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4
Funding for Large-Scale Science
Obtaining funding is an essential step in launching any scientific
research project. For large-scale projects, the challenges encoun-
tered in securing funding to pursue an idea are amplified and in
many ways unique. Potential sources of funding include government
agencies, philanthropies and other nonprofit organizations, and indus-
try, each of which has its advantages and limitations. In the United States,
the federal government has traditionally been the primary fonder of
large-scale projects, as defined in this report, because of the high costs of
such activities.
Not surprisingly, however, the provision of federal funds for large-
scale projects has frequently been controversial, both across and within
scientific disciplines. The angst across disciplines stems from the sense
that large-scale projects funnel an inequitable or unjustified portion of the
funds available for science and technology in general to one particular
field, thus shortchanging other fields and impeding progress toward use-
ful advances. For example, this argument has been used in debates re-
garding the proposal to build a superconducting super collider, which
was eventually rejected, as well as the proposal for the international space
station, which was narrowly passed. The tension within a field stems
largely from disagreements over whether large projects or more tradi-
tional small-scale projects are the most efficient, economical, and benefi-
cial for moving a field forward in the long run. These questions were
widely debated in regard to the Human Genome Project (HGP).
Although the completion of the reference draft of the human genome
sequence has been widely hailed as a major achievement that will greatly
80
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FUNDING FOR LARGE-SCALE SCIENCE
81
advance the fields of biology and biomedical research, questions are still
being raised as to what role, if any, large-scale projects should have in
future biological research. Many believe that smaller conventional, hy-
pothesis-driven projects initiated by individual investigators are the most
effective way to advance the field. But given the success of the HOP, there
is also great interest in launching similar projects aimed at producing
databases and other research tools that could facilitate the progress and
potential of smaller, independent projects. Indeed, as noted in Chapter 3,
a number of such projects have already been initiated. Thus, perhaps the
most relevant question now is not whether the federal government should
fund large-scale biology projects, but what the appropriate balance is
between funding for large- and small-scale science in biomedical research
and how funding for large-scale projects should be allocated. Yet little
effort has been made to reach a consensus on the latter question, either in
the broad fields of biology and biomedical research or in the more fo-
cused field of cancer research.
Even if providing funds for large-scale science is now culturally ac-
ceptable in biomedical research, questions remain as to whether NIH is
structured to fund such research. There is no agreed-upon method for
allocating funds to large-scale projects, and there are many obstacles to
overcome in designating funding for such projects, in part because the
procedures and mechanisms used to disburse funds are still based on the
more traditional approach to science. For example, the current, conven-
tional NIH peer review process for vetting most research proposals is not
very favorable to large-scale projects, which may not be hypothesis driven
and often have nontraditional goals. But such a vetting process is essen-
tial for achieving credibility and buy-in by the scientific community.
Knowledgeable members of the community must be able to evaluate ad-
equately and fairly the importance of the large-scale research goals, the
feasibility of the plan, the value of the end products, and the level of
opportunity to move the field forward. Such evaluation is challenging
within the confines of the current system in part because the nature, and
thus the assessment, of the goals and deliverables of large-scale biomedi-
cal projects are quite different than from those for the customary smaller
projects. The organization and planning requirements for large-scale proj-
ects are also more elaborate, and therefore likely to require additional
oversight and interim endpoints to achieve long-term accountability.
Meeting these requirements necessitates additional resources and efforts
on the part of the fonder as well as the investigator.
This chapter provides an overview of the funding sources and mecha-
nisms available for scientific research, both in general and specifically for
biomedical research, with special emphasis on issues that are most rel-
evant to large-scale projects in biomedical research. The discussion begins
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LARGE-SCALE BIOMEDICAL SCIENCE
with a brief review of the history of and process for allocation of federal
funds for scientific research. A detailed description of funding for NIH is
then presented, followed by a discussion of nonfederal funding of large-
scale biomedical research projects. Issues associated with international
collaborations are also examined.
HISTORY OF FEDERAL SUPPORT FOR SCIENTIFIC RESEARCH
The U.S government has often used its monetary resources to pursue
matters of national interest. As the country's foundations were being laid,
scientific research was not a national priority because the nation relied
less on matters of science than it does today. But although federal scien-
tific pursuits had a slow start, strong foundations were formed in the
early nineteenth century that made possible the significant momentum in
government sponsorship of public-based scientific endeavors experienced
in the early part of the twentieth century (see Appendix). While early
government investment in scientific research programs focused on agri-
culture, national security, exploration, and commerce, many private foun-
dations, such as Carnegie, Rockefeller, and Smithsonian, were supporting
a variety of university-based basic research projects. That dichotomy is no
longer true, as the U.S. federal government now supports the majority of
basic scientific research undertaken at the nation's universities.
