PUBLIC HEALTH:
Enhanced: Grand Challenges in Global Health

On 26 January 2003, at the World Economic Forum [HN1] in Davos, Switzerland, Bill Gates [HN2] announced a $200-million medical research initiative--the Grand Challenges in Global Health [HN3]--based on a century-old model, the grand challenges formulated by the mathematician David Hilbert (1) [HN4]. Hilbert's list of important unsolved problems in mathematics (1) has spurred major research innovations in the field. The Global Health initiative was proposed by the Bill & Melinda Gates Foundation [HN5] (BMGF) on the assumption that, with greater encouragement and funding, contemporary science and technology could remove some of the obstacles to more rapid progress against diseases that disproportionately affect the developing world.

The efforts to identify Grand Challenges in Global Health relied on financial and administrative resources of two collaborating foundations, the BMGF and the Foundation for the National Institutes of Health (NIH) [HN6]; on a selection panel (scientific board) of 20 scientists and public health experts from 13 countries, including several from the developing world (2); and on the scientific community 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 P.A.S., T.A., and A.S.D. as scholars who provided support to the selection process) describe the deliberations that led up to this week's announcement of an initial list of Grand Challenges in Global Health (see table, below). We also outline the next steps that will be taken to fund research that addresses those challenges and plans to formulate additional grand challenges in subsequent years.

What Is a Grand Challenge?
On 1 May 2003, in a solicitation widely advertised in the developed and developing world, a grand challenge was described as "a call for a specific scientific or technological innovation that would remove a critical barrier to solving an important health problem in the developing world with a high likelihood of global impact and feasibility." Throughout the process of developing the grand challenges, 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 HIV/AIDS, malnutrition, the lack of access to medical care, or the lack of adequate resources. A grand challenge is meant to direct investigators to a specific scientific or technical breakthrough that would be expected to overcome one or more bottlenecks in an imagined path toward a solution to one or preferably several significant health problems. To satisfy this intent, a successful proposal would need to foresee a critical path of this type to get past a clearly defined roadblock. This formulation worked most effectively for those medical problems that are well enough understood to allow a description of what needs to be done, even if we do not yet know precisely how to do it. Thus, although the Grand Challenges initiative would ideally inspire unexpected and even radical solutions, the board also recognized the advantages of being able to envision solutions that have a high likelihood of being successful. The constraint of describing a "critical path past a bottle-neck" ruled out the broad field-building and exploratory research that usually underlies breakthroughs. Capacity building is another important approach (for example, increasing the number of biomedical research laboratories in the developing world, providing greater financial support for the study of global health or expanding professional training programs in global health) but beyond the purview of the program.

The scope of the initiative is broad, potentially encompassing many strategies for improving health through surveillance, prevention, detection, diagnosis, and treatment of diseases. Scientific disciplines underlying these strategies are also likely to be diverse, including immunology, microbiology, genetics, molecular and cellular biology, entomology, agricultural sciences, clinical sciences, epidemiology, population and behavioral sciences, and ecology and evolutionary biology. For example, control of pathogen-transmitting insect vectors [HN7] is likely to make a big difference in reducing the incidence of diseases such as malaria [HN8] and dengue fever [HN9] that are common in the developing world. Chemical interventions, e.g., insecticides, have been thwarted by the emergence of insecticide resistance [HN10] and constrained by environmental concerns. Two of the selected grand challenges are meant to encourage the development of novel chemical or genetic strategies for rendering mosquitoes incapable of transmitting disease agents, without adverse ecological or other environmental effects (3).

How Were Grand Challenges Selected?
The announcement of the Call for Ideas [HN11] on 1 May 2003, was accompanied by a dissemination campaign that included a Web site (4), advertisements in scientific journals, and e-mail notifications, with the intent of engaging 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 topics in the selected list of grand challenges.

The scientific board met on 17 and 18 August. To expedite discussion, the executive committee aggregated multiple, highly regarded, and closely related submissions into single proposals in advance of the meeting. The format chosen for presentation was the following: a brief statement of the background of the problem, followed by descriptions of the "roadblock" (the obstacle to progress) and the challenge itself, supplemented by lists of potential benefits, and, if appropriate, diseases or health conditions 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 proposed earlier, but they also illustrated the difficulties 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 redundant? What are possible impacts on various diseases if the challenge is successfully met? Will envisioned advances be suitable for implementation in poorer parts of the world?

During, and especially after, the selection process, it became apparent that the challenges could be instructively grouped according to seven long-range goals (see table, above). 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 impede progress against multiple disorders.

