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OCR for page 192
8
Findings and Recommendations
The nature of biomedical research has been evolving in recent years.
Relatively small projects initiated by single investigators have
traditionally been and continue to be the mainstay of cancer re-
search, as well as biomedical research in other fields. Recently, however,
technological advances that make it easier to study the vast complexity of
biological systems have led to the initiation of projects with a larger scale
and scope. For instance, a new approach to biological experimentation
known as "discovery science" first aims to develop a detailed inventory
of genes, proteins, and metabolites in a particular cell type or tissue as a
key information source (Lake and Hood, 2001~. But even that information
is not sufficient to understand the cell's complexity, so the ultimate goal
of such research is to identify and characterize the elaborate networks of
gene and protein interactions in the entire system that contribute to dis-
ease. This concept of systems biology is based on the premise that a dis-
ease can be fully comprehended only when its cause is understood from
the molecular to the organismal level (Thomas and Gilbert, 2002~. For
example, rather than focusing on single aberrant genes or pathways, it is
essential to understand the comprehensive and complex nature of cancer
cells and their interaction with surrounding tissues. In many cases, large-
scale analyses in which many parameters can be studied at once may be
the most efficient and effective way to extract functional information and
interactions from such complex biological systems.
The Human Genome Project is the biggest and best-known large-
scale biomedical research project undertaken to date. Another project of
192
OCR for page 193
FINDINGS AND RECOMMENDATIONS
193
that size is not likely to be launched in the near future, but many other
projects that fall somewhere between the Human Genome Project and the
traditional small projects have already been initiated, and many more
have been contemplated. Indeed, the director of the National Institutes of
Health (NIH) recently presented to his advisory council a "road maple for
the agency's future that includes a greater emphasis on "revolutionary
methods of research" focused on scientific questions too complex to be
addressed by the single-investigator scientific approach. He noted that
the NIH grant process will need to be adapted to accommodate this new
large-scale approach to scientific investigation, which may conflict with
traditional paradigms for proposing, funding, and managing science
projects that were designed for smaller-scale, hypothesis-driven research
(Science and Government Alert, 2002~.
Although the initial intent of this study was to examine large-scale
cancer research, it quickly became clear that issues pertaining to large-
scale science projects have broad implications that cut across all sectors
and fields of biomedical research. Large-scale endeavors in the biomedi-
cal sciences often involve multiple disciplines and contribute to many
fields and specialties. The Human Genome Project is a classic example of
this concept, in that its products can benefit all fields of biology and
biomedicine. The same is likely to be true for many other large-scale
projects now under consideration or underway, such as the Protein Struc-
ture Initiative (PSI) and the International HapMap Project. Furthermore,
given the funding structures of NIH, the launch of a large-scale project in
one field could potentially impact progress as well as funding in other
fields. Thus, while this report emphasizes examples from cancer research
whenever feasible, the committee's recommendations are generally not
specific to the National Cancer Institute (NCI) or to the field of cancer
research; rather, they are directed toward the biomedical research com-
munity as a whole. Indeed, it is the committee's belief that all fields of
biomedical research, including cancer research, could benefit from imple-
mentation of the recommendations presented herein.
Ideally, large-scale and small-scale research should complement each
other and work synergistically to advance the field of biomedical research
in the long term. For example, many large-scale projects generate hypoth-
eses that can then be tested in smaller research projects. However, the
new large-scale research opportunities are challenging traditional aca-
demic research structures because the projects are bigger, more costly,
More than 100 scientists were consulted during the plan's preparation, and all of the
agency's Institute and Center directors discussed it during a two-day retreat held in Sep-
tember 2002. Additional consultations are now planned with extramural researchers, as
well as public and patient groups.
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94
LARGE-SCALE BIOMEDICAL SCIENCE
often more technologically sophisticated, and require greater planning
and oversight. These challenges raise the question of how the large-scale
approach to biomedical research could be improved if such projects are to
be undertaken in the future.
Ideally, large-scale and small-scale research should complement each
other and work synergistically to advance the field of biomedical research
in the long term. For example, many large-scale projects generate hy-
potheses that can then be tested in smaller research projects. However,
the new large-scale research opportunities are challenging traditional aca-
demic research structures because the projects are bigger, more costly,
often more technologically sophisticated, and require greater planning
and oversight. These challenges raise the question of how the large-scale
approach to biomedical research could be improved if such projects are to
be undertaken in the future. The committee concluded that such im-
provement could be achieved by adopting the seven recommendations
presented here to address these issues.