The earliest federal support for civilian research was authorized in the
1800s, and included large-scale projects such as the U.S. Coast Survey and
the U.S. Geological Survey. However, these initial efforts did not support
the scientific education, training, and basic research that is now the hall-
mark of universities. The first federal support for basic research within
universities was initiated by the creation of the Department of Agriculture
and the Land Grant Colleges. A series of congressional acts, starting with
the Morrill Act of 1862, provided the mechanism by which scientists at
universities could propose research projects and obtain federal funding to
carry them out. These developments played a substantial role in the forma-
tion of a number of biological sciences in the United States, including bac-
teriology, biochemistry, and genetics (Goldberg, 1995~. The creation of NIH
eventually led to an analogous impact on biomedical research when it
began providing federal funds for extramural projects at universities. Simi-
larly, the creation of NCI in 1937 was instrumental in launching a federally
sponsored campaign to understand and eliminate human cancer.
The period of time surrounding World War II had a particularly sig-
nificant impact on the government's investment in university-based sci-
entific research and its willingness to underwrite big-science projects.
During the decade from 1940 to 1950, several key events facilitated the
creation or expansion of science-oriented agencies, such as the Office of
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FUNDING FOR LARGE-SCALE SCIENCE
83
Naval Research, the National Science Foundation (NSF), and NIH, whose
main objectives became the sponsorship of public research. A key initial
impetus for the expansion of federally sponsored scientific research was
Vannevar Bush's 1945 report to the President Science: The Endless Fron-
tier but other leaders also played important roles in developing the cur-
rent mechanisms for federal support of science, particularly with respect
to the more applied fields of research. (For a detailed review, see Appen-
dix.) The resultant changes ensured that federal funding for university-
based scientific research would become the accepted and expected norm
that it is today. These changes also paved the way for federal support of
future big-science projects in such fields as high-energy physics, space
science, and biology.
ALLOCATION OF FEDERAL FUNDS FOR SCIENTIFIC RESEARCH
The process for appropriating federal funds is both complex and
treacherous. The separation of powers between the executive and legisla-
tive branches of the U.S. government makes it difficult to ascribe respon-
sibility for any particular government action. Decisions regarding bud-
gets and funding priorities are made through complex procedures that
are influenced by many factors and federal entities. Determining funding
priorities in a fluctuating social and economic environment is difficult,
and by its very nature controversial. The U.S. government must deter-
mine how much money should be allocated for scientific research as a
whole, and how to divide that money among the various claimants in the
science and technology community (Green, 1995~. Yet broad priority set-
ting is generally resisted by the recipients of federal funding because it
orders the importance of research investments in ways that groups within
the scientific community often do not support (Office of Technology As-
sessment, 1991; McGeary and Merrill, 1999~. The process is inherently
contentious because priority setting creates winners and losers. Although
American science is unparalleled in its scale and scope compared with
that of other nations, the publicly financed sector exists in an economy of
scarcity because scientists and institutions will always have more ideas
for research projects than can be funded (Greenberg, 2001~. In resisting
priority setting, the scientific community aims to maintain high levels of
funding for all fields, instead of risking cuts in any particular one.
There are few established methods for comparing, evaluating, and
ranking research programs regardless of their size, although criteria have
been proposed (Office of Technology Assessment, 1991; see Box 4-1~. Even
~ Vannevar Bush made a strong distinction between basic and applied research, and gen-
erally did not advocate government support of applied research.
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84
LARGE-SCALE BIOMEDICAL SCIENCE
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FUNDING FOR LARGE-SCALE SCIENCE
85
within a discipline, distribution of funds can be contentious, as demon-
strated by the 1995 National Research Council (NRC) study that pro-
duced the report Setting Priorities in Space Research: An Experiment in Meth-
odology, in which no consensus was reached on how to make allocations.
The challenges associated with allocating funds across scientific fields are
even greater. No single organization looks across the federal research
system to determine priorities, and there is currently no formal or explicit
mechanism for evaluating the total research portfolio of the federal gov-
ernment in terms of progress toward national objectives. Mechanisms
that may help determine priorities include the individual agency advi-
sory committees (see Box 4-2) and peer review procedures, the Office of
Science and Technology Policy and other White House advisory com-
mittees, and the NRC system. Even with these mechanisms in place,
however, there is no way to avoid competition among the various
claims on federal science funds or to balance the federal research portfolio
systematically.
As described in more detail below, a variety of unrelated agency
budgets could be in competition for the funds available under the juris-
diction of an individual appropriations committee, and no single sub-
committee is responsible for all science funding agencies, making it very
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86
LARGE-SCALE BIOMEDICAL SCIENCE
difficult to prioritize across disciplines. The NRC (1995) identified this
predicament as a major obstacle in allocating federal funds for science
and technology equitably and appropriately across the various fields and
agencies. The report recommended changes to the process that would
allow presentation and examination of the entire, comprehensive science
and technology budget before it is disaggregated among the various com-
mittees and subcommittees. Only recently have Congress and the Admin-
istration begun to discuss the balance of funding among fields. For the
fiscal year (FY) 2001 budget cycle, the Bush Administration stated for the
first time that balance would be an explicit criterion in developing its
budget request. The budget contained a component called "Federal Sci-
ence and Technology," which was meant to represent investment in new
knowledge and know-how. This was a break from tradition, but still does
not enable priority setting among fields (National Research Council,
2001a). Thus, the NRC report recommended that the executive branch
and Congress institutionalize processes for conducting and acting on an
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FUNDING FOR LARGE-SCALE SCIENCE
87
integrated analysis of the federal budget for research, by field as well as
by agency, national purpose, and other perspectives.
