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New Opportunities, New Challenges:
The Changing Nature of Biomedical Science
The frontier of biomedical science has rarely been as exciting and as full of
spectacular opportunities as it is today. From basic science through clinical research
to health services research, the opportunities made available through the impressive
advances of recent decades in the biomedical as well as the physical, computational,
and behavioral and social sciences have brought us to a frontier of unprecedented
opportunity. Those developments have also begun to transform the conduct of both
large- and small-scale biological and biomedical research in rather dramatic ways.
Although traditionally structured laboratory and clinical investigations are still its
most essential components, several technical and scientific breakthroughs have
altered how research is conducted. For example, high-throughput technologies are
enabling rapid accumulation of unprecedented amounts of biological and health-
related information. Nucleic acid and protein databases are revolutionizing some of
the ways in which the structure and function of biomolecules and cells are studied.
Databases and biological repositories have become ever more essential resources for
scientists, and biocomputing and bioinformatics are indispensable tools in new
types of investigations that are based on these vast amounts of data. Moreover, in
some fields the scientific enterprise is characterized by the increased importance of
large-scale and complex projects. All those additions to the traditional research
paradigm are placing new demands on approaches to research funding and manage-
ment because some parts of the scientific frontier require the creation of larger-scale
products, significant new infrastructure investments, or the mobilization of inter-
lAt the same time that the present committee was conducting its work, the National Cancer Policy
Board of the National Academies was preparing a report, Large-Scale Biomedical Science: Exploring
51
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Enhancing the Vitality of the National Institutes of Health
disciplinary research teams, sometimes involving large numbers of investigators at
many institutions. More strategic planning and coordination of investigators on the
part of the National Institutes of Health (NIH) as a whole are required if it is to
make the most effective use of its resources.
Increasingly, investigators will need to integrate knowledge gained from high-
throughput molecular research and high-powered imaging studies with knowledge
from population-based epidemiological studies and clinical trials to learn what
works and what does not work, what is safe and what is not safe. It seems clear, for
example, that there will be a greater need for research on interactions among genetic
variation, cell dynamics and behavioral, metabolic, nutritional, environmental, and
pharmaceutical variables. And greater prominence must be given to research in the
behavioral and social sciences, to health services research that is related to the more
effective treatment of diseases and improvement of quality of life, and to the
continuing evaluation of preventive interventions. Growing awareness of the asso-
ciation between socioeconomic status and health and health disparities provides
new challenges as well as opportunities for research. The opportunities and needs
raise the issues of setting research priorities and defining appropriate boundaries for
NIH research, but they also raise questions about whether NIH's current institu-
tional structure facilitates or limits the adaptability of its programs.
Finally, international and economic factors are changing the nature of science.
First, a greater sense of urgency permeates some fields of research, given the threat
of bioterrorism, persistent and emerging infectious diseases, and the complexity of
the international environment for science with its pressing health needs. Second,
private industry and foreign governments have substantially increased their funding
of biomedical research and development (R&D) (National Science Foundation,
20021. Third, the increasingly global nature of science raises new challenges to the
NIH structure with respect to international collaboration, capacity-building, and
. .
tralnlng.
An overview of how biomedical science has developed in the last decade and
where it might be leading is helpful in determining whether NIH's current organiza-
tional structure is best suited to address emerging scientific opportunities and partner
effectively with other federal agencies and the private sector. This chapter presents
a snapshot of certain aspects of the current research environment with some specula-
. . . .
tlon as to ~ tow It IS C" langlng.
CLINICAL RESEARCH NEEDS
Clinical research informs and stimulates fundamental science; conversely, basic
laboratory and epidemiological research inform and stimulate clinical research. As
Strategies for Future Research (Institute of Medicine, 2003a). Some of the material in this chapter was
gathered by the National Cancer Policy Board during its deliberations.
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New Opportunities, New Challenges: The Changing Nature of Biomedical Science
defined broadly by NIH in a report of a task force chaired by David G. Nathan
(National Institutes of Health, 1997a),2 clinical research includes
· Research conducted with human subjects or on material of human origin
(tissues, specimens, and cognitive phenomena) in which an investigator inter-
acts directly with human subjects. This research includes mechanisms of
human disease, therapeutic interventions, clinical trials, and development of
new technologies.
· Epidemiologic and behavioral studies.
· Outcomes and health services research.
Others might define clinical research more broadly to include some aspects of drug
screening, and development of diagnostics and gene therapy all laboratory-based
activities but nonetheless patient-focused forms of research.