The first three recommendations suggest a number of changes in the
way scientific opportunities for large-scale research are initially assessed
as they emerge from the scientific community, as well as in the way
specific projects are subsequently selected, funded, launched, and evalu-
ated. Although the procedures of NIH and other federal agencies have a
degree of flexibility that has allowed some large-scale research endeavors
to be undertaken, a mechanism is needed through which input from inno-
vators in research can be routinely collected and incorporated into the
institutional decision-making processes. Also needed is a more standard
mechanism for vetting various proposals for large-scale projects. For
example, none of the large projects initiated by NCI to date has been
evaluated in a systematic manner. There is also a need for greater plan-
ning and oversight by federal sponsors during both the initiation and
phase-out of a large-scale project. Careful assessment of past and current
large-scale projects to identify best practices and determine whether the
large-scale approach adds value to the traditional models of research
would also provide highly useful information for future endeavors.
Recommendation 1: NIH and other federal funding agencies that
support large-scale biomedical science (including the National Sci-
ence Foundation [NSF], the U.S. Department of Energy [DOE], the
2 The findings and recommendations presented in this chapter are based on the informa-
tion reviewed in the previous chapters, which include literature reviews, compilations of
data, and summaries of findings. Detailed discussions and references can be found in those
chapters and are merely summarized here.
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FINDINGS AND RECOMMENDATIONS
195
U.S. Department of Agriculture [USDA], and the U.S. Department
of Defense [DOD]) should develop a more open and systematic
method for assessing important new research opportunities emerg-
ing from the scientific community in which a large-scale approach
is likely to achieve the scientific goals more effectively or efficiently
than traditional research efforts.
· This method should include a mechanism for soliciting and evaluat-
ing proposals from individuals or small groups as well as from large
groups, but in either case, broad consultation within the relevant
scientific community should occur before funding is made available,
perhaps through ad hoc public conferences. Whenever feasible, these
discussions should be NIH-wide and multidisciplinary.
· An NIH-wide, transinstitute panel of experts appointed by the NIH
director would facilitate the vetting process for assessing scientific
opportunities that could benefit from a large-scale approach.
· Once the most promising concepts for large-scale research have been
selected by the director's panel, appropriate guidelines for peer re-
view of specific project proposals should be established. These guide-
lines should be applied by the institutions that oversee the projects.
· Collaborations among institutes could encourage participation by
smaller institutes that may not have the resources to launch their
own large-scale projects.
· NIH should continue to explore alternative funding mechanisms
for large-scale endeavors, perhaps including approaches similar to
those used by NCI's Unconventional Innovations Program, as well
as funding collaborations with industry and other federal funding
agencies.
J ~
· International collaborations should be encouraged, but an ap-
proach for achieving such cooperation should be determined on a
case by case basis.
Recommendation 2: Large-scale research endeavors should have
clear but flexible plans for entry into and phase out from projects
once the stated ends have been achieved.
· It is essential to define the goals of a project clearly and to monitor
and assess its progress regularly against well-defined milestones.
· Carefully planning and orchestrating the launch of a large-scale
project is imperative for its long-term success and efficiency.
· NIH should be very cautious about establishing permanent infra-
structures, such as centers or institutes, to undertake large-scale
projects, in order to avoid the accumulation of additional Institutes
via this mechanism.
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196
LARGE-SCALE BIOMEDICAL SCIENCE
· Historically, NIH has not had a good mechanism for phasing out
established research programs, but large-scale projects should not
become institutionalized by default simply because of their size.
· If national centers with short-term missions are to be established,
this should be done with a clear understanding that they are
temporary and are not meant to continue once a project has been
completed.
- Leasing space is one way to facilitate downsizing upon comple-
tion of a project.
Phase-out funding could enable investigators to downsize over
a period of 2-3 years.
Recommendation 3: NCI and NIH, as well as other federal funding
agencies that support large-scale biomedical science, should com-
mission a thorough analysis of their recent large-scale initiatives
once they are well established to determine whether those efforts
have been effective and efficient in achieving their stated goals and
to aid in the planning of future large-scale projects.
NIH should develop a set of metrics for assessing the technical and
scientific output (such as data and research tools) of large-scale
projects. The assessment should include an evaluation of whether
the field has benefited from such a project in terms of increased
speed of discoveries and their application or a reduction in costs.
· The assessment should be undertaken by external, independent
peer review panels with relevant expertise that include academic,
government, and industry scientists.
To help guide future large-scale projects, the assessment should
pay particular attention to a project's management and organiza-
tional structure, including how scientific and program managers
and staff were selected, trained, and retained and how well they
performed.
The assessment should include tracking of any trainees involved in
a project (graduate students and postdoctoral scientists) to deter-
mine the value of the training environment and the impact on
career trajectories.
· The assessment should examine the impact of industry contracts or
collaborations within large-scale research projects. Industry has
many potential strengths to offer such projects, including efficiency
and effective project management and staffing, but intellectual
property issues represent a potential barrier to such collaborations.
Thus, some balance must be sought between providing incentives
for producing the data and facilitating the research community's
access to the resultant data.