One ongoing change in budget allocations is the effort by the Office of
Management and Budget (OMB) to apply stricter performance measures
in funding federal research agencies based on the Government Perfor-
mance and Results Act (GPRA) of 1993 (Hafner, 2002~. GPRA requires
agencies to manage and budget according to performance standards as a
way of promoting efficiency, accountability, and effectiveness in govern-
ment spending. However, it is still unclear to what extent Congress will
adopt more definitive guidelines, with an emphasis on output, for scien-
tific research. In the past, Congress has been amenable to investing in
undifferentiated science, with knowledge as the outcome. Indeed, GRPA
has caused consternation among the research agencies because few have
had any experience in actually measuring the results of their programs,
and they are unaccustomed to the increased scrutiny. Many researchers
have argued that the results of ongoing basic research cannot be bench-
marked or measured (Lekowski, 1999~.
A 1999 report addressing the issue of assessing research in compli-
ance with GPRA agreed that basic research cannot be measured directly
on an annual basis because its outcomes are unpredictable, and there is
generally a significant time delay between the generation of new knowl-
edge and its practical application (National Research Council, l999~. How-
ever, the report did suggest that measures of quality, relevance, and lead-
ership are sound indicators of eventual usefulness and can be reported
regularly while research is in progress. The report also encouraged bench-
marking of programs in one agency against other federal programs, as
well as international benchmarking, as a measure for fostering quality
and leadership in a given field of research. The report made two addi-
tional major recommendations: that research programs also be graded on
whether they perform an effective education and training function, and
that interagency programs be graded according to how well they are
coordinated.
The FY 2003 federal budget marks the first year that OMB has actually
linked management performance with research budget priorities (Softcheck,
2002~. The process for using the new performance criteria and standards for
applied research and development (R&D) was piloted with the Department
of Energy (DOE) (Hafner, 2002~. Standards for evaluating basic R&D are still
in development, with plans to implement them in FY 2004 across all federal
research agencies. Assessment parameters will be refined in consultation
with a variety of scientific bodies, such as the National Academies' Commit-
tee on Science, Engineering, and Public Policy (COSEPUP).
As part of the new focus on performance, OMB recently released a
red/yellow/green scorecard for each federal agency (with red being the
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88
LARGE-SCALE BIOMEDICAL SCIENCE
lowest score). Almost 80 percent of those reviewed received red scores in
the five rating categories. Only one agency, NSF, received a green score in
one of the five categories for financial management (Softcheck, 2002~.
However, a recent follow-up study by COSEPUP also examined the ways
in which federal agencies that support science and engineering research
are responding to GPRA (National Academies, 2001~. The committee
found that although there is significant variation in responses, NIH, NSF,
the Department of Defense (DOD), DOE, and the National Aeronautics
and Space Administration (NASA) have all taken steps to develop report-
ing procedures to comply with GPRA requirements. The committee also
concluded that some agencies were using GPRA to improve their opera-
tions, but that oversight bodies needed clearer procedures to validate and
verify the agency evaluations, and that communication between over-
sight bodies and the agencies was not adequate.
An overview of the process for appropriating and allocating federal
funds in the United States is shown in Figure 4-1. Briefly, the President, in
conjunction with OMB, submits a detailed budget that includes many
line-item requests about 15 months prior to the start of the budget's fiscal
year. OMB crafts the budgets of research programs to reflect the priorities
of the President, and attempts to compare the projected costs, benefits,
and risks of certain programs to set realistic targets for the budget. The
President's budget is submitted to both the House and Senate budget
committees. These two committees review the budget and make changes
to broad funding areas, called functions, in the areas of health, defense,
civilian R&D, and so on. Congressional authorizing committees2 then can
either authorize or not authorize (as nearly occurred with the space sta-
tion) the use of the funds by specific government agencies and programs.
The revised budget is next given to the House and Senate full appropria-
tions committees and is divided among the 13 corresponding appropria-
tion subcommittees,3 which are mirrored on the House and Senate sides
(see Table 4-1~. Although specific budget items may have been outlined
by the President, the budget committees, the authorizing committees, and
the appropriations committees have the decisive influence over the funds
distributed to R&D agencies.
Each of the 13 appropriations subcommittees from the House and
Senate writes a bill that is submitted back to the respective full committee,
and the bills are taken to the House or Senate floor. Once the bills have
2 Authorizing committees supervise the activities of agencies under their jurisdiction and
pass laws (authorization bills) directing those activities and setting nonbinding ceilings for
their budgets.
