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OCR for page 1
Executive Summary
The nature of biomedical research has been evolving in recent years.
Relatively small projects initiated by single investigators have tra-
ditionally been and continue to be the mainstay of cancer research,
as well as biomedical research in other fields. Recently, however, techno-
logical advances that make it easier to study the vast complexity of bio-
logical systems have led to the initiation of projects with a larger scale and
scope (Figure ES-1. For instance, a new approach to biological experi-
mentation 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. But even that information is not suffi-
cient 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 disease.
This concept of systems biology is based on the premise that a disease can
be fully comprehended only when its cause is understood from the mo-
lecular to the organismal level. For example, rather than focusing on single
aberrant genes or pathways, it is essential to understand the comprehen-
sive and complex nature of cancer cells and their interaction with sur-
rounding tissues. In many cases, large-scale analyses in which many pa-
rameters 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
that size is not likely to be launched in the near future, but many other
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2
LARGE-SCALE BIOMEDICAL SCIENCE
Conventional small-scale research ~ Large-scale ~ Very large-scale collaborative research
Smaller, more specific goals
Short-term objectives
Relatively shorter time Dame
Lower total cost, higher unit cost
Hypothesis driven, undefined deliverables
Broad goals (encompassing an entire field of
. .
Inquiry
Requires long-range strategic planning
Often a longer time Fame
Higher total cost, lower unit cost
Problem-directed with well-defined
deliverables and endpoints
Small peer review group approval sufficient ~ Acceptance by the field as a whole important
Minimal management structure
Minimal oversight by Finders
Single principal investigator
More dependent on scientists in training
Generally Ended by unsolicited,
investigator-initiated (Ret) grants
Larger, more complex management
structure
More oversight by Finders
Multi-investigator and multi-institutional
More dependent on technical staff
Often funded through solicited cooperative
agreements
More discipline-oriented ~ Often interdisciplinary
Takes advantage of infrastructure and
technologies generated by large-scale projects
May or may not involve bioinformatics
Develops scientific research capacity,
infrastructure, and technologies
Data and outcome analysis highly
dependent on bioinformatics
FIGURE ES-1 The range of attributes that may characterize scientific research.
There is no absolute distinction indeed there is much overlap between the
characteristic of small- and large-scale research. Rather, these characteristics vary
along a continuum that extends from traditional independent small-scale projects
through very large, collaborative projects. Any single project may share some
characteristics with either of these extremes.
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 map" 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.
OCR for page 3
EXECUTIVE SUMMARY
3
The recent interest in adopting large-scale research methods has gen-
erated many questions, then, as to how such research in the biomedical
sciences should be financed and conducted. Accordingly, the National
Cancer Policy Board determined that a careful examination of these issues
was warranted at this time. The purpose of this study was to (1) define the
concept of "large-scale science" with respect to cancer research; (2) iden-
tify examples of ongoing large-scale projects to determine the current
state of the field; (3) identify obstacles to the implementation of large-
scale projects in biomedical research; and (4) make recommendations for
improving the process for conducting large-scale biomedical science
projects, should such projects be undertaken in the future.
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,
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 improve-
ment could be achieved by adopting the seven recommendations pre-
sented here to address these issues.
The first three recommendations suggest a number of changes in the
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4
LARGE-SCALE BIOMEDICAL SCIENCE
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 (Table ES-1. 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 innovators in research can be routinely collected and
incorporated into the institutional decisionmaking 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 planning and oversight by federal sponsors during both the ini-
tiation 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 en-
deavors.
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
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
evaluating 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 con-
ferences. Whenever feasible, these discussions should be NIH-
wide and multidisciplinary.
· An NIH-wide, trans-institute panel of experts appointed by the
NIH director would facilitate the vetting process for assessing sci-
entific 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 review of specific project proposals should be established.
These guidelines should be applied by the institutions that oversee
the projects.
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EXECUTIVE SUMMARY
TABLE ES-1 Summary of the Challenges Associated with Large-Scale
Biomedical Research Projects, and the Committee's Recommendations
to Overcome These Difficulties
5
Difficulties Associated with
Large-Scale Projects
Potential Paths to Solutions
No systematic method for assessing
large-scale biomedical research
opportunities exists.
Carefully planning and orchestrating
the launch as well as the phase out of a
large-scale project is difficult, but
imperative for its long term success
and efficiency.
There are very few precedents to guide
the planning and oversight of large-
scale endeavors in biomedical science.
It is difficult to recruit and retain quali-
fied scientific managers and staff for
large-scale projects.
It can be costly and difficult for investi-
gators to maintain reagents produced
through large-scale projects and to share
them with the research community.
Licensing strategies can affect the
availability of research tools produced
by and used for large-scale research
projects.
A seamless transition between
discovery and clinical application is
lacking.
Develop an NIH-wide mechanism for
soliciting and reviewing proposals for
large-scale projects, with input from all
relevant sectors of biomedical science.
Clear but flexible plans for entry into
and phase out from projects should be
developed before funding is provided.
NCI and NIH should commission a
thorough analysis of their recent large-
scale initiatives to determine whether
those efforts have been effective and
efficient in meeting their stated goals
and to aid in the planning of future
large-scale projects.
Institutions should develop new ways
to recognize and reward scientific col-
laborations and team-building efforts.
NIH should provide funding to preserve
and distribute reagents and other research
tools once they have been created.
NIH should examine systematically the
impact of licensing strategies and
should promote licensing practices that
facilitate broad access to research tools.
Consideration should be given to
pursuing projects initiated by academic
scientists in cooperation with industry
to achieve large-scale research goals.
· 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.
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6
LARGE-SCALE BIOMEDICAL SCIENCE
· 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.
· 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 reduc-
tion 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-
OCR for page 7
EXECUTIVE SUMMARY
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.
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
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8
LARGE-SCALE BIOMEDICAL SCIENCE
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 indi-
viduals 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-
tion, 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 in-
structive models in achieving these goals, as they have a history
of rewarding 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-
OCR for page 9
EXECUTIVE SUMMARY
9
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
and tools would improve the quality of the data obtained through
research and make it easier to compare data from different investi-
gators.
· 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-
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10
LARGE-SCALE BIOMEDICAL SCIENCE
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
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
demonstrate the potential value of contributions by these entities to
large-scale research endeavors. The Single Nucleotide Polymorphism,
or SNP, consortium 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 coordinat-
ing and managing teams of scientists working toward a common goal.
Combining the respective strengths of academia and industry could
optimize the pace of biomedical research and development, potentially
leading to more rapid improvements in human health. Thus, the com-
mittee recommends that cooperation 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
OCR for page 11
EXECUTIVE SUMMARY
11
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-
tives 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
