COLLABORATIVE RESEARCH ON TROPICAL DISEASES (1985)  p.3 of 12

III. COLLABORATIVE PROGRAMS

          A. Overview: Bases of Comparison

          American institutions, public and private, combat tropical diseases through a variety of mechanisms. In this section, some of the mechanisms successfully employed now or in the recent past are reviewed as a guide to future action. The examples selected, with the help of the study Steering Committee, are not encyclopedic; on the other hand, the list of useful efforts is not exceedingly long.

          Examples selected include the military laboratories overseas, both the NAMRUs which played so vital a role in the cholera story and the Army’s labs; the ICMRT program, of which the Johns Hopkins group in Calcutta was an example, and its successors; the ICDDR/B which grew out of the SEATO Cholera Research Laboratory; The Gorgas Memorial Laboratory in Panama; and research grant programs on tropical diseases funded by private foundations. The WHO smallpox eradication campaign and WHO/World Bank/UNDP’s Expanded Program for Tropical Disease Research (TDR), though not primarily American efforts, are also discussed briefly.

          For convenience, the examples may be considered in three categories: American-established research laboratories in the Third World; research grant programs; and the smallpox eradication program. The smallpox program was not primarily a research program, nor was it an American effort, but it is illustrative of an effective mobilization of American talent and institutional resources in an international program.

          The overseas laboratories receive special attention in these pages because of their unique role in American efforts to deal with tropical diseases. Temperate zone laboratory research can, of course take us only so far in the process of understanding a disease and learning to conquer or, more often, control it. Information about the natural history of a disease, its incidence, prevalence, case-fatality, and patterns of transmission, can only be collected in the field. Clinical research requires ready access to a patient population. The fruits of research -- drugs, vaccines and vector control programs -- must be tested where the diseases occur. Also, training in tropical medicine can most effectively take place in the tropics.

          There is, of course, no single lens through which to view such a variety of efforts on such complex subjects. The objectives of the programs differ significantly, the nature of different diseases dictates varying approaches, and circumstances of origin sometimes shape programs in unusual ways. Nevertheless, if we are to gain from comparison, we need some skeletal framework on which to graft our observations. The principal elements of our comparative framework are the following:

1.     The scope of the program along the spectrum of research needed to learn to deal with a disease. Research on a tropical disease must normally seek to increase understanding of the biological nature of the pathogen, clinical manifestations and efficacy of treatment, the distribution and transmission patterns of the disease, and social and economic factors that constrain public health interventions to control it. Simply stated, research is needed on the nature of the disease organism, the ways it affects human beings, the means and extent of transmission, and the human behavior and natural environment which may need to change if the disease is to be controlled. The locus of research may be an advanced biological laboratory, a hospital, a field station, or a community. Relatively few programs span the entire range of research activities necessary to disease management, but we need to recognize that laboratory research on tropical diseases can be part of a coherent effort and not an isolated set of activities with little potential impact on human suffering.

2.     The degree of collaboration with scientists and institutions in the developing countries involved. This point is closely related to the one above. Because work on a tropical disease must be done in field conditions where the disease thrives, as well as in advanced medical laboratories, collaboration between Third World scientists and our own is desirable and usually necessary if the work is to go on. Changes in the world political climate in recent years have made collaboration more difficult unless collaboration includes an element of training to strengthen the collaborating institution in the tropics. Patterns of fruitful collaboration therefore deserve special scrutiny.

3.     Results, in terms of the impact on our understanding or controlling a disease. Not all research or control efforts can document progress in the control of a disease. Indeed, it is sometimes difficult to know in advance just how research on tropical pathogens will result in new methods to control the disease or treat its victims. Most of the laboratory work on African trypanosomes in humans, for example, is devoted to understanding how the body’s immune system responds to the ability of the invading organism to change its protein coat. Such research is required if we are to have a protective vaccine against trypanosomiasis. More efforts designed to understand and control tropical diseases are needed.

