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OCR for page 86
7
Implementation and
Management Strategies
Earlier chapters have outlined the scientific strategies that seem
most reasonable for genome mapping and sequencing studies and
have argued in favor of an intensive effort to characterize the human
genome in detail. In those chapters the committee has discussed the
technological advances required for completion of the different human
genome maps desired: a genetic map with REAP markers spaced at
about 1-cM intervals, a physical map of expressed genes (cDNA map),
an ordered DNA clone collection that covers the entire genome, and
physical maps of increasing resolution culminating in the DNA
sequence. However, such a large endeavor requires a degree of
organization and coordination that has no precedent in the biological
sciences. The committee-has argued specifically against establishing
at this time one or a few very large production centers to carry out
this project. Yet a concerted approach to project management will be
required, and many of the benefits of a singular effort will be lost if
results and materials are not quickly and efficiently shared.
The committee's recommendations immediately raise a number of
obvious questions, such as, How should such an effort be funded so
that its quality and success are ensured? How can the efforts of the
different laboratories best be coordinated? How can the scientific
community guarantee ready accessibility to all the information and
materials to be generated? This chapter deals chiefly with the com-
mittee's attempts to answer these important questions.
86
OCR for page 87
IMPLEMENTATION AND MANAGEMENT STRATEGIES
FUNDING A HUMAN GENOME PROJECT
Projects with the Potential to Make Substantial Technological
Improvements in Genome Analysis Should Receive Top Priority
87
Mapping and sequencing the human genome poses a severe tech-
nological challenge to our present abilities. A complete restriction
map has recently been produced for the genome of the bacterium
Escherichia colt, which is only No the size of the human genome
(Smith et al., 1987, Kohara et al., 19871. In addition, the human
genome is 20,000 times as long as the longest continuous stretch of
DNA sequence of 150,000 nucleotides thus far produced in a single
laboratory project. Interpreting the large amounts of information
produced by large-scale DNA sequencing will be an even more
formidable task. Thus, the human genome project is more ambitious
by orders of magnitude than any single biology project completed
thus far. Technological advances are needed in many different areas,
and determining the most efficient technology to obtain the desired
knowledge requires further research.
In view of the current situation, the committee recommends the
establishment of a competitive grant program specifically focused on
improving in 5- to 10-fold increments the scale or efficiency of mapping
and sequencing the human genome. These grants would be designed
to support work that is more technologically oriented than most
ongoing biological research. For example, a project that aims at
sequencing a fragment containing a contiguous segment of a million
nucleotides or more might qualify for support, as might a project
aimed at developing and testing an entirely new approach to DNA
cloning or sequencing. In contrast, a project that aims to use standard
approaches to isolate and characterize a single interesting human gene
of 10,000 nucleotides would be more appropriately funded elsewhere.
Both Small Research Laboratories and Larger Multidisciplinary
Centers Should Be Encouraged
Nearly all the major methodological breakthroughs that have driven
the modern revolution in biology have come from the efforts of small
research laboratories, frequently those led by young investigators in
the early stages of their careers. This trend will no doubt continue,
and small groups that are already active in developing or improving
relevant technologies should be supported by this project, irrespective
of the particular genome that they are characterizing.
There is also much to be said for the establishment of multidisci
OCR for page 88
88 MAPPING AND SEQUENCING THE HUMAN GENOME
plinary centers, in which 3 to 10 research groups in a single facility,
each with a different but related focus, share equipment and personnel
and collaborate to accomplish a larger goal than any single group
could readily achieve. For the most part, these should be located at
universities or research institutes that can help provide the projects
with a constant influx of new people and ideas. Efficient mapping
requires the coordination of a large number of different experimental
and computer techniques. It also demands flexibility in developing
and incorporating new technologies. The methods will probably evolve
very rapidly, and the strongest and most efficient mapping efforts will
provide their first critical tests. For these reasons, a substantial portion
of the human genome mapping effort should probably be organized
into medium-sized research centers, each with ongoing activities in
both development of techniques and actual mapping and each with a
reasonable fraction of the various technologies in place or under
development. Such centers can set the stage for subsequent large-
scale DNA sequencing projects. The sequencing effort will benefit
from close contact with mapping efforts, some of which provide the
samples to sequence, while others provide the framework to organize
the sequence data generated and to assist in its interpretation.