.
.
OCR for page 197
FINDINGS AND RECOMMENDATIONS
197
In pursuing large-scale projects with industry, NIH should care-
fully consider the data dissemination goals of the endeavor be-
fore making the funds available.
To the extent appropriate, NIH should mandate timely and un-
restricted release of data within the terms of the grant or con-
tract, in the same spirit as the Bermuda rules adopted for the
release of data in the Human Genome Project.
The committee has formulated four additional recommendations
aimed at improving the conduct of possible future large-scale projects.
These recommendations emerged from the committee's identification of
various potential obstacles to conducting a large-scale research project
successfully and efficiently. To begin with, human resources are key to
the success of any large-scale project. If large-scale projects are deemed
worthy of substantial sums of federal support, they also clearly warrant
the highest-caliber staff to perform and oversee the work. But if qualified
individuals, especially at the doctoral level, are expected to participate in
such undertakings, they must have sufficient incentives to take on the
risks and responsibilities involved. In particular, effective administrative
management and committed scientific leadership are crucial for meeting
expected milestones on schedule and within budget; thus the success of a
large-scale project is greatly dependent upon the skills and knowledge of
the scientists and administrators who manage it, including those within
the federal funding agencies. However, it may be quite difficult to recruit
staff with the skills to meet this need because of the unusual status of such
managerial positions within the scientific career structure, and because
scientists rarely undergo formal training in management. Young investi-
gators and trainees also need recognition for their efforts that contribute
to elaborate, long-term, and large multi-institutional efforts. Thus, the
committee concluded that both universities and government agencies
need to develop new approaches for assessing teamwork and manage-
ment, as well as novel ways of recognizing and rewarding accomplish-
ment in such positions.
Recommendation 4: Institutions should develop the necessary in-
centives for recruiting and retaining qualified scientific managers
and staff for large-scale projects, and for recognizing and reward-
ing scientific collaborations and team-building efforts.
· Funding agencies should develop appropriate career paths for in-
dividuals who serve as program managers for the large-scale
projects they fund.
· Academic institutions should develop appropriate career paths,
including suitable criteria for performance evaluation and promo-
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198
LARGE-SCALE BIOMEDICAL SCIENCE
lion, for those individuals who manage and staff large-scale col-
laborative projects carried out under their purview.
Industry and The National Laboratories may both serve as instruc-
tive models in achieving these goals, as they have a history of re-
warding scientists for their participation in team-oriented research.
It is important to establish guiding principles for such issues as
equitable pay and benefits, job stability, and potential for advance-
ment to avoid relegating these valuable scientists and managers to
a "second-tier" status. Federal agencies should provide adequate
funding to universities engaged in large-scale biomedical research
projects so that these individuals can be sufficiently compensated
for their role and contribution.
Universities, especially those engaged in large-scale research, should
develop training programs for scientists involved in such projects.
Examples include courses dealing with such topics as managing
teams of people and working toward milestones within timelines.
Input from industry experts who deal routinely with these issues
would be highly valuable.
The committee also identified potential impediments to deriving the
greatest benefits from the products of large-scale endeavors in terms of
scientific progress for biomedical research in general. Large-scale projects
are most likely to speed the progress of biomedical research as a whole
when their products are made widely available to the broad scientific
community. However, concerns have been raised in recent years about
the willingness and ability of scientists and their institutions to share
data, reagents, and other tools derived from their research. Since a pri-
mary goal of many large-scale biomedical research projects is to produce
data and research tools, NIH should facilitate the sharing of data and the
distribution of reagents to the extent feasible. Currently, NIH grants gen-
erally do not provide funds for this purpose, making it difficult for inves-
tigators to maintain reagents and share them with the research commu-
nity. This obstacle could be reduced if NIH provided such funds for
large-scale research projects.
Recommendation 5: NIH should draft contracts with industry to
preserve reagents and other research tools and distribute them to
the scientific community once they have been produced through
large-scale projects.
· The Pathogen Functional Genomics Resource Center, established
through a contract with the National Institute of Allergy and Infec-
tious Diseases, could serve as a model for this undertaking.
· The distribution of standardized and quality-controlled reagents
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FINDINGS AND RECOMMENDATIONS
199
and tools would improve the quality of the data obtained through
research and make it easier to compare data from different
investigators.
Producing the reagents and making them widely available to many
researchers would be more cost-effective than providing funds to a
few scientists to produce their own.
