COLLABORATIVE RESEARCH ON TROPICAL DISEASES (1985)    p. 7  of 12

F. FOUNDATION-SUPPORTED AND INTERNATIONAL RESEARCH GRANT PROGRAMS

          In the examples considered so far, we have focused on centers located in the tropics, where American scientists study tropical diseases in laboratories where the diseases occur. In this section, we review some of the private research grant programs and the tropical disease research program of WHO.

          The distinction between programs designed to create centers for research and those that simply fund research at existing laboratories is meaningful and important to strategists and funding organizations, as we noted in the cholera story. Grant programs provide the necessary wherewithal to get institutional capacity moving towards a goal, but they don’t lay the same continuing claim to resources that institutional programs do. Grant programs can be terminated, truncated, or redirected with less bureaucratic turmoil than can institution-building programs, as we are able to observe in the cutback of NIH research funds for FY 1986.

          A few general remarks about foundation programs may be appropriate before we turn to specifics. Foundations are socially accountable, to their Boards of Trustees and to the public, but their time-horizon is long. They don’t need to produce a profit or win a vote in a short period of time; they can afford the long view, identifying and working on problems not yet high on the public agenda.

          The disadvantage of foundation funding is that it is likely to be short-lived. Foundations cannot be locked in to a particular set of expenditures for more than, say, ten or fifteen years without endangering their innovative character. Consequently, foundations tend to look for program initiative which, when well underway, will continue with financial support from other sources, public or private.

          Probably the most successful example of foundation innovation in an area pertinent to our subject is in the field of tropical agriculture. The Ford and Rockefeller Foundations established four international agricultural research centers that demonstrated the value of high-quality research in raising tropical food production potential. These four centers were the nucleus of the system of thirteen research institutions now funded through the Consultative Group for International Agricultural Research (CGIAR) at an annual cost of about $170 million. Almost none of that cost is currently borne by the foundations. This is an example of leveraging money, using foundation funds as seed to attract or lever larger funds to work on a problem. It is one yardstick by which to measure the effectiveness of foundation-supported programs.

          With that background, we can look at three major foundation-supported efforts in the field of tropical disease research.

1. THE GREAT NEGLECTED DISEASES OF MANKIND (GND) PROGRAM OF THE ROCKEFELLER FOUNDATION

          The Rockefeller Foundation, since its founding in 1913, has had the longest and most productive record of any American foundation in dealing with tropical diseases. Its objective from the first was to enhance “the well-being of mankind throughout the world”, and among its first efforts was a program to promote public sanitation and the spread of knowledge of scientific medicine. The early work of the Foundation on yellow fever and hookworm was pathbreaking, much of it carried out by staff scientists associated with research institutes around the world.

          The Foundation’s announced goal was the eradication of yellow fever, an aim that had to be revised when it was found in the early l930s that forest mammals maintained a reservoir of the disease long after human population seemed forever rid of it. Before abandoning the field in the late l930s, the Foundation demonstrated that with vector control and a new vaccine, any government interested in controlling yellow fever within its boundaries had the means at hand to do so. In Brazil, the Foundation’s successful campaign to eradicate A. aegypti, a vector for both malaria and yellow fever, was led by Fred L. Soper, who later established INCAP and was first director of the PSCRL.

          In 1951, the Foundation launched a major program to explore the field of arthropod-borne viruses, or arboviruses. These are viruses transmitted by mosquitoes and other invertebrates having a horny exterior covering. This coincided with expanded virus programs in the Army laboratories (directed by Smadel), NAMRUs 2 and 3, and NIH. The result over the ensuing 20 years was a vast advance in identifying and categorizing viruses and in understanding the part played by the arthropod vectors in transmitting them. The Foundation supported laboratory research in many parts of the world, often assigning its own staff researchers abroad, including two sent to NAMRU-3 in Cairo under Phillips in 1953.

          The Foundation created its own laboratory at Rockefeller University. This was moved in 1964 to New Haven, where it became the Yale University Arbovirus Research Unit (YARU), and is now the designated WHO reference center for arboviruses, although it no longer enjoys direct Rockefeller support.

          Despite this illustrious history, the Foundation virtually dropped out of the tropical diseases field in the early 1970s. Its medical program became centered on population issues to the near-exclusion of anything else. The balance was redressed with the inauguration in 1977 of the Great Neglected Diseases of Mankind program, “devoted to bringing the power of the finest scientific institutions of the world to the development of new and better tools (vaccines and drugs) and methods of control (diagnostic tests, appropriate targeting of therapy) for these vast scourges of mankind, such as malaria, schistosomiasis, and diarrheal diseases.”