4.     Results, in terms of enhancing individual and institutional capacities in the US and abroad. Few known diseases are, like smallpox, susceptible to eradication. We and the people of the Third World will be coping with familiar pestilences for generations to come. Increasingly, the battle will be waged on endemic grounds by the scientists whose people suffer most, but time and careful husbandry are needed for modern science to grow firm roots in most developing countries. The role of advanced-country scientists and institutions in the process of building research capacity in the tropics is of course crucial, so value must be assigned to the growth in institutional competencies that a program represents and leaves as a legacy.

B. THE DEPARTMENT OF DEFENSE OVERSEAS MEDICAL RESEARCH LABORATORIES

          The reasons the Department of Defense (DoD) maintains medical laboratories overseas are fairly clear: up until the 20th century, more combatants died from disease than from enemy action in every war in history. Even in this century, disease still has cost the loss of more soldier-days than has combat in every war. Military laboratories in the tropics are useful for field research on exotic diseases, for maintaining surveillance on diseases of potential military significance, for evaluating drugs and vaccines developed elsewhere, and for training medical staff to deal with diseases not generally found in the United States.

          The Department has had overseas facilities since 1900. Early efforts included the Yellow Fever Commission, with which Walter Reed was associated, and the Anemia Commission, which studied hookworm in Puerto Rico. The Army ran research laboratories in the Philippines from 1900 to 1934, and in Panama from 1936 to 1945. The Navy’s NAMRU system began in 1934 with a unit on the Berkeley campus. The first overseas NAMRU was set up in Guam during the Second World War. Since World War II, DoD has operated a total of 20 overseas medical research laboratories, units and teams for varying periods of time.

          At present, nine laboratories are functioning in the tropics. Five, in Brazil, Kenya, Malaysia, Thailand, and Pakistan, are US Army laboratories, and four, in Egypt, Indonesia and the Philippines, are Navy. The Navy labs are generally larger than their army counterparts, more broad-based and moderately self-sufficient. The Army lab in Bangkok is similarly organized, but the other Army units are small, more specialized, with limited objectives. The Army labs are administrative elements of WRAIR. They serve as branch laboratories for WRAIR research projects, and they have their own research programs as well. The Navy units report directly to the Navy Research and Development Command, a headquarters unit rather than a laboratory. This distinction allows the NAMRUs more autonomy in the field, but limits the scientific support and guidance that might be available to them if they had a home base laboratory.

          The overseas laboratories are operated by approximately 110 Americans, of whom 100 are military personnel, and 500 local staff. NAMRU-2, when operating out of Taiwan, benefited from a contract arrangement with the University of Washington, under which staff from the university were assigned to Taiwan for up to five years. This produced excellent scientific results, but the other military labs have not generally availed themselves of contract civilian workers.

          The origins of these labs and their primary missions may be briefly described as follows:

·            The US Army Medical Research Unit (USAMRU) - Brasilia was established in 1973 to identify new drugs to prevent and/or treat schistosomiasis. In 1978 the program was expanded to include a multidisciplinary study of the clinical, immunological, epidemiological, and vector transmission dynamics of malaria in the Amazon Basin.

·            USAMRU - Kenya was established in 1973 to pursue research leads concerning African trypanosomiasis that had been initiated at WRAIR. In 1979, a new program was added for the study of visceral leishmaniasis.

·            USAMRU - Malaysia was set up in 1948 by a figure familiar from the cholera story, J.E. Smadel, then at WRAIR. He was concerned with tests of the efficacy of new antibiotics in treating scrub typhus. In the intervening years, the unit made advances in the knowledge of arthropod-borne virus infections and leptospirosis. Scrub typhus remains the primary focus of concern.

·            The Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok is a joint operation with the Royal Thai Army. The US Army Component was set up in 1961, in a sense an outgrowth of the WRAIR involvement in the cholera outbreak of 1958-59. It was for a time a SEATO research center, but completely separate from the PSCRL. AFRIMS has six research departments: Medical Entomology, Bacteriology, Medicine, Virology, Veterinary Medicine, and Immunology. Its primary missions are to evaluate new drugs against naturally acquired drug-resistant malaria, to elucidate immunologic and entomologic aspects of the use of dengue virus vaccine, and to monitor all tropical diseases. AFRIMS is working closely with WRAIR on malaria, attempting to make a transition from an effective prophylactic drug to a new vaccine. AFRIMS has initiated work on Japanese encephalitis, which seasonally breaks out among children upcountry in Thailand, in collaboration with the children’s hospital. An expert in virology and neurology from Johns Hopkins University, a visiting scientist at AFRIMS, will attempt to validate a candidate Japanese vaccine that is available but not fully field-tested.