The Establishment of a Single Large Production'
Center Is Not Advisable at Present
The committee believes that it would not be wise to confine an
activity such as mapping or sequencing to a single, large center at
present. The task needs to be organized and coordinated, but it does
not need to take place in a single location or laboratory. Unlike many
physics projects of this magnitude, this large-scale biology project
can be subdivided along several different lines. For example, an
individual chromosome could be mapped by one laboratory, but even
this is not necessary since available methods permit one to work
efficiently with just a section of a chromosome. Similarly, while
restriction, genetic, and DNA-clone-collection mapping must be con-
ducted in parallel, they do not necessarily need to be done by the
same investigators, inasmuch as materials generated by one method
can readily be transferred for use in other laboratories.
There are strong technical and intellectual advantages to dispersing
much of the mapping efforts among medium-sized, multidisciplinary
centers (each with perhaps 30 to 100 persons). If adequately funded,
these units would be large enough to accommodate biologists, chem-
ists, physicists, and engineers with diverse skills and backgrounds,
thereby achieving the critical mass necessary for an effective approach.
OCR for page 89
IMPLEMENTATION AND MANAGEMENT STRATEGIES
89
At the same time, available resources should make it possible to
establish several centers with the same goals, each competing with
other centers to advance the technology. Such competition is healthy
and productive, and it permits subsequent judgments to be made on
relative quality, allowing additional resources to be directed to the
most successful units. Finally, the dispersal of these technology
centers into existing universities and research institutes will allow
members of the center to work closely with a large number of other
scientists. This interface should be of great value to both groups, and
it will ensure that the human genome effort will have the strong
support it needs from the scientific community at large.
Decisions for Funding Should Be Made by Peer Review
The committee envisions that funding would initially be offered in
the form of grants awarded for 3- to 7-year periods. It is imperative
that these grants be awarded solely on the basis of scientific merit,
as judged by panels of peer reviewers selected for their judgment and
scientific expertise. The committee specifically recommends the form
of review that has been routine for many years at the National
Institutes of Health (NTH), in which the reviewers meet to discuss
and debate the merits and faults of each grant application. Each
application is then ranked relative to the others by the assignment of
a priority score, which is forwarded to the individual NIH institute
that distributes the research funds. Generally, grants are awarded in
the order of their priority scores, until the allotment of funds for that
cycle is exhausted.
As technologies mature, production units, such as contract orga-
nizations or dedicated centers will be required in the human genome
project. For example, RAP mapping is already a relatively mature
technology. An REAP map at higher resolution can be attained mainly
by applying current methods on a larger scale. Such endeavors are
appropriately supported by contracts rather than by grants. The
central facilities that collect and distribute information and materials
should also be supported by contract. Such efforts should also be
subject to continuing peer review, both for technical competence and
to ensure continuing coordination with the overall effort to map and
sequence the human genome.
If a human genome project is funded by several separate U.S.
government agencies as well as by private funds, an effective reviewing
body will be needed to avoid excessive duplication of effort and to
oversee cooperation between research groups. The committee rec-
ommends that the same body also ensure a uniform standard of peer
review.
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90
MAPPING AND SEQUENCING THE HUMAN GENOME
The Human Genome Project Requires New and Distinctive Funding
of About $200 Million per Year
To create the multidisciplinary centers suggested, new laboratories
will need to be built, equipped, and staffed. Universities cannot be
expected to provide the necessary resources without a major new
source of funding from outside. The estimated cost of an effective
project to map and sequence the human genome is $200 million per
year. (This level of funding would be reached only during the third
year of the project, with the first 2 years having lower levels of funding
to allow a scale-up to an effective project.)