The research community recognizes a social compact with the public to help
improve health by advancing knowledge along all relevant parts of the scientific
frontier. At the same time, the translation of discoveries in fundamental and applied
science into useful clinical and public health interventions and uses of such interven-
tions to reduce disability, morbidity, and health disparities are the ways the public
measures the success of its investments in biological and behavioral research.
Yet for nearly 25 years there have been persistent concerns about the health and
future of our national efforts in clinical research (Wyngaarden, 19791. Reviews of
its status and recommendations for improvement have been conducted previously
and in a far more thorough manner than could this Committee. Most recently, the
NIH director's Pane! on Clinical Research was commissioned in the spring of 1995
by Harold Varmus, the director of NIH, because the "perception of crisis in clinical
research that had simmered for decades had intensified by a funding shortage
induced by managed care and new restrictions on the Federal budget" (National
Institutes of Health, 1997a). More recently, members of the Clinical Research
Roundtable of IOM published a review of the challenges facing the national clinical
research enterprise (Sung et al., 20031.
NIH sponsors a large set of programs in clinical research and training through
its institutes' and centers' extramural and intramural research programs; the agency
is the largest sponsor of clinical research in the world. NIH spent $7.6 billion on
clinical research in FY 2002, estimates it will spend $8.4 billion of its $27 billion
budget in FY 2003 and projects spending $8.7 billion in FY 2004. A large portion
of the clinical research supported by NIH occurs extramurally in hospitals and
clinics affiliated with medical schools, independent research institutes, and health
departments throughout the United States. A smaller but vitally important portion
2NTH's definition excludes in vitro studies that use human tissues but do not deal directly with
patients. That is, clinical, or patient-oriented, research is research in which it is necessary to know the
identity of the patient from whom the cells or tissues under study are derived.
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Enhancing the Vitality of the National Institutes of Health
of NIH's clinical research portfolio is conducted through the intramural research
programs of the institutes and at its Clinical Center.
The clinical research programs sponsored by NIH differ from most of those
supported by the private sector in that NIH-sponsored clinical research focuses
most heavily on increased understanding of disease prevalence, disease mechanisms,
and long-term outcomes of therapies. Appropriately, most clinical research spon-
sored by the private sector (such as pharmaceutical, biotechnology, and medical
device companies) focuses on testing the efficacy and safety of new drugs and
devices before their approval by the Food and Drug Administration (FDA). Both
types of clinical research are essential to advance human health, and they depend on
one another.
Clinical research is often conducted on a large-scale at multiple institutions
across the country or even around the world. For example, in 1991, NIH launched
the Women's Health Initiative (WHI) with the broad goal of investigating strategies
for the prevention and control of some of the most common causes of morbidity and
mortality among postmenopausal women, including cancers, cardiovascular disease,
and osteoporotic fractures.3 Congress provided special funding, totaling $213 mil-
lion over 4 years, through the Office of the Director. The WHI has functioned as a
trans-NIH consortium and is one of the largest studies of its kind ever undertaken in
the United States, involving more than 40 centers nationwide and 162,000 women.
The first results from the WHI have been reported, for example, the rates of cancers,
heart disease, and osteoporosis in women taking hormone replacement therapy
(Pradhan et al., 20021. The findings have had a large and prompt impact on medical
practice and on the ways physicians prescribe such therapy for their patients.
Another example is the Collaborative Programs of Excellence in Autism,
launched in 1997.4 At the request of Congress, NIH formed the Autism Coordinat-
ing Committee (ACC) to enhance the quality, pace, and coordination of NIH efforts
to find a cure for autism, and the ACC has been instrumental in the research into,
understanding of, and advances in autism. Five institutes (the National Institute of
Child Health and Human Development, National Institute of Environmental Health
Sciences, National Institute of Mental Health (NIMH), National Institute of Neuro-
logical Disorders and Stroke, and National Institute on Deafness and Communica-
tion Disorders) are members of the ACC. In addition, representatives of the National
Institute of Allergy and Infectious Diseases and the National Center for Comple-
mentary and Alternative Medicine participate in ACC meetings, as do representa-
tives of the Centers for Disease Control and Prevention (CDC), FDA, and the US
Department of Education.
Because many major diseases have common risk factors, broad-based,
potentially large-scale, and trans-NIH projects are sometimes required to share
information and show linkages more precisely. For example, smoking, high-fat and
3See http://www.nhlbi.nih.gov/health/public/heart/other/whi/wmn_hlt.htm.
4See http://www.nichd.nih.gov/autism/nihacc.cim.