·            NAMRU-2, originally established at the Rockefeller Institute in New York, where the cholera “old boy” network originated, was by 1942 located in Guam. It was deactivated at the end of the war, to be revived again by Phillips in Taipei in 1957. In April 1979, after the US reestablished diplomatic relationships with Peking, NAMRU-2 was moved to Manila. Its mission is to conduct medical research on infectious diseases of military importance in the Western Pacific and parts of Southeast Asia. The program includes the epidemiology of hepatitis B infection, immunodiagnosis of parasitic diseases, gonorrhea sensitivity, surveillance for drug-resistant malaria, and virological, parasitological, and entomological surveys in the Philippines. As a footnote, after Phillips left NAMRU-2, cholera was determined to be a disease of no further military importance, and work on it ceased.

·            The NAMRU-2 Detachment in Jakarta originated in 1968 when a team was invited to investigate a plague outbreak in Central Java. Subsequently, the Minister of Health issued an invitation to NAMRU to establish a permanent laboratory in Jakarta. Research efforts have expanded to include work on scrub typhus, diarrheal diseases and enteric fever, gonorrhea, filariasis, and dengue.

·            NAMRU-3 was, as we have seen, an outgrowth of the US Typhus Commission set up in Cairo in 1942. This laboratory played a major role in averting a serious typhus outbreak during World War II. At Egyptian Government request, the Navy took over the lab and set up NAMRU-3, which was headed by Phillips at the time of the rogue cholera outbreak in 1948. The unit has remained in full operation since that time, despite frequent conflicts in the area and fluctuating relationships between the Egyptian and US Governments. At one stage, in 1967, diplomatic relations were broken, and NAMRU-3 found itself the only US government agency allowed to function in Egypt.

          A somewhat expanded account of NAMRU-3 may be useful here, made possible by a brief site visit in April 1985.

          The NAMRU-3 program is a blend of the interest of DoD with the disease priorities of the Egyptian government. In virology, both the military and the government have a high degree of interest in Rift Valley fever, West Nile fever, and dengue. NAMRU-3 has the only virology lab in Egypt with a p-3 level of protection. Ain Shams University, which has an AID grant for trilateral research involving NIH and an Israeli institution, has plans to develop its own p-3 facility, but uses NAMRU-3 labs now and will continue to want NAMRU collaboration when their own lab is functional.

          On bacterial diseases, the military and government interests diverge. NAMRU-3 works on cholera in Somali and Ethiopian refugee camps, but is discouraged from working in Egypt for fear of adversely affecting tourism. In Egypt cholera does not officially exist, but summer diarrhea, an identical malady, does.

          Other problems in the bacterial disease area require sensitivity. For example, clinical trials of drugs are often sensationalized by allegations of human experimentation. Among parasitic diseases, schistosomiasis is the major infectious disease problem for Egypt. It does not have a high military importance, but substantial research is done for the benefit of the host country. Malaria has a very high military priority, but is of minor interest in Egypt so studies are conducted in other parts of Africa.

          Problems between the lab and the Government sometimes arise because of differing cost horizons. Some drugs are considered by the Government to be too expensive ever to be afforded in Egypt, so experimental trials are resisted.

          NAMRU-3 must clear all publications and all planned field work with the government. The NAMRU commander indicated this posed few problems, but an Ain Shams investigator said his program often has opportunities for field research denied to NAMRU-3.

          The majority of NAMRU’s staff of 300 people are Egyptian. The scientific staff consists of a dozen each of Egyptians and Americans. No area of the laboratories is off-limits to Egyptians. NAMRU is able to accept five to ten Egyptian graduate students or interns per year, although training is not part of the mission of the lab. The students are guided by Navy scientists who retain academic affiliation with the Armed Forces University. The students must bring their own funding and be working on topics of interest to NAMRU. In general they contribute more than they cost scientifically.