The money might be spent roughly as follows. In the first 5 years
of the project there might be about 10 medium-sized, multidisciplinary
Protons ~nr1 m~nv smaller research ground working, with perhaps half
of the projected total of 1,200 individuals in the multidisciplinary
groups. Each professional researcher costs about $100,000 annually
in pay and support (the standard number used in the biotechnology
industry); thus this cost would be an estimated $120 million annually.
=~~~r~ -----a ----I---- ----I---- =---¢~ --on
Construction and equipment might cost about $55 million per year,
the stock center, the data management center, the quality control
effort, and the Scientific Advisory Board (see below) might cost
approximately an additional $25 million per year.
As the project proceeds, annual construction costs will decrease,
but the number of indivicluals participating in the effort may increase
to about 1,500.
The committee's possible scenario for the project divides the effort
into three 5-year periods (l, It, and IlI). During each period, mapping
and sequencing efforts five times as complex as the next lower
numerical designation would be undertaken at constant cost, reflecting
five-fold increments in technological sophistication. Several points
should be stressed.
· Attaining two successive fivefold increases in the technology for
mapping and sequencing is an ambitious undertaking; if it is to
succeed, a major effort must be expended in developing the required
technology.
· The cost for sequencing must include preparation of the DNA
samples. New methods of DNA subcloning and processing will have
to be developed (or present ones automated) to attain the desired
costs.
· DNA clones from an ordered DNA clone collection will be
sequenced, thereby producing large, contiguous stretches of DNA
sequence that are immediately useful; isolating the last 10 to 15 percent
of these clones to fill in gaps in the map may be as expensive as
OCR for page 91
IMPLEMENTATION AND MANAGEMENT STRATEGIES
91
isolating the clones that cover the initial 85 to 90 percent of the
genome.
· An ambitious effort of this type will require the recruitment of
scientists with extensive experience in mapping and sequencing. The
multidisciplinary centers supported by the project will presumably
play a key role in training new independent scientists who can
participate. The committee believes that the training of young scientists
in the development of technology as well as its applications would be
of the major benefit to the biological community.
A major objective of the human genome project would be to achieve
an annual sequencing capacity of ~ billion nucleotides through the
combined efforts of a modest number of centers by the year 2000.
Once this ambitious goal is reached, it would be realistic to complete
the entire human genome sequence, and powerful comparative studies
on human polymorphisms and evolution would become possible.
Funding of the human genome project must not be at the expense
of currently funded biological research. The essential purpose of the
human genome project is to provide a resource to be used by biomedical
scientists to accelerate the understanding of human biology and the
application of this knowledge to human health. It would therefore
defeat the purpose of the project if biomedical research and training
were weakened by diverting funds from individual research programs
or training grants. Major advances being made in other aspects of
biology are expected to form the scaffolding required for interpreting
and utilizing information resulting from this project.
Mapping Efforts Should Be Accelerated and Coordinated
Most biologists feel that mapping the human genome is a valuable
and attainable objective. At the present rate this goal will not be
reached for many years. The committee strongly believes that this
effort should be accelerated. Funds should be invested in projects
that increase our technological skills, but large-scale mapping should
begin even with present-day techniques. It should be possible to
complete an RAP map within 5 years with the investment of more
money and the encouragement of coordinated efforts. Several types
of physical maps can also be completed in a similar length of time.
The Sequencing Effort Should Evolve andt Grow with Time
Most of the human genome will probably become available in the
ordered DNA clone collection as a result of the combined efforts of
several multidisciplinary centers. If the envisioned support is forth
OCR for page 92
92
MAPPING AND SEQUENCING THE HUMAN GENOME
coming, the ordered DNA clone collection could be completed within
10 years. In principle, sequencing major blocks of the human genome
could begin as soon as any contiguous area of a chromosome has
been accumulated in the ordered DNA clone collection. Decisions for
a major push on bulk sequence data collection, as distinct from the
envisioned pilot projects that push technology development, would
depend on how fast the new sequencing technologies develop.