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New Opportunities, New Challenges: The Changing Nature of Biomedical Science
low-fiber diets, physical inactivity, and exposures to exogenous and endogenous
toxins are all likely to contribute to the development and progression of numerous
diseases that are within the purview of multiple institutes. But despite a growing list
of successful trans-NIH collaborations, NIH officials told the Committee that NIH
has for decades had a notably difficult time in funding clinical, let alone population-
based, studies that involve major diseases that belong to multiple institutes, such as
cancers, heart disease, pregnancy outcomes, and duodenal ulcers related to smoking.
In addition to studies of causation, trials seeking reduction of lung cancer and heart
disease with other agents (such as beta-carotene in the 1980s and l990s and other
antioxidants now) have been difficult to fund across institutes.5 Generally, one
institute has had to be willing to fund the whole study, but this often results in less
than fully efficient investigations of diseases that fall outside the institute's mandate
(such as heart disease in trials supported by NCI or cancer in trials supported by
NHLBI) or in passing up the opportunity to broaden the benefit of a trial at a
modest cost.
Evidence-Based Medicine and Health Services Research
An increasingly important extension of the value of clinical trials is in research
to enhance evidence-based medicine, which aims to take the best available informa-
tion from clinical trials and observational studies and apply it in clinical practice.
For example, despite a rich evidence base for management of cardiovascular dis-
orders, study after study has demonstrated disconcertingly low rates of compliance
with widely disseminated evidence-based treatment guidelines for managing such
common cardiovascular conditions as coronary heart disease, congestive heart fail-
ure, and high blood pressure. The difficulty in translating the results of clinical trials
into clinical practice suggests the presence of multiple barriers to implementation.
Although there is substantial overlap, the barriers are in four general domains
related to science, the health profession, the patient, and the health system. Even
very well-designed randomized clinical trials may fail to examine all the relevant
risk factors and patient and cultural variables.
Barriers related to the health profession include lack of knowledge of the best
current evidence, time constraints, and the overriding desire to avoid iatrogenic
complications. Patient-related barriers include managing multiple prescriptions for
multiple chronic conditions, time and financial constraints, and difficulties in
engaging in health-modifying behaviors such as smoking cessation, exercise, and
dietary modification. Barriers related to the health system include lack of sufficient
insurance, lack of integrated approaches to the care of chronic illness, and the high
cost of health care. The complexity of issues involved mandates a comprehensive
and collaborative approach involving physicians and other health care professionals,
5These and related issues concerning trans-NIH initiatives were raised repeatedly during Committee
interviews with NIH senior management.
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Enhancing the Vitality of the National Institutes of Health
patients and their families or other support systems, and the health care system itself
if the myriad barriers to implementing evidence-based care are to be overcome
(Rich, 20021. Indeed, much of the complexity is not fully understood and requires
further research.
Health services research is within the mission of NIH. Some institutes, such as
the National Institute on Aging, National Cancer Institute (NCI), NIMH, the
National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and
Alcoholism, have substantial portfolios, even whole divisions, that focus specifically
on health services research. Another Department of Health and Human Services
agency, the Agency for Healthcare Research and Quality (AHRQY, takes the lead in
some aspects of health services research and recommends strategies for monitoring
and improving quality of care, but it cannot fully address the demand for the full
array of such research. Furthermore, health services research is closely related at the
disease or health-dimension level to treatment research, as well as to much more
basic behavioral science (such as social psychology theory or organizational theory).
Thus, there are many reasons to support health services research in multiple insti-
tutes. In fact, NIH estimates that it spends about $800 million per year on health
services research compared with $300 million per year for the entire AHRQ budget
(Sung et al., 2003; Helms, 20021. Clearly, more coordination across NIH and
between NIH and other agencies, such as AHRQ, the Department of Veterans
Affairs, and the Centers for Medicare and Medicaid Services, would advance this
developing field.
INCREASING URGENCY IN SOME FIELDS OF RESEARCH
In the last few years, the United States has become increasingly and uncomfort-
ably aware of its vulnerability to bioterrorist threats. Concerns about vaccine
supplies, efficacy and safety of older vaccines, and the documentation for handling
and storing materials that pose biological, chemical, and radioactive hazards have
reopened discussions about public health research in general and about openness
and secrecy in scientific communication (Omenn, 20031. The role of NIH in rapid
response to research needs arising from bioterrorism especially in areas where
there is little incentive for private investment has been the subject of recent
analyses; some have questioned the agency's ability to be flexible and responsive
(National Research Council, 20021.