3 The appropriations committees set the actual budgets of all agencies in the government.
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FUNDING FOR LARGE-SCALE SCIENCE
House
Budget
Committee
President's
Budget
Request
-
1 ~
Senate
Budget
Committee
Input from House authc
committees 1
*13 House ~ | House Full |
Appropriations ~ Appropriations
Subcommittees ~ U~~
| House | | Senate |
| Floor | | Floor |
1 1
*Subcommittees:
Agriculture
Commerce
Defense
District of Columbia
Energy and Water
Foreign Operations
Homeland Security
Interior
Labor, HHS, and Education
Legislative
Military Construction
Transportation, Treasury,
and Independent Agencies
VA, HUD, and Independent House
Agencies Floor
1
89
1 1
1 3 Congressional
Conference Committees
Input from Senate authorizing
~ committees
Senat'3 Full ~ *13 Senate
Appropriations _ Appropriations
Committee _
Subcommittees
| Senate |
L:
1 ~
Presidential Approval
FIGURE 4-1 Federal budget approval process.
been approved, they go to a congressional conference committee made up
of House and Senate members from the corresponding appropriations
subcommittees. The further revised individual bills, often a compromise
between House and Senate versions, are taken back to the floor and sub-
mitted for a vote. If approved, each bill goes back to the President for
signing. As the President signs the final bills, they become laws. The
"budget" for R&D is contained in the aggregate of appropriations bills
passed for the year.
One limitation of this system that may be especially relevant to the
funding of large-scale research projects is that federal appropriations are
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LARGE-SCALE BIOMEDICAL SCIENCE
TABLE 4-1 Selected Congressional Appropriations Committee
Jurisdictions
Committee Jurisdiction
Appropriations
Committee or
Subcommittee
Name
Senate
House
Agriculture
1. Department of Agriculture
(except Forest Service)
2. Farm Credit Administration
3. Commodity Futures Trading
, - . .
Commission
4. Food and Drug Administration
(DHHS)
4.
7.
1. Adulteration of seeds,
insect pests, and
protection of birds and
animals in forest reserves
2. Agriculture generally
3. Agricultural and
industrial chemistry
Agricultural colleges and
experiment stations
5. Agricultural economics
and research
6. Agricultural education
extension services
Agricultural production
and marketing and
stabilization of prices of
agricultural products and
commodities (not
including distribution
outside the United States)
8. Animal industry and
diseases of animals
9. Crop insurance and soil
conservation
10. Dairy industry
11. Entomology and plant
quarantine
12. Extension of farm credit
and farm security
13. Forestry in general, and
forest reserves other than
those created from the
public domain
14. Human nutrition and
home economics
15. Inspection of livestock
and meat products
16. Plant industry, soils, and
agricultural engineering
17. Rural electrification
18. Commodities exchanges
19. Rural development
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FUNDING FOR LARGE-SCALE SCIENCE
119
2,500 -
2,000 -
cn 1,500-
Cal
o
. _
1,000-
500 -
/,,f'/
A../
/,W,,f
600 - /-
500 -
(A 400- '~
/.f) ...
300-
200- Fox
100 -
o
/
/
/
j,,f'k'
Genomics firms Pharmaceutical and Government and
biotechnology firms non-profit organizations
U.S. government Foreign
governments
non-profits Foreign
non-profits
FIGURE 4-3 Worldwide funding for genomics research, 2000 (millions of SU.S.~.
SOURCE: World Survey of Funding for Genomics and Stanford in Washington
Program, http: / /www.stanford.edu/class/siwl98q/websites/genomics.
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120
LARGE-SCALE BIOMEDICAL SCIENCE
80 -
70 -
60 -
50 -
40 -
A. Number of genomics firms with publicly traded stock
o
#firms
................ ................. .................. .................. ................... ................. ..................
1994 1995 1996 1997 1998 1999 2000
8 10 14 19 25 28 73
Year
100
90
80
oh
~ 70
a)
0 60
. _
5]
.- 50
g 40
30
20
10
o
B. Growth in market value of nenomics firms
1994 1996 1998 2000
Year
FIGURE 4-4 Growth of commercial genomics. A: Number of firms with pub-
licly traded stock. B: Growth in market value of genomics firms.
SOURCE: World Survey of Funding for Genomics, Stanford in Washington Pro-
gram, http: / /www.stanford.edu/class/siwl98q/websites/genomics.
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FUNDING FOR LARGE-SCALE SCIENCE
121
large-scale projects undertaken solely in the private sector, as is discussed
further in Chapter 7.