          The program refers to “neglected” diseases because, as noted in a report to the Foundation’s Trustees, for the last forty years the scientific establishment of the world has focused on wealthy populations and their diseases, most of which are degenerative. It is not just tropical diseases that are neglected, but the mostly rural, poor people of the less developed countries who have them.

          The decision to embark on the GND program was prompted by several factors, including increased awareness of the destructive impact of the diseases upon tropical societies, and the potential for gains at relatively modest cost because of recent advances in biomedical sciences. Many new research technologies have not been extensively employed against tropical diseases because of funding constraints.

          The GND program did not set out to create new facilities, but to build on existing centers of excellence, making it possible for the neglected diseases to bid for the attentions of the most able scientists. The scientific interest of the diseases fortunately is high, in part because their previous neglect may allow fairly dramatic gains to be made through the application of advanced research techniques.

          Fourteen recipients were identified in the first two years of the program, six general medical units, four units devoted to research in biochemistry and pharmacology, and four immunology units. Seven are in American institutions, and the others are at Oxford, Cairo, Tel Aviv, Stockholm, Mexico City and Bangkok. Each received assured funding for eight years of from $50,000 to $100,000 per year. Although only three units are in less developed countries, collaborative efforts in 22 different countries bring research expenditures in the Third World to 35% of the program. (See Table X.)  In the first six years of the program, $12 million was devoted to institutional grants. In addition, eight Career Development Fellowships were awarded, including research expenditures and travel costs as well as salary.

          In five years, the GND program involved 200 scientists and 200 trainees who together produced 736 publications, many in the most prestigious journals of the medical field. A team of three distinguished external examiners, headed by Dr. Ivan Bennett, Jr. of the NYU Medical Center, reviewed the program and found it of high quality, innovative, timely and productive. They unanimously disagreed, however, with the announced intention of the Foundation to discontinue core funding for the 14 units as each achieved its eighth anniversary, particularly for the three units in developing countries. They did concur with the phasing out of the Career Development Awards, but suggested that the annual meetings of scientists, an integral an important part of the program to date, be continued at their present size and scope. Savings from a decline in funding for fellowships and core support for units in developed countries should, they thought, be used for unrestricted grants, amounting to 10% of the prior year’s budget for each GND unit, plus a structured grants program for specified research in tropical diseases.

2. THE SCHISTOSOMIASIS RESEARCH PROGRAM OF THE EDNA McCONNELL CLARK FOUNDATION

          “We live in a wormy world,” as John Knowles of the Rockefeller Foundation once observed. Worms, or helminths, are the most prevalent infective agents of mankind, with ascariasis and trichuriasis, each infecting about a billion persons; hookworm, 600 million; filariasis, 300 million; and schistosomiasis, 200 million.  As the roundness of these figures suggests, they are rather crude estimates. Schistosomiasis estimates range from 100 to 200 million, a substantial margin for error, because a microscope is required for accurate diagnosis.

          Schistosomiasis is one of the oldest diseases known to have afflicted mankind. Egyptian mummies from 1000 years BC have been found with calcified schistosome eggs in their kidneys. Chinese literature dating from 400 BC describes something like schistosomiasis, and two bodies from the second century BC, exhumed in China in the l970s, substantiate the early existence of the disease. It has been around a long time, particularly in societies where the control of water is essential to production.

          Unlike most diseases, schistosomiasis has probably been on the rise since the Second World War. As irrigation brings economic benefits to many areas of the Third World, it also enlarges the habitat of the snails that are the indispensable intermediate hosts to the schistosome. It is a cruel disease in social terms, hitting hardest school age children who play in the water and farmers, fishermen and launderers who work in it.

          When the Edna McConnell Clark Foundation decided to focus on the disease in the early l970s, probably less than $1.5 million was spent worldwide each year on investigating the malady. Clark put in $2 million per year, galvanizing the field. Somewhat later, the inter­national TDR program selected schistosomiasis as one of its six priority diseases, adding another $2 million per year. With the additional work on schistosomiasis under Rockefeller’s GND Program, expenditures now run at about $8 million annually, a very healthy addition of funds which has been well rewarded by advancing knowledge. To maintain perspective, however, the $8 million should be stacked up against the $40 million available for research from the American Cancer Society alone, in addition to the $1 billion for cancer research from NIH. (“The Relevance of Schistosomiasis,” Kenneth S. Warren, M.D., The New England Journal of Medicine, July 24, 1980.)  Put another way, $209 research dollars are spent for each case of cancer, but only 4 1/2 cents each year for each case of schistosomiasis.

          The Clark Foundation took a novel approach; it started its program by producing a Strategic Plan for Schistosomiasis Research as a guide to their investments. The plan was devised with the help of a broad range of scientific experts. It sought to ensure that the program focused on developing the means to control schistosomiasis and that the fruits of research were put into practical use as soon as possible.