New infectious diseases (West Nile virus and Severe Acute Respiratory Syn-
drome ESARS]) and reemerging infectious diseases (malaria in Virginia and tuber-
culosis worIdwide), increasing antibiotic-resistance in pathogenic bacteria, and the
threat of bioterrorism have caused renewed interest in infectious disease agents,
epidemiology, and surveillance of potentially exposed populations (Omenn, 20031.
Those research subjects require reaching across public health, agriculture, ecology,
and other fields in ways that might not be typical or easy with NIH's current
structural configuration. Beyond NIH, greater collaboration with the intelligence
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New Opportunities, New Challenges: The Changing Nature of Biomedical Science
community, emergency workers, law enforcement, and the pharmaceutical, com-
munications, and information industries will be required (National Research
Council, 20021. The sudden spread of SARS in China and several other countries
also highlights the need for rapid detection, identification, and response. Working
with CDC and international health organizations, NIH can play a pivotal role in
improving scientific knowledge of the coronavirus that will be important in develop-
. .
ng vaccines anc treatments.
ADDRESSING HEALTH DISPARITIES
Increasing attention is being directed to the biological, genetic, and socio-
economic basis of health and whether all Americans are benefiting from health-
related research advances. The life expectancy of members of many minority groups
in the United States is still much shorter than that of white Americans. Recent years
have seen gains in longevity and lessening of the impact of chronic diseases, but
minority populations have not benefited as much as the white population. The
disparities have many causes (Institute of Medicine, 20021.
The influence of racial bias is not limited to access to health care. Racial
prejudice and discrimination can be sources of acute and chronic stress that have
been linked to such conditions as cardiovascular disease and alcohol abuse (Cooper,
2001; Yen et al., 19991. Discrimination can restrict people's educational, employ-
ment, economic, residential, and partner choices, affecting health through pathways
linked with what psychosocial scientists refer to as human capital. Environmental
influences of industry, toxic waste disposal sites, and other geographic characteris-
tics linked with poverty and minority status can result in serious disadvantages to
minority groups' health (Institute of Medicine, 19991.
The increasingly recognized links among genetics, health, socioeconomic status,
and macroeconomics emphasize the importance of research to examine and decrease
the magnitude of health disparities. In 2000, the National Center on Minority
Health and Health Disparities was established by the passage of the Minority Health
and Health Disparities Research and Education Act of 2000 (PL 106-525), reflect-
ing a concern among policymakers that NIH was not paying sufficient attention to
this issue.6
THE GROWTH OF LARGE-SCALE AND DISCOVERY-DRIVEN SCIENCE
Most federally-supported biomedical research has been conducted through small
independent projects initiated by individual investigators working in relatively small
6In particular, see July 26, 2000, hearing of the Senate Health, Education, Labor and Pensions
Committee's Subcommittee on Public Health on health disparities of minorities, women, and under-
served populations, and NIH's role in addressing them. Witnesses were also asked to comment on the
proposed Health Care Fairness Act, S. 1880 and H.R. 3250.
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Enhancing the Vitality of the National Institutes of Health
research groups. Such research is typically hypothesis-driven, that is, aiming to
address specific biological questions. That approach to research remains essential,
but developments on the scientific frontier have encouraged scientists to consider
also the increased importance of carefully selected broader and larger-scale projects,
for example, to develop extensive pools of data and other research tools that can
then facilitate the more conventional approach to research. This approach, often
called "discovery" science, is based on the assumption that the analysis of a com-
plete data set collected across the breadth of a biological system (for example, an
entire genome) is likely to yield clues and patterns on which to base hypotheses
about the relationships of important biomolecules operating in the system.
The Human Genome Project: An Important Additional Paradigm in Basic Biology
The biggest and most visible large-scale, discovery-driven research project in
biology is the Human Genome Project (HGP), an international effort to map and
sequence the entire human genome. When it was first proposed, many scientists
opposed the project on the basis of its cost and size and the fact that it was managed
science; they assumed it would take funding away from other, more important
projects. It was also viewed by many as a forced transition away from hypothesis-
driven science to a directed, hierarchical mode of "Big Science" (Cook-Deegan,
19941. Many argued that it was technically infeasible. Proponents of the HOP won
out, especially as the Department of Energy began on its own, and NIH secured
designated funds that allowed it to make its first awards in 1988. A draft sequence
of the entire human genome was completed in 2000, and the full sequence in April
2003 (Pennisi, 2003~. The data from the HGP constitute a vast and rich resource
for biomedical research for many years to come.