These very concerns recently led to a unique public-private collabo-
ration to sequence the mouse genome. NHGRI began a mouse sequencing
project in 1999 by providing funding to 10 laboratories using a combina-
tion of sequencing strategies, such as sequencing randomly chosen DNA
or particular DNA regions of biological interest. In the spring of 2000, the
publicly funded group chose to a adopt a hybrid strategy combining
data generated by the whole-genome shotgun approach for most of the
genome with some sequences generated the more traditional way, using
genomic maps. This decision was based on the success of the Drosophila
sequencing project26 and on pilot projects conducted by the mouse se-
quencers (Pennisi,2000b). Shortly thereafter, Celera began sequencing the
genomes of three different strains of laboratory mice on its own. Within 6
months, Celera was offering access to a database of these sequences to
anyone willing and able to pay a user fee. Because of a strong desire at
NIH and in the research community to have a sequence that was freely
available to the public, a new public-private consortium was announced
in the fall of 2000, with the goal of sequencing the genome of a fourth
mouse strain (Marshall, 2000~. Six Institutes at NIH, including NCI, two
companies, and two nonprofit organizations provided $58 million to se-
quence the genome in 6 months using the whole-genome shotgun ap-
proach employed by Celera. The new money was divided among only
three sequencing centers two in the United States and one in the United
Kingdom to complete the work. On May 6, 2002, the Mouse Genome
Sequencing Consortium announced the completion of a draft sequence
for one common laboratory strain of mouse, which is available free of
charge through the Internet (Marshall, 2002b). In fact, the consortium
released data in real time to a public database throughout the project,
with no restrictions. However, the public project was criticized initially
for not making a greater effort to assemble the mouse genome sequences
into a form that would enable the study of gene structure and function
(Marshall, 2001~.
A less competitive approach was subsequently taken in sequencing the
rat genome through a public-private consortium. That project, which is
also using a strategy that combines a map-based sequencing approach and
Celera's whole-genome shotgun approach, is funded jointly by NHGRI
and the National Heart, Lung, and Blood Institute (NHLBI) (Marshall, 2001;
Hafner, 2001~. In this case, however, a substantial fraction ($21 million out
26 In the case of the Drosophila genome, a group of NHGRI-funded researchers supplied
Celera with more than 10,000 cloned fragments of DNA to which the company applied the
shotgun sequencing method. The data were released to the public (Pennisi, 1999~.
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LARGE-SCALE BIOMEDICAL SCIENCE
of a $58 million total) of the most recent batch of NIH funding will go to
Celera to perform the sequencing. Much of the remaining funding will go
to a second sequencing company, Genome Therapeutics Corporation. Be-
cause the funding is derived from federal sources, the participants agreed
to abide by a set of mandatory data-release rules that require grantees to
publicly release raw sequence data on a weekly basis. This approach may
be a model for future endeavors. While avoiding duplication of public and
private efforts, it provides a cost-effective mechanism for producing a pub-
lic good (a freely available sequence database) using industry standards for
staffing, management, and quality control.
Another approach to establishing public-private collaborations is a
cooperative research and development agreement (CRADA). Under the
Federal Technology Transfer Act (FTTA) of 1986, federal agencies have
been mandated to encourage and facilitate collaboration among federal
laboratories, state and local governments, universities, and the private
sector in order to assist in the transfer of federal technology to the market
place. One vehicle for this collaboration is through a CRADA. Examples
of products that have resulted in part through a CRADA include Havrix~
and Taxol~.
A CRADA is a contractual agreements between one or more federal
laboratories and one or more industrial or university partners, under which
the federal laboratories provide personnel, services, facilities, equipment,
or other resources with or without reimbursement and the nonfederal par-
ties provide funds, personnel, services, facilities, equipment, or other re-
sources toward the conduct of a particular R&D program. The purpose of a
CRADA is to make available government facilities, intellectual property,
and expertise for collaborative interactions aimed at developing useful,
marketable products that would benefit the public. The terms of a CRADA
are usually brief and flexible so that each agreement can be negotiated and
tailored to the needs and resources of the participating parties. There must
be an intellectual contribution, which may take the form of materials, in-
strumentation, or expertise, from all parties to the agreement, but the fed-
eral government does not provide funding to nonfederal parties. However,
a major benefit to an industrial collaborator is that it may obtain a first
option for licensing of patents that result from the CRADA.
This type of agreement was recently used to establish a joint project
between DOE and two companiesCelera and Compaq to develop the
next generation of software and computer hardware tools for computa-
tional biology (Washington Fax, lanuary 29, 2001~. Such bioinformatics tools
27 See , and NIH Office of Technology Trans-
fer, .
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FUNDING FOR LARGE-SCALE SCIENCE
123
are necessary to process data from large-scale projects such as the HOP,
structural genomics, and proteomics. DOE will provide $10 million for
work at Sandia National Laboratories. The exact financial contributions
from the two firms have not been disclosed, but are also probably in the
multimillion dollar range. Compaq and Sandia will work together on de-
veloping system hardware and software, while Celera and Sandia will col-
laborate on new visualization technologies for analyzing the massive quan-
tities of experimental data generated by high-throughput instruments.