A survey of the list, however, also reveals 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 developing economies (5) [HN12], and, in part, because the causes of infectious diseases are well known, making the formulation of technical and scientific obstacles to progress easier to envision than for poorly understood diseases. Nevertheless, the scientific board recognizes and discussed at length the problems increasingly posed by chronic noncommunicable disorders [HN13] and the importance of underlying living conditions, particularly access to clean water and adequate 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 issue 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 challenge and how many of the 14 challenges will have funded grants will depend on the quality of the proposals and the available resources. Applications will be invited from anywhere in the world, from one or multiple institutions or countries in the developed or developing world and from nonprofit or for-profit institutions. The staff of the Foundation for NIH will oversee the application and award processes, will encourage the participation of developing-country researchers, and will be available to advise about organizing interinstitutional or international 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 before the annual meeting of the scientific board, late in the summer of 2004. The scientific 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 defined topics, and continued discussion among members of the board. In the very design of its gift, the BMGF has challenged the world's scientists to produce a program that has the potential to improve the lives of many people.

References and Notes

1. D. Hilbert, Bull. Am. Math. Soc. 8, 437 (1901-02).
2. 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 Puijalon, 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 Yuthavong, Thai Academy of Science and Technology.
3. See supporting online material for further discussion.
4. www.grandchallengesgh.org.
5. World Health Organization, "Macroeconomics and Health: Investing in Health for Economic Development" (World Health Organization, Geneva, 2001).

www.sciencemag.org/cgi/content/full/302/5644/398/DC1

HyperNotes
Related Resources on the World Wide Web

General Hypernotes

Dictionaries and Glossaries

The On-line Medical Dictionary is available on CancerWEB.

A medical dictionary and a medical encyclopedia are offered by MedlinePLUS, a service of the National Library of Medicine.

Web Collections, References, and Resource Lists

Biology Links are provided by the Department of Molecular and Cellular Biology, Harvard University.

MedlinePLUS provides links to Internet resources on biomedical topics.

HealthWeb, a collaborative project of health sciences libraries of the Greater Midwest Region, is an evaluated guide to Internet health sciences resources.

OMNI, provided by the University of Nottingham, UK, is a searchable catalogue of Internet sites covering health and medicine.

The library of the Karolinska Institutet, Stockholm, Sweden, provides links to Internet resources on biomedical information resources with a section on diseases, disorders, and related topics.

Public Health InfoLinks are provided by the Rollins School of Public Health, Emory University.

The Google Directory provides links to Internet resources on public health and safety.

The Global Forum for Health Research provides a collection of Internet links related to health research and communication.

Online Texts and Lecture Notes

The Grand Challenges in Global Health (GCGH) Web site provides a FAQ about GCGH.

The World Health Organization (WHO) provides an index of health topics, as well as other resources relating to global health issues.

The Centers for Disease and Control Prevention (CDC) provides links to disease and health topics.

The globalhealth.gov Web site, provided by the U.S. Department of Health and Human Services, addresses global health and the link between domestic and international health issues.

The United States Agency for International Development provides a Global Health Web site.

J. Kimball provides Kimball's Biology Pages, an online biology textbook and glossary.

The Bookshelf from the National Center for Biotechnology Information makes available biomedical textbooks.

Medical Microbiology is a Web textbook edited by S. Baron, Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston.

Microbiology and Immunology On-line is a Web textbook provided by the Department of Pathology and Microbiology, University of South Carolina School of Medicine.

Lecture notes for the Supercourse on Epidemiology, the Internet, and Global Health are made available by R. LaPorte, Graduate School of Public Health, University of Pittsburgh.

General Reports and Articles

The World Health Report 2002: Reducing Risks, Promoting Healthy Life is made available by WHO.

The 5 October 2001 issue of Science had a Viewpoint article by P. Singer and A. Daar titled "Harnessing genomics and biotechnology to improve global health equity." The 15 March 2002 issue had a Viewpoint article by P. Jha et al. titled "Improving the health of the global poor." The 27 June 2003 issue had an editorial by V. McGovern and Q. Bond titled "Global health research."

The 10 September 2003 issue of the Journal of the American Medical Association had an editorial by A. Flanagin and M. Winker titled "Global health--Targeting problems and achieving solutions."

The University of Toronto Joint Centre for Bioethics makes available its study and related documents on the top ten biotechnologies for improving health in developing countries.

The 24 February 2003 issue of The Scientist had an opinion article by S. Fitzpatrick titled "Keep philanthropic funding distinct" (free registration required).

Numbered Hypernotes

1. World Economic Forum. The World Economic Forum provides information about its January 2003 annual meeting in Davos, Switzerland, as well as information about its Global Health Initiative program.

2. Bill Gates has a home page at Microsoft. The Bill & Melinda Gates Foundation provides a brief profile of Bill Gates and links to his speeches. Health, Wealth and Bill Gates, a presentation of the Public Broadcasting System's NOW with Bill Moyers, explores some of Gates's activities with respect to global health.

