Enhanced online at POLICY FORUM PUBLIC HEALTH Grand Challenges in Global Health H. Varmus, R. Klausner, E. Zerhouni, T. Acharya, A. S. Daar, P. A. Singer n 26 January 2003, at the World O ers Forum in Davos, Swit- zerland, Bill Gates announced a $200-million medical research initiative— the Grand Challenges in Global Health— based on a century-old model, the grand challenges formulated by the mathematician David Hilbert (/). Hilbert’s list of important unsolved problems in mathematics (/) has spurred major research innovations in the field. www.sciencemag.org/cgi/. The Global Health ini- content/full/302/5644/398_ tiative was proposed by 398 the Bill & Melinda Gates Foundation (BMGF) on the assump- tion that, with greater encouragement and funding, contemporary science and technolo- gy could remove some of the obstacles to more rapid progress against diseases that dis- proportionately affect the developing world. The efforts to identify Grand Challenges in Global Health relied on financial and ad- ministrative resources of two collaborating foundations, the BMGF and the Foundation for the National Institutes of Health (NIH); on a selection panel (scientific board) of 20 sci- entists and public health experts from 13 countries, including several from the develop- ing world (2); and on the scientific communi- ty to supply ideas for challenges. In this Policy Forum, some of us involved in these events (H.V., R.K., and E.Z. as members of the Scientific Board’s Executive Committee and PA.S., T.A., and A.S.D. as scholars who provided support to the selection process) de- scribe the deliberations that led up to this weck’s announcement of an initial list of Grand Challenges in Global Health (see table, page 399). We also outline the next steps that will be taken to fund research that addresses those challenges and plans to formulate addi- tional grand challenges in subsequent years. What Is a Grand Challenge? On | May 2003, in a solicitation widely ad- vertised in the developed and developing H. Varmus is the president and CEO of Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. R. Klausner is the executive director of the Global Health Program, BMGF, Seattle, WA 98102, USA. E. Zerhouni is the director of the NIH, Bethesda, MD 20892, USA. T. Acharya, A. S. Daar, and P.A. Singer are at the University of Toronto Joint Centre for Bioethics, Toronto, Ontario, Canada MSG 1L4. Copyright of this work is retained by the authors. 17 OCTOBER 2003 VOL 302 SCIENCE world, a grand challenge was described as “a call for a specific scientific or technological innovation that would remove a critical barri- er to solving an important health problem in the developing world with a high likelihood of vlobal impact and feasibility.’ Throughout the process of developing the grand chal- icnges, the board struggled with how best to define them. A grand challenge is envisioned as distinct from a simple statement of one of the many “big problems” in global health, such as HFV/AIDS, malnutrition, the lack of access to medical care, or the lack of ade- quate resources. A grand challenge is meant to direct investigators to a specific scientific or technical breakthrough that would be ex- pected to overcome one or more bottlenecks in an imagined path toward a solution to one or preferably several significant health prob- lems. To satisfy this intent, a successful pro- posal would need to foresee a critical path of this type to get past a clearly defined road- block. This formulation worked most effec- tively for those medical problems that are well enough understood to allow a descrip- tion of what needs to be done, even if we do not yet know precisely how to do it. Thus, al- though the Grand Challenges initiative would ideally inspire unexpected and even radical solutions, the board also recognized the ad- vantages of being able to envision solutions that have a high likelihood of being success- ful. The constraint of describing a “critical path past a bottle-neck” ruled out the broad ficld-building and exploratory research that usually underlies breakthroughs. Capacity building is another important approach (for example, increasing the number of biomed- ical research laboratories in the developing world, providing greater financial support for the study of global health or expanding pro- fessional training programs in global health) but beyond the purview of the program. The scope of the initiative is broad, poten- tially encompassing many strategies for im- proving health through surveillance, preven- tion, detection, diagnosis, and treatment of diseases. Scientific disciplines underlying these strategies are also likely to be diverse, including immunology, microbiology, genct- ics, molecular and cellular biology, entomol- ovy, agricultural