Nonprofit Funding of Large-Scale Biomedical Research
Nonprofit organizations, while making a small funding contribution
in comparison with private industry and the government, have also
played an important role in genomics research and could potentially con-
tribute to other large-scale biology projects. Nonprofit28 organizations
come in a variety of different forms, including volunteer organizations,
such as the American Cancer Society, that continually raise money to
support research; endowed philanthropies, such as HHMI29; and even
organizations set up by for-profit companies, such as the SNP Consor-
tium. Examples of science-funding philanthropies are listed in Table 4-4.
Profits generated by the bull stock market of the 1990s fueled unprec-
edented growth in philanthropic foundation assets and giving. In 1998,
grant-making nonprofits spent more than $1 billion on science, but the
recent downturn of the U.S. stock market has quelled that growth.
As noted earlier, philanthropies such as the Carnegie and Rockefeller
Foundations played a leading role in funding and shaping basic science in
the United States before World War II and by doing so even gave rise to
new fields, such as molecular biology. Many organizations try to continue
that tradition today by focusing on filling perceived gaps in federal funding
and by defining highly specific targets for research (Cohen, 1999~. In some
ways, nonprofits have an advantage over government funding in their
ability to change course quickly and to pursue nontraditional or high-risk
projects. They often undertake peer review in a form much different from
that of NIH, and some ignore the peer review process altogether. Many also
have less-stringent reporting requirements with respect to progress and
outcomes than does the federal government. While these characteristics
may be considered risky at the very least, they certainly facilitate the fund-
28A nonprofit organization must spend 5 percent of its assets each year or face tax penal-
ties.
29 Because HHMI hires researchers as employees instead of awarding grants, it is in a
different category and has to spend only 3.5 percent of its assets annually.
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LARGE-SCALE BIOMEDICAL SCIENCE
TABLE 4-4 Selected Science-Funding Philanthropies
1999*
1999* Science
Name Founded Assets Expenses Research Focus
Wellcome Trust 1936 $19.2B $640M Biomedical, no cancer
Bill and Melinda 1994 $17.1B $230M Vaccines, reproductive
Gates Foundation medicine, public health
David and Lucite 1964 $13.5B $84.7M Ocean sciences, computer
Packard science, math, natural
Foundation science, engineering,
interdisciplinary
Howard Hughes 1953 $12B $427.7M Biomedical
Medical Research
Institute
Pew Charitable 1948-79 $4.7B $6.95M Biomedical, neuroscience
Trusts
Rockefeller 1913 $3.5B $20M Reproductive health,
Foundation agriculture, vaccines,
epidemiology, malaria
Andrew W. Mellon 1940-69 $3.5B $3.1M Contraception, repro-
Foundation ductive biology, ecology
Kresge Foundation 1924 $2.1B $4.6M Scientific equipment
Carnegie 1911 $1.7B $1M Russian science
Corporation
W. M. Keck 1954 $1.7B $38.M1 Science, engineering,
Foundation medical, astronomy
Donald Reynolds 1954 $1.4B $35.2M Cardiovascular clinical
Foundation over 5 research, geriatrics
years
Doris Duke 1997 $1.4B $13.8M Physician-scientists, no
Charitable Trust animal research
Alfred P. Sloan 1934 $1.2B $5.6M Astronomy, molecular
Foundation evolution, neurobiology,
marine biology, compu-
tational biology
Burroughs 1955 $669M $35M Biomedical
Wellcome Fund
Edna McConnell 1969 $640M $898,000 Trachoma, onchocerciasis
Clark Foundation vaccine
Welch Foundation 1954 $362M $23M Chemistry, primarily in
Texas
Carnegie Institution 1902 $527.1M $31.4M Astronomy, geophysics,
of Washington plant biology, embryology
M. J. Murdock 1975 $525M $4M Natural sciences, primarily
Charitable Trust in Pacific NW
James S. McDonnell 1950 $480M $19M Neuroscience, genetics,
Foundation astronomy, complex
systems
Arnold and Mabel 1977 $450M NA Chemistry, biochemistry,
Beckman medicine
Foundation
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FUNDING FOR LARGE-SCALE SCIENCE
TABLE 4-4 continued
125
Name
Founded
1999*
Assets
1999*
Science
Expenses Research Focus
Whitaker
Foundation
Charles A. Dana
Foundation
Research
Corporation
Camille and Henry
Dreyfus
Foundation
Ellison Medical
Foundation
1975
1950
1912
1946
1998
$390M
$311M
$152.3M
$125M
N/A
$65.7M Biomedical engineering
$10M
$6.4M
$3.4M
100M over Aging
5 years
Neurosciences
Chemistry, physics,
astronomy
Chemistry
*Many of these are estimates.