3. The Grand Challenges in Global Health. The Bill & Melinda Gates Foundation makes available the 26 January 2003 announcement titled "$200 million grant to accelerate research on 'grand challenges' in global health." The 27 January 2003 issue of the Seattle Post-Intelligencer had an article by T. Paulson titled "Gates issues a global challenge on health." BBC News makes available a 26 January 2003 article by M. Verdin titled "Billionaire Gates backs philanthropy."

4. David Hilbert's grand challenges in mathematics. D. Joyce, Department of Mathematics and Computer Science, Clark University, offers a presentation on the 23 problems for future mathematicians described by Hilbert in 1900. Another presentation on the same topic is offered by I. Kersten, Mathematisches Institut, Göttingen, Germany.

5. The Bill & Melinda Gates Foundation. The Bill & Melinda Gates Foundation was created in January 2000 through the merger of the Gates Learning Foundation and the William H. Gates Foundation.

6. The Foundation for the National Institutes of Health. The Foundation for the National Institutes of Health, established at the direction of the United States Congress in 1996, builds and fosters collaborative relationships with philanthropy, industry, and academia to support the NIH mission of improving health through scientific discovery.

7. Insects as disease vectors and their control. Insects, Disease, and History, a presentation by R. Peterson, Department of Entomology, Montana State University, includes a section about diseases and the insects that transmit them. The Entomology Department, Virginia Tech, makes available lecture notes on insects and human diseases (parts one and two) for a course on insects and human society. Radcliffe's IPM World Textbook, an electronic textbook of integrated pest management from the University of Minnesota, includes a chapter by C. Curtis on the control of malaria vectors in Africa and Asia. The NIH's National Institute of Allergy and Infectious Diseases offers a presentation titled "Focus on bug-borne disease research: International."

8. Malaria. WHO's Special Programme for Research and Training in Tropical Diseases (TDR) provides information about malaria. The CDC's Division of Parasitic Diseases (DPD) provides links to malaria information; the DPDx Web site provides information about the malaria parasite Plasmodium. The Malaria Foundation International provides information about malaria and global malaria initiatives, as well as links to scientific information. The 4 Oct 2002 issue of Science, a special issue on the mosquito genome, included a Viewpoint article by L. Miller and B. Greenwood titled "Malaria--a shadow over Africa" and a Viewpoint article by L. Alphey et al. titled "Malaria control with genetically manipulated insect vectors." The UK National Institute for Medical Research makes available a 2002 Mill Hill essay by T. Holder titled "The malaria revolution: From mosquitoes to molecules."

9. Dengue fever. A fact sheet on dengue is provided on the World Water Day Web site. WHO's TDR provides information about dengue. The CDC's Division of Vector-Borne Infectious Diseases maintains a dengue fever home page. The Hawai'i Department of Health offers a resource page on dengue fever. The eMedicine Web site provides a review article by D. Price on dengue fever.

10. Insecticide resistance. J. Meyer, Department of Entomology, North Carolina State University, makes available lecture notes on pesticide resistance and pest control tactics for an entomology course. The 4 Oct 2002 issue of Science, a special issue on the mosquito genome, had a Viewpoint article by J. Hemingway, L. Field, and J. Vontas titled "An overview of insecticide resistance."

11. The GCGH Call for Ideas. The GCGH Web site includes a section on the "Call for Ideas." The 27 May 2003 issue of the NIH Record had an article titled "Varmus invites 'Grand Challenge' ideas, stimulates new thinking."

12. Infectious diseases and the disparity between advanced and developing economies. WHO provides an infectious diseases resource page. WHO's Macroeconomics and Health Web site makes available the report Macroeconomics and Health: Investing in Health for Economic Development (5) and related documents, as well as a collection of Internet links. The World Bank Group provides an issue brief on communicable diseases, as well as a Health, Nutrition & Population Web site and a Poverty and Health Web site, which offers a collection of Internet links. The 13 May 2002 issue of The Scientist had an article by R. Lewis titled "Fighting the 10/90 gap."

13. Problems of noncommunicable disorders and living conditions in developing world. WHO's Noncommunicable Disease Prevention and Health Promotion Web site provides links to related Internet resources; a presentation on nutrition and the prevention of noncommunicable disorders is provided, as is the 2002 report Globalization, Diet and Noncommunicable Diseases (in PDF format). WHO provides nutrition and water, sanitation and health Web sites; the publication The Right to Water is available in PDF format. The Canadian Agency for International Development offers a presentation on the clean water problem.

14. H. Varmus is at the Memorial Sloan-Kettering Cancer Center. R. Klausner is in the Global Health Program of the Bill & Melinda Gates Foundation. E. Zerhouni is at the National Institutes of Health. T. Acharya, A. S. Daar, and P. A. Singer are at the University of Toronto Joint Centre for Bioethics. Copyright of this work is retained by the authors.

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