          The library at NAMRU, the best medical library in Egypt though its collection is geared to the NAMRU mission, is open to graduate students to the extent space and library staff time permit. Around 50 students per day use the library, but 100-200 would like to do so.

          A new laboratory building, completed only a year ago at a cost of about $10 million in PL-480 blocked currency, and $4.5 million in hard currency for equipment, sets NAMRU-3 apart from the other military labs overseas. Unfortunately, the operating budget and ceilings of NAMRU-3 were not raised to take advantage of the new facility so it is at present seriously underutilized.

          The NAMRU-3 commander has authority to compete for external funds beyond the DoD budget, and has in fact won a Clark Foundation grant for research on trachoma. Funding is not the limiting factor at the moment, however; it is staff.

          Three other military laboratories, located in the Congo, Uganda and Ethiopia, have had to close due to changes in host country political relationships with the United States. In general, however, the military laboratories seem among the most popular of American institutions abroad, as demonstrated by the continued welcome of NAMRU-3 in Egypt and of AFRIMS in Thailand, when other US military units were asked to leave in 1976.

          The cost of maintaining the seven facilities abroad in 1980, including military pay and special foreign currency allocations, was approximately $6 million. In the late 1970s, the overseas laboratory system of the military services came close to extinction. Ambassadors complained that the number of official Americans attached to their embassies from other agencies was often burdensomely high. In order to cut expenses and lower the official profile abroad, the Office of Management and Budget (OMB) instituted a manpower accountability system known as MODE (Monitoring Overseas Direct Employment). MODE teams reviewed the status of official representation in six of the countries in which DoD had labs. In the reports of two of these teams, the labs were not mentioned. In the other four, the review specifically recommended that the DoD medical research laboratories staffing not be reduced. At the end of the process, however, these recommendations were ignored, and DoD was directed to prepare for the elimination of the overseas laboratories through closure or conversion to contractor operation. At no point in the process were the value and quality of the labs questioned; at issue was simply a numbers game concerning official Americans abroad.

          The DoD responded by conducting an exercise culminating in a report by Col. Phillip Winter that made a solid and persuasive case for maintaining the laboratories under direct military control. A group of distinguished civilian scientists agreed to serve as consultants to the study, and their statements contain the main arguments of the DoD case. They reviewed the history, missions and functions of the laboratories, and some of them visited four of the overseas locations: Kenya, Indonesia, Egypt and Thailand. Appendix A contains brief summaries of scientific accomplishments at these laboratories.

          The Winter report concluded that contracting out the operation of these laboratories would be neither desirable nor feasible. They found no evidence that changing the mode of operation of the labs would increase productivity or efficiency, or produce savings of manpower or dollars. To the contrary, they found that contractor operation would decrease the research productivity of the units, increase costs and administrative problems, degrade the ability of the labs to respond to changing military requirements or emergencies, deprive the DoD of valuable recruitment, retention and training incentives, and incur unfavorable host-country reactions.

          The report does not pretend to be an objective document; it is a marshalling of arguments for retaining the overseas laboratory system as it was and is. The quality of the consultants and the cogency of their statements nevertheless make a compelling case for the DoD position. One of the most comprehensive statements was made by Dr. John R. Seal, co-author of the source book we used on cholera and formerly commander of NAMRUs 3 and 4. Seal was at the time Deputy Director of the National Institute of Allergy and Infectious Disease (NIAID) at NIH, and had direct knowledge of the ICMRT program. In his letter of support for the overseas laboratories, Seal goes into some detail in comparing their effectiveness with that of the ICMRT laboratories. We will consider his position in some detail in connection with the latter program, but it should be noted here that he thought few universities have the capacity to conduct multidisciplinary research programs in infectious diseases abroad, and none can mount as broad a program as carried out by the largest DoD labs overseas, those in Cairo and Bangkok. Nor did he think contractors could be found with the staff or experience to conduct an acceptable program to meet military needs.

