance of environmental
conditions that may trigger disease, and possible augmentation or even
replacement of defective genes through gene therapy.
In 1994, taking advantage of new
capabilities developed by the genome project, DOE formulated the Microbial
Genome Initiative to sequence the genomes of bacteria useful in the
areas of energy production, environmental remediation, toxic waste reduction,
and industrial processing. In the resulting Microbial Genome Project, six
microbes that live under extreme conditions of temperature and pressure
have been sequenced completely as of August 1997. Structural studies are
under way to learn what is unique about the proteins of these organisms—the
ultimate aim being to use the microbes and their enzymes for such practical
purposes as waste control and environmental cleanup.
The potential for commercial development
presents U.S. industry with a wealth of opportunities. Sales of biotechnology
products are projected to exceed $20 billion by the year 2000. The genome
project already has stimulated significant investment by large corporations
and prompted the creation of new biotechnology companies hoping to capitalize
on the far-reaching implications of its research.
Biotechnology, fueled by insights
reaped from the genome project, will 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 technologies. Biotechnology promises
to help address these needs by providing cleaner means for the bioconversion
of raw materials to refined products. In addition, there is the possibility
of developing entirely new biomass-based energy sources. Having the genomic
sequence of the methane-producing microorganism Methanococcus jannaschii,
for example, will enable researchers to explore the process of methanogenesis
in more detail and could lead to cheaper production of fuel-grade methane.
Understanding the human genome
will have an enormous impact on the ability to assess risks posed to individuals
by environmental exposure to toxic agents. Scientists know that genetic
differences make some people more susceptible and others more resistant
to such agents. Far more work must be done to determine the genetic basis
of such variability. This knowledge will directly address DOE's long-term
mission to understand the effects of low-level exposures to radiation and
other energy-related agents, especially in terms of cancer risk.
The National Research Council issued a report in 1988 recommending
a dedicated research budget of $200 million annually for 15 years to determine
the sequence of the 3 billion chemical subunits (base pairs) in the human
genome and to map and identify all human genes.
To launch the nation's Human Genome Project, Congress appropriated funds
to DOE and also to NIH, which had long supported research in genetics and
molecular biology as an integral part of its mission to improve the health
of all Americans. Other federal agencies and foundations outside the Human
Genome Project also contribute to genome research, and many other countries
are making important contributions through their own genome research projects.
In 1988 DOE and NIH signed a Memorandum of Understanding in which the
agencies agreed to work together, coordinate technical research and activities,
and share results. The two agencies assumed a joint systematic approach
toward establishing goals to satisfy both short- and long-term project
Early guidelines projected three 5-year phases, for which the first
plan was presented to Congress in 1990. The 1990 plan emphasized the creation
of chromosome maps, software, and automated technologies to enable sequencing.
By 1993, unexpectedly rapid progress in chromosome
mapping required updating the goals [Science
262, 4346 (October 1, 1993)], which now project through 1998.
This plan is being revised again in anticipation of the approaching high-throughput
sequencing phase of the project. Last year marked an early transition to
this phase as many more genome sequencing projects were funded. The second
and third phases of the project will optimize resources, refine sequencing
strategies, and, finally, completely determine the sequence of all base
pairs in the genome.
Another area of DOE and NIH cooperation is in exploring the ethical,
legal, and social issues (ELSI) arising from increased availability of
genetic data and growing genetic-testing capabilities. The two agencies
established a joint working group to confront these ELSI challenges and
have cosponsored joint projects and workshops.
A general overview follows of recent progress made in the DOE Human
Genome Program. Refer to Evolution of a Vision: Genome
Project Origins, Present and Futre Challenges, Far-Reaching Benefits
and the timeline for other achievements toward
U.S. goals, including contributions made outside DOE.
For DOE, an early goal was to develop chromosome physical maps, which
involves reconstructing the order of cloned DNA fragments to represent
their specific originating chromosomes. (A set of such cloned fragments
is called a library.) Critical to this effort were the libraries of individual
human chromosomes produced at Los Alamos National Laboratory (LANL) and
Lawrence Livermore National Laboratory (LLNL). These libraries allowed
the huge task of mapping and sequencing the entire 3 billion bases in the
human genome to be broken down into 24 much smaller single-chromosome units.
Availability of the libraries has enabled the participation of many laboratories
worldwide. Some three generations of clone libraries with improving characteristics
have been produced and widely distributed. In the DOE-supported projects,
DNA clones representing chromosomes 16, 19, and 22 have been ordered (mapped)
and are now providing material needed for large-scale sequencing.
Toward the goal of greatly increasing the speed and decreasing the
cost of DNA sequencing, DOE has supported improvements in standard technologies
and has pioneered support for revolutionary sequencing systems. Marked
improvements have been made in reagents, enzymes, and raw data quality.
Such novel approaches as sequencing by hybridization (using DNA "chips")
and mass spectrometry have already found important, previously unanticipated
applications outside the Human Genome Project.
Joint Genome Institute
In early 1997, the human genome centers at Lawrence Berkeley National
Laboratory, LANL, and LLNL began collaborating in the Joint Genome Institute
(JGI), within which high-throughput sequencing will be implemented [see
JGI and Human
Genome News 8(2), 12]. The initial JGI focus will be
on sequencing areas of high biological interest on several chromosomes,
including human chromosomes 5, 16, and 19. Establishment of JGI represents
a major transition in the DOE Human Genome Program.
Previously, most goals were pursued by small- to medium-sized teams,
with modest multisite collaborations. The JGI will house high-throughput
implementations of successful technologies that will be run with increasingly
stringent process- and quality-control systems.
In addition, a small component aimed at understanding how genes function
in the body—a field known
as functional genomics—has
been established and will grow as sequencing targets are met. High-throughput
functional genomics represents a new era in human biology, one which will
have profound implications for solving biological problems.
In preparation for the production-sequencing phase, many algorithms
for interpreting DNA sequence have been developed, and an increasing number
have become available as services over the Internet. Last year, the GRAIL
(for Gene Recognition and Analysis Internet Link) and GenQuest servers,
developed and maintained at Oak Ridge National Laboratory, processed an
average of almost 40 million bases of sequence each month.
As technology improves and data accumulates exponentially, continued
progress in the Human Genome Project will depend increasingly on the development
of sophisticated computational tools and resources to manage and interpret
the information. The ease with which researchers can access and use the
data will provide a measure of the project's success. Critical to this
success is the creation of interoperable databases and other computing
and informatics tools to collect, organize, and interpret thousands of
For additional information on the DOE genome programs, refer to Research
Highlights, Research Narratives, this
report's Part 2, 1996 Research Abstracts,