SOURCE: Cohen (1999~.
ing of unconventional or controversial projects. With the exception of the
largest organizations, such as HHMI, the Wellcome Trust,30 and the Gates
Foundation, however, single-handedly funding a large-scale initiative or
providing long-term support beyond pilot projects may not be feasible. A
joint venture is a possibility, but philanthropies often find it unpalatable to
work together or with the federal government, fearing that they will dilute
their own impact and identity (Cohen, 1999~. Such was not the case, how-
ever, for the Wellcome Trust, which contributed heavily to several recent
large-scale projects, including the internationally funded HGP. In most
cases, investigators look to federal funding sources to continue a project
that was launched successfully in a pilot or proof-of-principle stage using
philanthropic sources. Such grant applications may then be viewed as less
risky, but investigators may still encounter difficulties in obtaining NIH
funds if the projects are very costly and the applications have not been
solicited through a PA or RFA.
ISSUES ASSOCIATED WITH
INTERNATIONAL COLLABORATIONS
The drive to achieve international standing and recognition in a par-
ticular field can promote competition and impede scientific cooperation.
Nonetheless, the international collaborative approach for scientific re-
30The Wellcome Trust outspends the combined budgets of the United Kingdom's main
government funders of biological research. Wellcome targets specific diseases, but avoids
those that are relatively well funded (including cancer).
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26
LARGE-SCALE BIOMEDICAL SCIENCE
search has become commonplace for large-scale projects in such fields as
high-energy physics, which require very large and expensive facilities.
These collaborations may still be contentious because of competition
among research groups or nations, but the end products of the research
generally do not have direct commercial value. In the case of molecular
biology and biomedical research, however, international competition is
exacerbated by the fact that patents on new discoveries can be extremely
lucrative. The lure of potential profits and market shares adds an addi-
tional level of complexity to negotiations for collaborative projects. These
challenges are intensified by basic difficulties in organizing and manag-
ing projects undertaken on a global scale. Establishing uniform priorities
and goals for the overall project and for each participant is highly prob-
lematic and is complicated by difficulties in communication across cul-
tures, languages, and political environments.
Nonetheless, the scientific and engineering communities in the United
States benefit from ideas and technologies developed around the world,
and participating in international scientific and technical collaborations
and exchanges may provide unique opportunities for addressing major
problems or questions. Indeed, a 1995 NRC report recommends that the
United States should pursue international cooperation to share costs, to
tap into the world's best science and technology, and to meet national
goals (National Research Council, 1995~. The World Health Organization
has led the way in creating structures to enable international cooperation
for health R&D as a tool for economic and social development. According
to the Global Forum for Health Research, the international activities bud-
get for NIH increased steadily from 1991 to more than $200 million in
1998. There are international programs within the various NIH Institutes,
but a breakdown of these activities was not available to the committee,
and it is unclear how much of that funding went toward projects that
would qualify as large-scale research as defined in this report.
SUMMARY
It is difficult, if not impossible, to quantify the total amount or pro-
portion of biomedical research funding that is spent on large-scale re-
search projects, primarily because of variation in definitions and report-
ing practices. As examples described here and in Chapter 3 clearly
indicate, however, large-scale science projects are certainly being under-
taken with funding from federal as well as nonfederal sources (the latter
including industry and philanthropies and other nonprofits). The objec-
tives and cultures of these different sources may vary considerably, yet
partnerships among diverse funding sources could offer unique opportu-
nities for undertaking large-scale endeavors if the challenges entailed can
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FUNDING FOR LARGE-SCALE SCIENCE
127
be overcome. In particular, public-private collaborations provide a way
to share the costs and risks, as well as the benefits, of such efforts. Interna-
tional collaborations may present the greatest challenge of all, but also
offer potentially unique opportunities. Some of the challenges involved,
such as organization and management of projects and concerns about
intellectual property, are covered in more detail in Chapters 5 and 7.
Federal funding for large-scale science projects continues to be con-
troversial. Proposals for undertaking such projects often generate criti-
cism and debate, both across and within fields. Although this debate on
the relative value of such projects is crucial to their success, resolving
these arguments is complicated by the fact that there is no consistent,
established way to balance the allocation of funds across the various dis-
ciplines, or across big versus small projects. Over the course of the last
century, however, scientists have come to expect federal funding for re-
search, and those pursuing large-scale projects are no exception. Further-
more, former acting NIH director Ruth Kirschstein has noted that while
the "bedrock" of the agency's research will continue to be individual
investigator-initiated inquiry, the nature of scientific investigation is
changing such that current research questions are more likely to require
the efforts of multidisciplinary teams working with expensive instruments
in specialized facilities (Haley, 2001~. Similarly, current NIH director Elias
Zerhouni has remarked that the model of the traditional NIH grant "will
evolve into different shapes because multidisciplinary science requires
collaborations." But he has also noted that "at the end of the day you also
need [principal investigators] who themselves have an inherent under-
standing of [multiple] fields so they can ask the right questions" (Kaiser,
2002:1~. According to Lake and Hood (2001), one of the outstanding chal-
lenges for contemporary biology is the integration of hypothesis-driven
science with a new discovery approach to science that is, defining all the
elements of a biological system as a key information resource, and study-
ing the entire system rather than asking questions about highly specific
components.