The next challenge lies in identifying the functions of the genes and the complex
regulatory dynamics of the cell to understand the mechanisms that lead to the
creation of proteins and their functions (Burley, 2000~. Sequences from the genome
project are being analyzed with improved understanding of cell dynamics to help to
identify protein families. Structural genomics uses computational analyses with
structural determinations of the protein products to advance the study of protein
function. Proteomics permits simultaneous examination of changes in expression
levels and modifications of structure and function in health and disease. The
resulting data must be assessed against a background of population-based studies
entailing the generation, storage, and analysis of enormous quantities of epidemio-
logic, genotypic, and phenotypic data. The process of hunting for disease-related
mechanisms that seem to be directly related to genetic material once an expensive
and arduous undertaking conducted by individual laboratories and investigators-
has become rapid and highly automated; it is limited primarily by the incomplete-
ness of our understanding of cell regulation, the unexpected complexity of many
diseases, and the lack of a rich information base regarding many nongenetic risk
factors in the relevant human populations. Despite the spectacular discoveries of
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New Opportunities, New Challenges: The Changing Nature of Biomedical Science
recent decades there remain large gaps in our understanding of how genetic infor-
mation is transformed into biological meaning. The challenge of this task has led
some to warn of the prospect of a bottleneck between genome-based scientific
advances and translation to clinical improvement (Nathan and Varmus, 20001.
The Mounting Importance of Biocomputing, Bioinformatics,
and Clinical Informatics
As a result of the HOP, associated projects, and imaging research, biologists
and clinical investigators are faced with more opportunity and data and a greater
need to organize the data in a meaningful, coherent, and public manner than ever
before. For example, automation has allowed fewer people to accomplish more
sequencing in shorter periods. The immense amount of information generated by
this class of projects is stimulating new collaborations among clinical medicine,
biology, chemistry, physics, and the fields of bioinformatics, computer science, and
mathematics. Large amounts of computational expertise are a necessity. To under-
stand the similarities and differences among organisms of the same and different
species, sophisticated comparisons must be conducted, and many of them cannot be
conducted effectively solely with traditional tools. Using appropriately designed
databases and powerful computers, bioinformatics is providing a view of the rela-
tionships among organisms that are sometimes separated in evolution by many
millions of years. Computers can display patterns and periodicities that would
rarely be found if searched for with traditional approaches and techniques (Hood,
20031. Thus, in many ways, biology is becoming an information science (Botstein,
20001. The creation and development of such databases and database technologies
(methods for storing, retrieving, sharing, and analyzing biomedical data) are becom-
ing more important in all biomedical fields. As more information from clinical trials
becomes available, the need for standardization and interoperability of clinical
databases will increase. Coordinating knowledge gained from a large and growing
set of clinical trials with new insights from genetic research could appreciably
advance knowledge about the treatment of disease. A system of interoperable data-
bases would allow clinical researchers to track more efficiently any finding back to
its basic scientific roots; conversely, a research scientist might track forward to
postulate from hypotheses through potential applications on the basis of innovative
uses of existing data (NIH, 1999b). Similarly, linkages between genetic databases or
clinical databases and environmental exposure databases will be essential for under-
standing and modifying gene-environment interactions (National Research Council,
20021.
Other Large-Scale and Trans-NIH Science Initiatives
As a result of the success of the HOP, there is considerable interest in developing
other larger scale projects with broad potential benefits. One well established
59
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Enhancing the Vitality of the National Institutes of Health
example in cancer research is the Cancer Genome Anatomy Project (CGAP) of NCI.
The goal of the CGAP is to develop gene-expression profiles of normal, pre-
cancerous, and cancer cells, which could be used by many investigators to search for
new methods of cancer detection, diagnosis, and treatment. In addition to the
CGAP, the number of large-scale initiatives in genomics involving multiple institutes
has grown. The successful initiation of many of them depended on the institutional
leadership at the time combined with growing budgets, according to Francis Collins,
director of the National Human Genome Research Institute. In his presentation to
the Committee, Collins described other plans for large-scale, trans-NIH projects
that include building libraries of small molecules and tools for screening; longitudi-
nal cohort studies to connect genotype, phenotype, and environmental risks; highly
annotated databases of gene and protein structures and function; development of a
computational mode! of the cell; and large-scale efforts in imaging and other
population-based studies.
Recently, 18 institutes co-funded a bioengineering nanotechnology initiative,
12 co-funded initiatives in structural biology of membrane proteins, and 16 insti-
tutes and centers supported an effort in methods and measurement in the behavioral
and social sciences.
The examples cited above indicate that there is some flexibility in NIH's admin-
istrative and priority-setting procedures to respond to new developments and allow
for the initiation of large-scale research endeavors. However, recent funding patterns
indicate that the institutes with the largest budgets, such as NCI, the National
Institute of General Medical Sciences (NIGMS), and the National Heart, Lung, and
Blood Institute, are more likely to initiate and support large-scale research projects.