An issue closely related to the sharing of data and reagents is the
licensing of intellectual property. Many concerns have been raised in re-
cent years about the challenges and expenses associated with the transfer
of patented technology from one organization to another. Innovations
that can be used as research tools may offer the greatest challenge in this
regard because it is difficult to predict the future applications and value
of a particular tool, and because a number of different tools may be needed
for a single research project. Since many large-scale projects in the bio-
sciences aim to produce data and other tools for future research, this
subject is especially salient for large-scale research. The committee con-
cluded that NIH should continue to promote the broad accessibility of
research tools derived from federally funded large-scale research to the
extent feasible, while at the same time considering the appropriate role
for intellectual property rights in a given project. However, in the absence
of adequate information and scholarly assessment, it is difficult to deter-
mine how NIH could best accomplish that goal. Thus, the committee
recommends that such an assessment be undertaken, and that appropri-
ate actions be taken based on the findings of the study.
Recommendation 6: NIH should commission a study to examine
systematically the ways in which licensing practices affect the avail-
ability of research tools produced by and used for large-scale bio-
medical research projects.
· Whenever possible, NIH and NCI should use their leverage and
resources to promote the free and open exchange of scientific
knowledge and information, and to help minimize the time and
expense of technology transfer.
· Depending on the findings of the proposed study, NIH should
promote licensing practices that facilitate broad access to research
tools by issuing licensing guidelines for NIH-funded discoveries.
In addition to the role of federal funding agencies, the committee
considered the role of industry and philanthropies in conducting large-
scale biomedical research. Public-private collaborations provide a way to
share the costs and risks of innovative research, as well as the benefits.
Philanthropies and other nonprofit organizations can play an important
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200
LARGE-SCALE BIOMEDICAL SCIENCE
role in launching nontraditional projects that do not fit well with federal
funding mechanisms. Pharmaceutical and biotechnology companies also
make enormous contributions to biomedical research worldwide. Tradi-
tionally, the role of independent companies has been to pursue applied
research aimed at producing an end product; however, the distinction
between "applied" and "basic" research has blurred in recent years, in
part because of novel approaches used for drug discovery and develop-
ment. A recent focus by academic scientists on translational research,
which aims to translate fundamental discoveries into clinically useful
practices, has further obscured the distinction.
.
Several recent projects initiated and funded by industry or carried out
In cooperation with industry and nonprofit organizations clearly demon-
strate the potential value of contributions by these entities to large-scale
research endeavors. The Single Nucleotide Polymorphism, or SNP, Con-
sortium is a prime example of how effective these sectors can be when
involved in a large-scale research projects. Industry in particular has many
inherent strengths that could be brought to bear on large-scale biomedical
research efforts, such as experience in coordinating and managing teams
of scientists working toward a common goal. Combining the respective
strengths of academia and industry could optimize the pace of biomedi-
cal research and development, potentially leading to more rapid improve-
ments in human health. Thus, the committee recommends that coop-
eration between academia and industry be encouraged for large-scale
research projects whenever feasible.
Recommendation 7: Given the changing nature of biomedical re-
search, consideration should be given to pursuing projects initiated
by academic scientists in cooperation with industry to achieve the
goals of large-scale research. When feasible, such cooperative ef-
forts could entail collaborative projects, as well as direct funding of
academic research by industry, if the goals of the research are mutu-
ally beneficial.
· Academia is generally best suited for making scientific discoveries,
while the strength of industry most often lies in its ability to de-
velop or add value to these discoveries.
Establishing a more seamless connection between the two endeav-
ors could greatly facilitate translational research and thus speed
clinical applications of new discoveries.
Great strides in biomedical research have been made in recent de-
cades, due largely to a robust investigator-initiated research enterprise.
Recent technological advances have provided new opportunities to fur-
ther accelerate the pace of discovery through large-scale research initia-
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FINDINGS AND RECOMMENDATIONS
201
fives that can provide valuable information and tools to facilitate this
traditional approach to experimentation. Recent large-scale collaborations
have also allowed scientists to tackle complex research questions that
could not readily be addressed by a single investigator or institution. The
current leadership of NIH and many scientists in the field clearly have
expressed an interest in integrating the discovery approach to biomedical
science with hypothesis-driven experimentation. As a result, at least some
large-scale endeavors in the biomedical sciences are likely to be under-
taken in the future as well. But because the large-scale approach is rela-
tively new to the life sciences, there are few precedents to follow or learn
from when planning and launching a new large-scale project. Moreover,
there has been little formal or scholarly assessment of large-scale projects
already undertaken.
Now is the time to address the critical issues identified in this report
in order to optimize future investments in large-scale endeavors, what-
ever they may be. The ultimate goal of biomedical research, both large-
and small-scale, is to advance knowledge and provide society with useful
innovations. Determining the best and most efficient method for accom-
plishing that goal, however, is a continuing and evolving challenge. Fol-
lowing the recommendations presented here could facilitate a move to-
ward a more open, inclusive, and accountable approach to large-scale
biomedical research, and help strike the appropriate balance between
large- and small-scale research to maximize progress in understanding
and controlling human disease.
Representative terms from entire chapter:
research tools
