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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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52 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. 53

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54 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. 55

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56 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. 57

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58 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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60 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. 61

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62 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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New Opportunities, New Challenges: The Changing Nature of Biomedical Science 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. 63

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64 Enhancing the Vitality of the National Institutes of Health 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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New Opportunities, New Challenges: The Changing Nature of Biomedical Science 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 65

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66 Enhancing the Vitality of the National Institutes of Health 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.