Several relatively small genomes should be sequenced early in the
project. Such genomes include that of yeast (0.5 percent of the size
of the human genome), the nematode Caenorhabditis elegans (2
percent of the human), and the fruit fly Drosophila melanogaster (3
percent of the human). It is important to give these projects high
priority, since they deal with widely studied experimental organisms,
which, along with the mouse, provide the most important of the many
mode! systems that will be required for interpreting all the sequence
data that will be collected on humans.
International Collaboration on the Project Is Desirable
There is a strong tradition of international cooperation in the
biological sciences that has greatly speeded the rate of scientific
progress in the past. This tradition must continue in any human
genome project. Some portion of research on the human genome is
bound to be done outside the United States, mainly in Europe and
Japan. One project already started in Japan is supported by major
industrial companies, which intend to automate DNA sequencing at
the rate of 1 million nucleotides per day. In Europe, developments in
semiautomatic DNA sequencing at the European Molecular Biology
Laboratory in Heidelberg have resembled those at the California
Institute of Technology. Work on new methods for physically mapping
complex genomes, including the human genome, is progressing in
Cambridge and London. In addition, extensive research on human
genetics is under way in several European countries. The reference
set of 40 families collected by the Centre d' etude du Polymorphisme
Humain and used throughout the world for mapping RF~Ps was
established in Paris, from which reference cells and DNA are distrib-
uted worldwide. GenBank in the United States currently shares on a
50:50 basis the collection and entry of DNA sequence data with the
EMBE Data Bank in Heidelberg.
These examples suggest that the United States does not and cannot
expect to monopolize information and innovation in this field. More-
over, the initiation of a human genome project in the United States
will probably not deter work in other countries, but rather will
OCR for page 93
IMPLEMENTATION AND MANAGEMENT STRATEGIES
93
stimulate it. Given this assumption, the importance of past traditions,
and the magnitude of the task of mapping and sequencing the entire
human genome, every effort should be made to enhance the existing
contacts between U.S. laboratories and those overseas, so as to speed
the work. Indeed, we believe it will become necessary to have some
major organized mechanism for international cooperation. In partic-
ular, its objective would be to collate data and ensure rapid accessibility
to it, as well as to distribute materials, such as cloned DNA fragments.
MANAGING A HUMAN GENOME PROJECT
The human genome project presents complexities of organization
and management at both the scientific and policy levels. At the
biological level, the project differs from conventional biological re-
search in that it must be coordinated in terms of mapping, definition
of overlapping cosmids, distribution of DNA clones, sequencing,
technology development, and data base design. At the policy and
funding level, a number of governmental and private foundations will
probably be involved. For these reasons, it is imperative to design a
management system that will provide oversight, coordination, review
of progress, and forward planning. The committee was convinced of
the need for strong leadership for the project, and presents three
possible management plans. We also recognize that the management
of the human genome project may need to evolve as the project
evolves, as have management mechanisms for similar projects with
federal research support.
Three Possible Organizational Plans
Briefly summarized, each of the possible organizational plans
(designated A, B. and C) includes a Scientific Advisory Board, but
differs in the administrative and funding leadership. In plan A a single
federal agency serves as the lead for the project. This agency, which
would be assisted by a Scientific Advisory Board composed of experts
who provide scientific advice for the project, would be responsible
for all aspects of the project.
In plan B an Interagency Committee, consisting of representatives
of the National Institutes of Health (NTH), the Department of Energy
(DOE), the National Science Foundation (NSF), and other federal
agencies interested in the project, would be responsible for all aspects
of the project. The Interagency Committee would' be assisted by a
Scientific Advisory Board that would provide advice on the project,
as in plan A.
In plan C, an Interagency Committee would have the ultimate
responsibility for the coordination and funding of the activities to be
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94
MAPPING AND SEQUENCING THE HUMAN GENOME
supported, while a single agency would be responsible for the daily
administration of the project. In this plan, a Scientific Advisory Board
would provide advice to both the Interagency Committee and the
administrative agency.
Each of these management plans has advantages and disadvantages.