          Other testimony of note included statements by the president and research director of two prominent pharmaceutical companies, to the effect that contracting out to private industry would not provide a satisfactory substitute for the military labs abroad. The reasons cited mostly have to do with skill shortages and career patterns. There is not now a surplus of qualified scientists and clinicians who could be engaged to conduct the work of the labs abroad. Competent scientists who are available would risk career disadvantages by taking an assignment abroad for a year or two. The military services would be deprived of the pool of trained and experienced tropical disease specialists that the system now produces.

          Among the unsolicited comments cited in the Winter Report is one from Professor Thomas Weller, Nobel Laureate and head of the Department of Tropical Public Health at Harvard University from 1954 to 1983. Prof. Weller, too, concentrates on the skilled manpower issue. He points out that there is a global shortage of specialists with knowledge of tropical diseases, particularly epidemiologists, pathologists, medical entomologists, and medical malacologists. Few academic institutions, he notes, have faculty qualified in the scientific disciplines basic to the study of tropical diseases, and no U.S. academic institution could provide from its ranks the equivalent of the scientific staff of the Navy lab in Cairo. Even an academic consortium, if one were formed to take over a laboratory, would be faced with providing dual salaries, to cover the discipline in the parent institution while the alternate was abroad; salary guarantees upon return home for those who accepted service overseas; and staffing complications from family factors and academic pressures for publication.

          Turning to our comparative framework, we can make the following points about the military labs abroad:

1. Scope of the Program

          The military labs, and the R & D Commands of which they are a part, are responsible for a very broad range of actions along the spectrum. They conduct biomedical research on the nature of disease organisms, clinical research on the effects of a disease on people, epidemiological research, and drug and vaccine development and testing. Their mission is not complete until they find the means to protect American servicemen from the deleterious effects of diseases.

          In pursuing their mission, the military labs generate a great deal of knowledge useful to host country scientists and health practitioners, and this knowledge is freely shared. This range of action and responsibility, broad as it is, does not of course cover the spectrum. The military labs do not need to concern themselves with the sociological problems of the village, or the economic problem of finding low-cost preventions and remedies.

2. Degree of Collaboration

          The nature and extent of collaboration with local scientists and institutions by each military laboratory abroad varies from country to country:

·            USAMRU-Brasilia is fully integrated into the Nucleo de Medicine Tropical of the University of Brasilia. A small number of USAMRU researchers work under the direction of Professor Aluzia Prata, head of the Nucleo.

·            USAMRU-Kenya has strong ties with the Kenya Institute for Medical Research where it conducts collaborative research on visceral leishmaniasis. It is also linked with the Kenya Trypanosomiasis Research Institute at Mugugu.

·            USAMRU-Malaysia conducts collaborative research with the Malaysian Institute of Medical Research on the immunology and epidemiology of scrub typhus and vector chiggers.

·            AFRIMS-Bangkok is really a two-country laboratory. The Thai military component shares the same quarters as the American component, but each tends to conduct its own research. Vaccine trials have been conducted in cooperation with the Thai military medical staff. Additional collaboration occurs with Mahidol University and with the children’s hospital across the street from AFRIMS on Japanese encephalitis.

·            NAMRU-2 in Manila has collaborative relationships with the San Lazaro Hospital, the Bureau of Research and Laboratories, the Schistosomiasis Control Council, provincial and city health departments, the University of the Philippines Medical School and Institute of Public Health Veterans Hospital, the Santo Thomas University Hospital, the Subic Naval Hospital, and the Clark Air Force Base Hospital. 

·            The NAMRU-2 Detachment in Jakarta uses laboratory space provided by the Ministry of Health in the compound of the National Institutes of Health, Research and Development (NIHRD) and the Communicable Disease Center. Collaborative working relationships are maintained with the NIHRD, the CDC, provincial and city health departments, the Indonesian Navy, the University of Indonesia Medical School and Hospital, the Sumber Waras Hospital, and the University of Gadja Mata Department of Microbiology. Program content is subject to approval by a joint US-Indonesia coordinating committee.

·            NAMRU-3 was considered by Egyptian officials interviewed by the Winter team to be one of Egypt’s major health assets, the leading local institution for training in medical research. Since 1945, all Egyptians of note in medical research have trained or worked at NAMRU-3 at some time in their careers.