sciences, clinical sciences, epidemiology, population and behavioral sci- ences, and ecology and evolutionary biology. For example, control of pathogen-transmit- ting insect vectors is likely to make a big dif- ference in reducing the incidence of diseases such as malaria and dengue fever that are common in the developing world. Chemical interventions, e.g., insecticides, have been thwarted by the emergence of insecticide re- sistance and constrained by environmental concerns. Two of the selected grand chal- lenges are meant to encourage the develop- ment of novel chemical or genetic strategies for rendering mosquitoes incapable of trans- mitting disease agents, without adverse eco- logical or other environmental effects (3). How Were Grand Challenges Selected? The announcement of the Call for Ideas on 1 May 2003, was accompanied by a dissemina- tion campaign that included a Web site (4), advertisements in scientific journals, and e- mail notifications, with the intent of engag- ing and eliciting ideas from scientists throughout the world. Between 1 May and 20 July, 1048 submissions were received from scientists and institutions in 75 countries. The large volume was gratifying but also required categorization according to topical content and the extent to which each submission met the criteria (4). The difference in number of proposals in various categories that met the criteria is reflected in the distribution of top- ics in the selected list of grand challenges. The scientific board met on 17 and 18 August. To expedite discussion, the execu- tive committee aggregated multiple, highly regarded, and closely related submissions into single proposals in advance of the meeting. The format chosen for presenta- tion was the following: a brief statement of the background of the problem, followed by descriptions of the “roadblock” (the ob- stacle to progress) and the challenge itself, supplemented by lists of potential benefits, and, if appropriate, diseases or health con- ditions that are likely to be priority areas for study and application of findings. Each candidate was presented orally by two or more board members and then discussed by the full board. Wide participation was encouraged, so that ultimately all decisions were reached by oral consensus. Questions raised during the discussions reflected the criteria that the board had pro- posed earlier, but they also illustrated the dif- ficulties of defining grand challenges in global health. Does the proposal describe a difficult and discrete roadblock to progress? What is the likelihood that creative solutions are required and that grant proposals worthy of funding will be received to address it? Is there already substantial scientific activity aimed at solving the problem, which would make the intent of a grand challenge redun- www.sciencemag.org dant? What are possible impacts on various diseases if the challenge is successfully met? Will envisioned advances be suitable for im- plementation in poorer parts of the world? During, and especially after, the selec- tion process, it became apparent that the challenges could be instructively grouped according to seven long-range goals (see table, below). None of the goals or selected grand challenges addresses a single disease. We believe this reflects successful pursuit of the original aim: to identify underlying scientific and technical problems that im- pede progress against multiple disorders. A survey of the list, however, also re- veals that both the goals and the selected challenges are heavily oriented toward the control of infectious diseases. This is so, in part, because infectious diseases account for the most profound disparities in health outcomes between the advanced and devel- oping economies (5), and, in part, because the causes of infectious diseases are well known, making the formulation of techni- cal and scientific obstacles to progress eas- ier to envision than for poorly understood diseases. Nevertheless, the scientific board recognizes and discussed at length the problems increasingly posed by chronic noncommunicable disorders and the im- portance of underlying living conditions, particularly access to clean water and ade- quate food, in large parts of the developing world. The board intends to pursue these issues by convening workshops on such topics and considering additional grand challenges in subsequent years. Next Steps Following the announcement of the Grand Challenges, the Foundation for NIH will is- sue a Request for Proposals (RFP) to address each of the challenges with grants of up to a total of $20 million over 5 years or less. How many grants will be made toward each chal- lene and how many of the 14 challenges will have funded grants will depend on the quality of the proposals and the