Although the primary charge to the committee was not to develop an
organizational plan, and decisions on management organization include
considerations outside the committee's areas of expertise, a majority
of the committee members favors plan A, which therefore is presented
in the greatest detail.
Organizational Plan A: A Lead Agency and a
Scientific Advisory Board
The Human Genome Project Should Be Assigned to a Major Federal
Agency In this plan the human genome project would be sited within
a federal agency as an independently funded endeavor. This would
place both the responsibility and the operation of the project within
a single unit. Already there are aspects of the human genome project
being supported by three federal agencies, N]:H, DOE, and NSF.
Each of these agencies has the potential capability to provide an
effective home for the project.
Although the committee did not fee! it was its role to designate a
lead agency, it did discuss some of the merits of each agency. The
NTH is the major agency today supporting research on the structure
and functioning of DNA. It is also the agency with the mandate to
foster biomedical research in the United States. It has a long history
of successful support of peer-reviewed extramural research, successful
intramural laboratories on the NTH campus, and has been involved
in the oversight of large projects in biology, such as the viral cancer
program. Recently, the NTH has shown interest in establishing a
human genome project. DOE has successfully managed many impor-
tant projects for the physics community, has supported some life
science programs, has extensive computer facilities for data manage-
ment, and has expressed strong interest in overseeing the human
genome project. The NSF has been involved in the development of
technology and instrumentation relevant to the human genome project,
in the general support of basic biological research, and has a well-
established peer review system.
Locating the project within one agency does not mean that all the
funding for the project would flow from it or that scientists associated
with another agency would not be able to obtain funding. For example,
even if DOE were not the lead agency, scientists at the national
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IMPLEMENTATION AND MANAGEMENT STRATEGIES
95
laboratories and DOE grantees should be eligible to compete for
research support relevant to the human genome project. The same
would apply for scientists at the NTH and NTH grantees, if NTH were
not the lead agency.
Scientific Advisory Board Although the lead agency would have
the ultimate authority and responsibility for the funding and admin-
istration of the project, our committee believes that the overall
scientific oversight of the project should draw upon the experience
and be guided by a Scientific Advisory Board (SAB) made up
predominately of scientists with expertise in the methods and goals
of the project, and chaired by a full-time chairman who is a distin-
guished scientist. We recommend that the members of the SAB be
appointed by the lead agency for staggered terms. The chairman
should be appointed for a fixed term with a possibility for reappoint-
ment and should be provided with a full-time staff sufficient to carry
out the directives of the lead agency and the SAB. The role anticipated
for the Board is somewhat stronger than that of a typical scientific
advisory board.
The major responsibilities of the SAB include:
· To facilitate coordination of the efforts of the many laboratories
that are expected to participate in this effort.
· To help assure the accessibility of all information and materials
generated in the project by advising on the oversight of the data center
and the stock center and recommending contracts where appropriate.
It would oversee formation of standard terminologies and reporting
formats so that the large body of information to be obtained can be
readily communicated and analyzed by the entire scientific community.
· To monitor the quality of research by helping to assure a uniform
standard of peer review.
· To suggest mechanisms for strict quality controls on the sequence
and mapping data collected.
· To promote international cooperation, serving as a liaison to
projects outside the United States regardless of their funding sources.
· To make recommendations concerning the establishment of large
sequencing endeavors, thereby balancing focus with breadth.
· To publish periodic reports stating progress, problems, and
recommendations for research.
The Scientific Advisory Board Should Provide Advice on the Peer
Review Process and on Coordination of the Project A human genome
project cannot succeed unless the various mapping and sequencing
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96
MAPPING AND SEQUENCING THE HUMAN GENOME
efforts are coordinated. Standards must be set and the rapid distribution
of materials and information must be facilitated. The failure of a unit
to coordinate its efforts with others should jeopardize the support of
the unit not in compliance.
The lead agency and SAB should work closely in developing and
implementing a high standard of peer review. After the committee
considered several options, it concluded that this system would
function best if the SAB were involved in monitoring the evaluation
of proposals for funds. After consideration of the advice of the SAB,
the lead agency would then fund selected applications.