Smaller institutes do not have enough funds or flexibility in their budgets to begin
such projects although they often leverage their resources through a larger institute's
investment. It is not clear to what extent these projects are true collaborations in the
sense that the participating institutes identify a challenge or an opportunity, work
together toward developing a project, co-fund investigators and/or institutions, and
manage and oversee the ongoing work. Thus, "multi-institute funding" should be
distinguished from "trans-NIH initiatives," with the latter referring to activities that
involve more than one institute in planning and implementation from start to finish.
Unanticipated fluctuations in annual congressional allocations and the appro-
priations process (which provides separate budgets for each IC) make strategic
planning for new long-range, large-scale, or trans-NIH projects more difficult. In
years in which the budget remains flat, new projects, especially large-scale new
projects, are especially difficult to initiate. Moreover, because large-scale science is
costly, it has the potential to reduce the funding available for the critical, but
smaller, investigator-initiated projects. It is a bit more complicated for small research
groups to initiate larger-scale projects because of the requirement that applicants for
R01 grants >$500,000 per year in direct costs obtain institute or center agreement
at least six weeks prior to the anticipated submissions deadline before they can
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New Opportunities, New Challenges: The Changing Nature of Biomedical Science
apply.7 Thus, these requests require special budgetary and program planning in
addition to scientific merit and budget justification. Applications submitted in
response to NIH Program Announcements or Requests for Applications (RFAs),
which include their own specific budgetary limits, are not subject to the same limits.
In addition to cost considerations, NIH management told the committee that
true collaborations across institutes and centers can be made more difficult for a
number of administrative reasons, such as: lack of clear support from leadership
about the importance of such work; insufficient rewards for work conducted beyond
the purview of an institute's specific mission; placement of "available" staff on such
projects rather than individuals with the most appropriate skills or background; and
insufficient financial resources and office space dedicated to get the work done.
NEW RESOURCE REQUIREMENTS:
PATIENT DATABASES AND SPECIMEN BANKS
Other trends in biomedical science are influencing the importance of some
kinds of data. For example, collections of archived patient information including
clinical data, family history, and risk factors and such human biological materials
as tissue, blood, urine, and DNA samples are essential for studying the biology,
etiology, and epidemiology of diseases, especially if the diseases are linked. Such
data can also be used to examine the long-term effects of medical interventions.
In 1999, the National Bioethics Advisory Commission estimated that more than
282 million specimens of human biological materials were stored in the United
States and that they were accumulating at a rate of more than 20 million cases per
year (NBAC, 19991. Maintenance, cataloging, and storage of these specimen banks
and related data in a format that is widely accessible to the research community
would require a long-term investment. Ensuring the quality and usefulness of
specimen banks after the project-based funding ends is an unresolved issue now
managed on a case-by-case basis.
The capacity to link medical records of individuals with family histories and
disease phenotypes is an important point of departure for genetic analysis. Investi-
gators at centers that have developed the capability and permission to search their
patient database for informative patients and families will be well positioned to
compete for the increasing proportion of federal and industrial research resources
that will be devoted to genetic research, especially if non-genetic variables can be
measured and linked (Silverstein, 2001; Omenn, 20001. Electronic medical records
could make the work of specialists in one discipline widely accessible to specialists
in many disciplines. If appropriate protocols can be developed, these records could
7NIH Notice for Acceptance for review of unsolicited applications that request more than $500,000
in direct costs, Effective June 1, 1998; see http://grants.nih.gov/grants/guide/notice-files/not98-030.html.
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Enhancing the Vitality of the National Institutes of Health
be used to integrate the work of clinicians with that of researchers and administra-
tors, and could permit better and more rapid assessments of the health of the public
in general and of individual patients in particular (Silverstein, 20011. It is important
to note, however, that such electronic medical records would be available only in
carefully reviewed and controlled circumstances under the federal Health Insurance
Portability and Accountability Act and provisions of the Common Rule (45 CFR
461.
Electronically accessible medical records also could be used to track the health
of the public in real time, for example, vaccine use or occurrence of hypertension,
bacterial and viral pneumonias, cardiac arrhythmias, and sexually transmitted dis-
eases. This would require substantial new federal money for equipment, personnel,
and infrastructure and the expertise and resources of agencies other than NIH
(Silverstein, 20011. In addition, the widespread use of the records raises a whole set
of new ethical issues concerning privacy and confidentiality that must be adequately
addressed if the public is to maintain its support for biomedical research. Non-
clinical database links will be essential to address environmental, dietary, and
behavioral interactions with genetic predispositions (Omenn 20001.