available re- sources. Applications will be invited from anywhere in the world, from one or multi- ple institutions or countries in the devel- oped or developing world and from non- profit or for-profit institutions. The staff of the Foundation for NIH will oversee the ap- GOALS AND GRAND CHALLENGES To improve childhood vaccines: GC 1: Create effective single-dose vaccines that can be used soon after birth; GC 2: P G that d ot require refrigeration, evelop needle-free delivery systems for vaccines. To create new vaccines: GC 4: Devise reliable tests in model systems to evaluate live attenuated vaccines; GC 5: Solve how to design antigens for effective, protective immunity; GC 6; Learn which immunological responses provide protective immunity. To control insects that transmit agents of disease: GC 7: Develop a genetic strategy to deplete or incapacitate a disease-transmitting insect population; GC 8: Develop a chemical strategy to deplete or incapacitate a disease-transmitting : insect population. To improve nutrition to promote health: GC 9: Create a full range of optimal bioavailable nutrients in a single staple plant species. To improve drug treatment of infectious diseases: GC 10: Discover drugs and delivery systems that minimize the likelihood of drug- resistant microorganisms. To cure latent and chronic infections: To measure disease and health status accurately and economically in poor countries: GC 13: Develop technologies that permit quantitative assessment of population health status; GC 14: Develop technologies that allow assessment of individuals for multiple , conditions or pathogens at point-of-care. www.sciencemag.org SCIENCE VOL 302 POLICY FORUM plication and award processes, will encour- age the participation of developing-country researchers, and will be available to advise about organizing interinstitutional or inter- national consortia where appropriate. The application process [described in detail at (4)] will require the submission of a letter of intent by 9 January 2004. These letters will be reviewed by Foundation for NIH staff, members of the scientific board, and other selected experts; suitable candidates will then be asked to submit full applications, which will be due in June 2004. This vetting process will permit Foundation for NIH staff to discourage applications with little or no likelihood of success, and to assemble the appropriate number and type of review groups. Full applications will be evaluated by specially constituted review groups be- fore the annual meeting of the scientific board, late in the summer of 2004. The sci- entific board will make recommendations to the Foundation for NIH, which expects to make awards around October 2004. Awards will likely exhibit a wide range of support levels and requirements for oversight. The scientific board expects to continue to seek candidate challenges through new solicitations of ideas, the convening of workshops with invited speakers on de- fined topics, and continued discussion among members of the board. In the very design of its gift, the BMGF has chal- lenged the world’s scientists to produce a program that has the potential to improve the lives of many people. References and Notes . D. Hilbert, Bull, Am. Math. Soc. 8, 437 (1901-02). . The members of the scientific board are Harold Varmus, Memorial Sloan-Kettering Cancer Center (Executive Committee, Chair); Richard Klausner, Bill & Melinda Gates Foundation (Executive Committee); Elias Zerhouni, National Institutes of Health (Executive Committee); Roy Anderson, Imperial College of the University of London; Mary Jane Cardosa, Universiti Malaysia Sarawak; Christine M. Debouck, GlaxoSmithKline Pharmaceuticals; Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, NIH; William H. Foege, Bill & Melinda Gates Foundation; Julio Frenk, Minister of Health, Mexico; Nirmal Kumar Ganguly, Indian Council for Medical Research; Julie Louise Gerberding, U.S. Centers for Disease Control; Fotis C. Kafatos, European Molecular Biology Laboratory; Gerald Keusch, Fogarty International Center, NIH; Francis Kwesi Nkrumah, University of Ghana, Legon; Gustav Nossal, University of Melbourne; Odile Puijaton, Institut Pasteur; Yiming Shao, Chinese Center for Disease Control and Prevention; Peter A. Singer, University of Toronto Joint Centre for Bioethics; Florence Wambugu, A Harvest Biotech Foundation International, Yongyuth Yutha- vong, Thai Academy of Science and Technology. 3. See supporting online material for further discussion. . www.grandchallengesgh.org. 5. World Health Organization, "Macroeconomics and Health: Investing in Health for Economic Develop- ment” (World Health Organization, Geneva, 2001). Na b Supporting Online Material www.sciencemag.org/cgi/content/full/302/5644/398/ 0c1 17 OCTOBER 2003 399