The Scientific Advisory Board Would Require Funding To be
effective, the SAB must be adequately funded. Although the lead
agency would provide much of the money for the SAB, private
foundations and institutes should be encouraged to help support it.
An appropriate mechanism for merging private and federal funds for
this purpose would have to be developed. If, in addition to its role as
scientific advisor and coordinator, the SAB is assigned such tasks as
oversight of peer review panels, funds will have to be provided to it
for these purposes.
Organizational Plan B: An Interagency Committee and Scientific
Advisory Board
The Interagency Committee Three government agencies can po-
tentially play leading roles in the human genome project: The National
Institutes of Health (NTH) because of their central responsibility for
human biomedical research and their exemplary peer-reviewed extra-
mural grant programs; the Department of Energy (DOE) because of
its interest in the project and experience in data management and the
management of large-scale projects; and the National Science Foun-
dation (NSF) because of its commitment to technology development
and basic research support of biology across the discipline. Private
foundations and institutes may also be interested in involvement in
the project.
In this plan the above three governmental agencies would form an
Interagency Committee (IAC) that also includes members from other
agencies interested in the project. The chairmanship of the IAC might
rotate among the three principal agencies (NIH, DOE, and NSF)
involved in the project.
The IAC would be responsible for overall administration of the
project, including funding of research programs and supporting serv-
ices; administration of a common peer review process, the stock
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IMPLEMENTATION AND MANAGEMENT STRATEGIES
97
center, and the data center; and the appointment of and response to
a Scientific Advisory Board (SAB). Because funding for this project
may come from several agencies it is important that the Interagency
Committee be responsible for the coordination of the funding. Each
year the committee should develop a total project budget and determine
what the contributions of each of the agencies would be to the project.
Representatives of each agency can then request the funds required
for the project from the administration and the respective appropria-
tions committees.
The Scientific Advisory Board would assume a role similar to that
outlined in organizational plan A, except that it would of course advise
the Interagency Committee rather than a lead agency.
Organizational Plan C: Interagency Committee, Ad~mir~istrat~ve
Agency, and, Scientific Advisory Board
In this final proposed plan aspects of organizational plans A and B
are combined to form a three-part administrative structure.
The Interagency Committee As discussed under organizational
plan B. an Interagency Committee would be established to oversee
the project. It would be ultimately responsible for the coordination
and funding of the activities to be supported, the administration of
the peer review process, the research program, the stock center, and
the data center. It is expected that this committee, which would
provide the administrative and the funding lead for the project, would
pay close attention to the recommendations of the Scientific Advisory
Board and the administrative agency.
The Administrative Agency In this plan, one of the member
agencies of the Interagency Committee would act as the administrative
agency responsible for the daily administration of the project. This
agency would be involved in the administration of funds and other
administrative aspects of the project, such as the operation of the
stock center and the data center. Questions and inquiries about the
project would be directed to this agency which would serve the
important role of clearinghouse for the effort. This agency would help
to guarantee that the project is well-run, and that the necessary details
in the operation of this large-scale project are completed.
The administrative agency would work closely with the SAB in
developing and implementing a high standard of peer review. This
agency would arrange the administrative details of the peer review
process, while the SAB would monitor the initial evaluation of grant
and contract proposals. After the assignment of a priority number to
each grant and contract, the Interagency Committee would select the
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98
MAPPING AND SEQUENCING THE HUMAN GENOME
applications to be funded.
The Scientific Advisory Board in this organizational plan would
have similar responsibilities to those outlined in plan A, but would
advise both the Interagency Committee and the administrative agency.
REFERENCE
Kohara, Y., K. Akiyama, and K. Isono. 1987. The physical map of the whole Escherichia
cold chromosome. Cell 50:495-508.
Smith, C. L., J. G. Econome. A. Schutt, S. Klco, and C. R. Cantor. 1987. A physical map
of the Escherichia cold K12 genome. Science 236:1448-1453.
Representative terms from entire chapter:
interagency committee