One issue that is common to all large-scale projects that generate research tools
or databases is accessibility. Concerns are often raised regarding intellectual property
rights, open communication among researchers, public dissemination of data and
assuring protection of privacy and confidentiality. Explicit understanding must be
negotiated and must be included in informed consent documents.
THE GROWING NEED FOR INTERDISCIPLINARY RESEARCH
Many of the projects described above are interdisciplinary. However, smaller-
scale studies in the biological and biomedical sciences are also requiring more
organized collaboration among disciplines. For example, data assessment, technol-
ogy development, and a deeper understanding of science increasingly necessitate the
involvement of non-biologists, such as engineers, physicists, and computer scientists.
Recognition of the value of interdisciplinary research is not new. Indeed, the history
of medicine demonstrates that many important advances have come from an inter-
disciplinary approach, for example, laser surgery involved ophthalmologists,
anatomists, and physicists; and gene discovery, such as the cloning of the gene
associated with Huntington disease, required the input of epidemiologists, neurolo-
gists, psychologists, sociologists, and geneticists. In fact, some of the newer fields in
science are hybrid or trans-disciplinary efforts, such as bioinformatics, neuroscience,
and health services research. The HOP has relied on the combined expertise of
biologists, chemists, computer scientists, mathematicians, and engineers. In the
behavioral sciences, psychologists increasingly use artificial intelligence, brain imag-
ing, and molecular biology to map behaviors (Institute of Medicine, 20001. And
psychiatric researchers long ago turned to epidemiologists and geneticists for help in
identifying risk factors.
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What is changing is the recognition that the need for interdisciplinary research
is likely to grow. Some of the most persistent and chronic causes of disease, dis-
ability, and death are proving to be vexingly complex. Elaborate and sometimes
subtle relationships among genes, environment, behavior, and disease and treatment
interventions underlie HIV/AIDS, heart disease, autoimmune diseases, cancers, and
substance abuse. Those conditions rarely lend themselves to the mode! of the single
investigator working in isolation in their own discipline.
Most scientists would agree that the collective framing of research questions
often leads to better answers. At the very least, most scientists are recognizing that
the variables of interest and the tools of other disciplines might be useful in their
own work. However, the organization of science and research administration, in
academia and funding agencies, often presents challenges to interdisciplinary work.
In 2000, an Institute of Medicine committee examining the need to foster inter-
disciplinary science in the brain, behavioral, and clinical sciences wrote that "long-
held biases, beliefs, educational practices, and research funding mechanisms have
created a system in which it is easier to conduct unidisciplinary than multidisciplin-
ary work" (Institute of Medicine, 20001. The committee concluded that the creation
of environments in which interdisciplinary research and training occur will prob-
ably require many changes and multiple integrated approaches. Creating a new
breed of interdisciplinary scientists requires rethinking of the training process,
including redesigning research training programs and funding mechanisms to sup-
port interdisciplinary training, research, and practice.
In 1999, NIGMS initiated a new funding mechanism referred to as glue grants,
intended to provide the resources to bring together and retain scientists from mul-
tiple disciplines to focus on a research topic. In 2003, the Fogarty International
Center announced a similar program. NIGMS's goal was to address problems that
are beyond the reach of individual investigators who already held funded research
grants related to a proposed topic of study. The RFA stated:
Biomedical science has entered a new era where these collaborations are becoming
critical to rapid progress. This is the result of several factors. First, not every
laboratory has the breadth to pursue problems that increasingly must be solved
through the application of a multitude of approaches. These include the involve-
ment of fields such as physics, engineering, mathematics, and computer science that
were previously considered peripheral to mainstream biomedical science. Second,
the ability to attack large projects that involve considerable data collection and
technology development require the collaboration of many groups and laboratories.
Finally, large-scale, expensive technologies such as combinatorial chemistry, DNA
chips, high throughput mass spectrometric analysis, etc., are not readily available
to all laboratories that could benefit from their use. These technologies require
specialized expertise, but could lend themselves to management by specialists who
collaborate or offer services to others.
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NIGMS originally conceived of the large-scale glue grants after consultations
with leaders in the scientific community who emphasized the importance of con-
fronting intractable biological problems with the expertise and input of large, multi-
faceted groups of scientists. Applicants are asked to consider what it would take to
solve a problem if a team of investigators already funded were to coordinate and
integrate their efforts and what approaches might be possible with the grant that
cannot be achieved with just R01 support. Efforts to disseminate information are
required, for example, meetings of participating investigators, newsletters, and Web
sites. Materials produced as a result of glue grants are to be made as available to the
wider community as is reasonable. One important objective of the glue grant
program is to benefit a broad scientific community (beyond those named in the
application).