The examples described in Chapter 3 indicate that there is flexibility
within the NIH procedures that allows for some large-scale research en-
deavors. Within NIH, however, recent funding patterns suggest that per-
haps only the Institutes with the largest budgets (e.g., NCI, NIGMS, and
NHLBI) can independently handle the launch and support of a large-
scale research project. Others may not have enough funds or flexibility in
their budgets. For the smaller Institutes, undertaking such projects may
require action and support on the part of the NIH director, or at least
collaborative efforts among smaller and larger Institutes. NHGRI may be
an exception to this generalization, since it was created specifically to
undertake the large-scale HOP.
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LARGE-SCALE BIOMEDICAL SCIENCE
Some currently available funding mechanisms at NIH are amenable
to large-scale projects and have already been used for such projects. Most
of these efforts depended upon the solicitation of applications through
PAs or RFAs that were issued for a specific topic of research. Unsolicited
proposals for large-scale projects face what may be insurmountable ob-
stacles in the form of grant size restrictions, traditional peer review expec-
tations, and yearly fluctuations in the congressional allocations to NIH
Institutes and Centers. Furthermore, using the RO1 funding mechanism
(the most common for unsolicited grants) for large-scale projects could
lead to greater competition in the short term between scientists conduct-
ing large-scale and small-scale biomedical research because, absent a net
increase in funding, each multimillion dollar grant would proportionally
reduce the number of traditionally sized ROls awarded. As NIH ap-
proaches the completion of the budget doubling of recent years, there is
already concern that the percentage of new applications funded will drop
because of commitments made during the growth years (Korn et al., 2002;
Jenkins, 2003b). At any given time, approximately 70 percent of the Insti-
tutes' funds are allocated for noncompeting renewals of awards made in
previous years.
How are decisions to be made regarding the types of projects to be
undertaken and the most pressing needs of the field? If NIH wishes to
facilitate the process of funding large-scale projects that generate data-
bases and other research tools, it may be helpful to change, or in some
cases standardize, the decision-making procedures within the Institutes
and Centers. For example, the traditional peer review process favor proj-
ects that are hypothesis driven. To date, in fact, none of the large projects
funded by NCI have been reviewed through the CSR.3~ According to
Craig Venter, the traditional dogmatic approach to peer review denies
that biology is descriptive and impedes the progress of discovery (Lewis,
2001~. While no one would deny the value of hypothesis-driven research,
balancing the research portfolio with multiple approaches could enhance
the progress of science overall. Changes in the peer review process could
provide a first step in achieving that balance. A critical assessment and
standardization of the procedures for issuing PAs and RFAs would also
be useful for facilitating the funding of large-scale projects, since those
mechanisms are currently the primary means of funding such projects.
There is a need for a mechanism through which input from innovators in
research can be routinely collected and incorporated into institutional
decision-making processes as well.
A possible alternative to issuing PAs or RFAs for large-scale projects
3~ Personal communication, Richard Klausner, former NCI director.
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FUNDING FOR LARGE-SCALE SCIENCE
129
aimed at particular topics would be to develop a special category, with
specific review criteria and oversight requirements, for large-scale projects
in general. Doing so would greatly speed the process for researchers with
novel ideas while still maintaining a rigorous vetting process.
A third possibility would be to make greater use of Defense Ad-
vanced Research Projects Agency (DARPA)-type strategies for funding
large-scale, technology-driven projects, as described in Chapter 3.NCI's
Cancer Genome Anatomy Project and Unconventional Innovations Pro-
gram could prove instructive in this regard. In any case, standardizing
the methods for institutional oversight of such projects with regard to
management structure and progress assessment over time would also
improve the process, as is discussed in greater detail in Chapter 5.
A fourth potential mechanism to speed and facilitate the launch of
large-scale projects would be to set up a loan program through NIH for
the purpose of developing scientific infrastructure, such as new buildings
or the purchase of expensive new technologies for research. Such a pro-
gram would allow extramural institutions to react quickly to changing
needs and opportunities in the field by securing funds from NIH early on,
and then repaying the loan through traditional fundraising activities.
As noted in Chapter 3, several novel NIH programs have been launched
in recent years in order to undertake large-scale research projects. These
efforts depended on the institutional leadership at the time. Since many of
those individuals have now left NIH, the future of such programs and the
potential for launching other new programs is unclear. One way to reduce
this variability is through long-term, Institute-wide strategic planning by
the NIH director, as Elias Zerhouni is currently striving to do (Metheny,
2002; Kaiser, 2002~. This planning process incorporates input from Institute
and Center directors, as well as from leaders among intramural and extra-
mural scientists in both academia and industry. Such an approach provides
the best opportunity to ensure that NIHis responding effectively to chang-
ing needs in the field by funding innovative and useful projects in a timely
fashion.
Representative terms from entire chapter:
grant applications