          The Foundation mapped out four areas of activity, with target dates for anticipated accomplishments. Hope centered on the development of a successful vaccine, which some thought would be possible within five years, although the Plan more prudently set 1986 as the target date. Drug development was a second line of action, beginning with further research on compounds with known activity in man or animals and, in the longer run, working on more specific drugs, based on the expanding knowledge of the biochemistry and physiology of the schistosome. The third line of action was to improve the tools for controlling the snail vector, and the fourth was to improve the awareness of those in a position to organize and fund control programs on the impact of schistosomiasis on society. The Clark strategy was to fund research along these lines, but also to offer coherence and direction to dispersed efforts in the field and to facilitate the communication of findings by sponsoring symposia, publishing progress reports, and supplying bibliographical materials to investigators at no charge.

          The goals listed in the Strategic Plan are revised annually, with the help of an expert advisory committee, currently chaired by Patricia Rosenfield of the TDR Program of the WHO. Early optimism concerning immunization has tempered; unanticipated benefits have come from drug development, although not exclusively that supported by the Foundation.

          After ten years of program effort, and expenditures of about $22 million, the Clark Foundation has begun to reduce its commitment to schistosomiasis and explore other tropical diseases, particularly those causing blindness. Again, a strategic plan is under preparation to guide program expenditures. The Rockefeller and MacArthur Foundations did not adopt the device of a strategic plan in mounting later research programs in the tropical disease field, but the Clark staff and trustees believe it offers useful coherence and focus to their efforts.

          We have learned a great deal about schistosomiasis and how to deal with it in the past ten years, although it is difficult to allocate credit for advances among particular programs. No single development has had the drama of the NAMRU-2 discovery of the therapeutic potential of the sodium transporter for oral rehydration, but perhaps the incremental gains made against the burden of schistosomiasis are more typical of scientific process than the Eurekas that more often attract our attention.

          On a worldwide basis we do not know, according to Joseph Cook, who directs the Clark Foundation program, whether the rate of new cases of schistosomiasis is increasing or decreasing. Surveillance techniques have improved since 1973, and the program played a key role in making progress possible, but data are still poor for a disease such as this that is neither epidemic nor generally fatal.

          It is possible, however, to assert confidently that control measures have improved to the point where the severe clinical effects of the disease can be drastically reduced. New antischistosomal drugs are now available that can be administered in a single oral dose, or several doses in one day, with only minor side effects. This is a great advance over the recent past, when only highly toxic drugs were available and they needed to be administered in doses several weeks apart. The advantage of treating the disease in infected persons with drugs is that it causes an immediate and drastic reduction in the intensity and prevalence of infection, ameliorating the impact of the disease on the victim and at the same time decreasing egg output into the environment and the infection rate in snails.

          Schistosomes don’t multiply in the body. The severity of infection is thus a consequence of the degree of exposure to water containing the infective agent. Thus, although a very high percentage of a population may be infected, the disease will have serious clinical implications for only those who are in the water a lot, for work or play. This permits the relatively efficient targeting of treatment programs.

          Other control techniques include the use of snail-killing chemicals (molluscicides), provision of fresh water, and improved sanitation. These measures are generally too expensive or, in the case of molluscicides, ineffective, to be relied upon alone, but they can be important adjuncts to drug treatment in controlling the disease. Health education is also important.

          Transmission of schistosomiasis will only be halted when an effective, affordable vaccine is available, and that is still years away. New techniques of molecular biology contain great promise, but at this point only candidate antigens have been identified, not fully protective in experimental animals. Even when adequate answers are found at the laboratory bench, a considerable period of further development and testing will be required before a vaccine becomes generally available.

          And so the Foundation moves on, in full recognition that much remains to be done in immunology, biochemistry, drug development, epidemiology and control, before we are able to deal with schistosomiasis satisfactorily. The catalytic value of the Foundation’s entry into the field has been realized, and it is thought to be time to begin anew on other tropical diseases.

3. THE MOLECULAR BIOLOGY PROGRAM OF THE MacARTHUR FOUNDATION

          Another foundation program that deserves mention because of its size, although not much is yet known about it, is the molecular biology program of the MacArthur Foundation. The Foundation announced in October 1984 that it has committed $20 million to establish a consortium of research groups devoted to the study of parasitic diseases.

          Jonas Salk, a Trustee of the Foundation, explains the program’s motivation in the following way:

          “In focusing this new initiative on basic research, the MacArthur Foundation demonstrates its conviction that intensive application of modern cellular and molecular biology, genetics, and immunology to the study of the biological bases of parasitic diseases will produce the most significant progress in finding effective means of reducing the worldwide suffering caused by parasites.