TRENDS IN PUBLIC-PRIVATE SECTOR
RESEARCH AND COLLABORATION
Changes in the financing, organization, and performance of R&D and tech-
nological innovation have altered how industry, research performers, and
governments in the United States and elsewhere invest in research. According to the
Pharmaceutical Research and Manufacturers of America (PhRMA), in 2001 member
companies spent over $30 billion on research to develop new treatments for dis-
eases an estimated 17% of sales, a higher it&D-to-sales ratio than any other US
industry. An additional $17 billion was spent on R&D by the biotechnology industry
(Pharmaceutical Research and Manufacturers of America, 2001; Biotechnology In-
dustry Organization, 20031.
Many initiatives such as the SNPs Consortium, the mouse genome project, the
structural genomics consortium, and the more general Small Business Innovation
Research Program have involved close collaborations between public funding
agencies and private industry. Furthermore, numerous NIH institutes have started
specific projects and grants that have been directed at enhancing public-private
collaboration. Those experiments promise to deliver benefits to patient care. At the
same time, they have raised important issues about intellectual property, ethical
conduct of research, and conflict of interest that need to be addressed. The develop-
ment of new products, processes, and services often entails gaining access to firm-
specific intellectual property and capabilities.
Firms and research performers have responded to these developments by outsourc-
ing R&D and by forming collaborations and alliances to share R&D costs, spread
market risk, and obtain access to needed information and know-how. Alliances,
cross-licensing of intellectual property, mergers and acquisitions, and other tools
have transformed industrial R&D and innovation. Universities have moved to
increase funding links, technology transfer, and collaborative research activities
with industry and government agencies. Government policies have supported these
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developments through changes in antitrust regulations, intellectual property regi-
mens, and initiatives in support of technology transfer and joint activities (NSF,
2002a).
In addition, numerous strategic research and technology alliances among a
variety of institutions and enterprises, many involving international partners, have
been created over the last two decades. Universities are important partners in these
research joint ventures, participating in 16% of themirom 1985 to 2000 (NSF,
2002a).
INCREASING INTERNATIONAL RESEARCH
The decline of global political blocs, expansion of convenient and inexpensive
air travel, and advent of the Internet have facilitated scientific communication,
contact, and collaboration. Data collected by NSF (2002a) show that the expansion
of R&D efforts in many countries is taking place against a backdrop of growing
international collaboration in the conduct of R&D. More R&D collaborations can
be expected to develop with Internet-facilitated innovations such as virtual research
laboratories and the simultaneous use of distributed virtual data banks by investiga-
tors around the globe.
In many countries, foreign sources of R&D funding have been increasing, and
this underlines the growing internationalization of industry R&D efforts. In Canada
and the United Kingdom, foreign funding has reached nearly 20% of total industrial
R&D; it stands at nearly 10% for France, Italy, and the European Union as a whole.
US firms are also investing in R&D conducted in other locations. R&D spending by
US companies abroad reached $17 billion in 1999; it rose by 28% over a 3-year
span. More than half that spending was in transportation equipment, chemicals
(including pharmaceuticals), and computer and electronics products (NSF, 2002a).
A particularly notable international collaboration is the Human Proteome Or-
ganization (HUPO), which has launched international initiatives in characterization
of proteins in plasma, liver, and brain and in underlying technologies, antibody
resources, and bioinformatics (Hanash and Celis, 2002~. NIH Director Zerhouni's
Roadmap exercise identified proteomics as a leading enabling technology for new
discoveries. NIH and FDA are closely involved with the not-for-profit HUPO, and
several individual institutes have mounted their own proteomics workshops.
SUMMARY
Multiple trends are changing the nature and environment of biomedical re-
search, including the persistent need for better approaches to clinical research,
health services research, and evidence-based medicine; continuing concerns about
health disparities; the looming threats of emerging infectious diseases and
bioterrorism; the increased need for large-scale and trans-NIH projects that require
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longer-term strategic planning and commitments; the emergence of discovery-driven
science and its attendant informatics and data requirements; the need to add new
infrastructure elements to the nation's biomedical enterprise; the essential role of
interdisciplinary research in many diseases; and expanding relationships between
the public and private sector and between the United States and the rest of the world
in research.
Representative terms from entire chapter:
services research