          NAMRU-3 collaborates closely with Ain Shams University, the Egyptian Vaccine Institute, and the Abbassia Fever Hospital. Outside of Egypt, NAMRU-3 cooperates with the ministries of health and agriculture in both Sudan and Somalia.

3. Results:  Impact on Disease

          The most famous contribution overseas of the military to the control of disease was of course made by Walter Reed in Cuba at the turn of the century. His work helped Col. William Crawford Gorgas to control yellow fever and malaria, and made possible the construction of the Panama Canal.

          Less dramatic but perhaps even larger-scale results flowed from the work of the U.S. Typhus Commission laboratory in Cairo. In World War I, six million deaths were attributed to typhus fever. To forestall a similar tragedy, President Roosevelt set up the Commission in 1942 with members from the Army, Navy and the Public Health Service. The Cairo lab was instrumental in curtailing a typhus outbreak in Egypt and a serious epidemic in Naples. In addition, the lab isolated various strains of typhus organism from Africa, Asia and Europe and sent them to the US for testing against vaccines. The lab first field-tested DDT as an insecticide against lice, the vector of typhus.

          We have already noted the contribution of NAMRU-2 to the development of effective therapies for cholera, including early work on oral rehydration. Other contributions singled out by Winter’s consultants include major advances in our understanding of the etiology, diagnosis, treatment and prevention of chloroquine-resistant malaria, several major viral diseases including dengue and Rift Valley fever, cerebrospinal fluid meningitis, hemorrhagic fever, schistosomiasis and leishmaniasis. A full list of accomplishments identified by the labs themselves in the Winter report is attached as Appendix A.

          Impressive as these contributions are, it seems apparent from the presentations of the consultants, and the unsolicited comments of other experts cited in the report, that greater value is assigned to the ability of the laboratories to develop medical manpower with experience and understanding of tropical disease, and to monitor disease status in strategic areas of the world. Research results per se, while not ignored, were stressed by few of the expert authors.

4. Results:  Capacity Building

          The utility of the DoD overseas laboratories in strengthening American capacity to understand and deal with tropical diseases is summarized in a report to the President in 1978 in the following terms:

          “DoD overseas laboratories offer on-site opportunities for understanding the prevalence, transmission, and reservoirs of disease that occur in tropical and subtropical areas. DoD laboratories serve as a base for specialists to become familiar and maintain familiarity with these diseases, which are not generally found in the United States. The laboratories assist medical personnel to maintain an inventory of medical capabilities and population disease profiles in several developing countries. They also permit essential in-country field-testing and evaluation of drugs and vaccines that have been developed against diseases that occur overseas. Such tests and evaluations are done as joint efforts with health authorities of the host countries.”

          The requirement that the overseas labs study only diseases of potential military importance is a constraint; for example it limits attention to childhood diseases, but in general it is not an onerous restriction in terms of the selection of maladies for investigation. The priority assigned to military matters is probably a greater constraint on the amount of effort the laboratories make to strengthen local capacities for work on tropical diseases.

          The discussion of collaborative arrangements above makes it evident that the military laboratories do contribute to strengthening local capacity in a variety of ways. The smaller labs function within or in direct association with local institutions, which benefits the latter through collaborative association, provision of equipment, and training. AFRIMS strengthens the medical research capabilities of the Royal Thai Army, although it has less of an impact on the university-based research community. NAMRU-3 in Cairo, as already noted, performs a valuable training function and maintains the best medical library in Egypt.

          It is to this area of strengthening local capacities, however, that most suggestions for improving the work of the overseas military laboratories are frequently directed. While noting that the military labs have many benefits for the countries in which they are located, the 1978 White House report suggests that more Third World medical personnel could be trained in these facilities. In addition, if additional resources could be made available, the functions of the laboratories could be augmented by a clinical role. The report recommends that one or more laboratories should test, on a pilot basis, the expanded role of becoming a regional center for clinical tropical medicine, research, and training. In this way, the report asserts, the great trust and good will DoD has built up with these laboratories abroad can be utilized for fostering the humanitarian goals of the United States. 

Conclusion

          The balance sheet on the overseas military labs is strongly positive. They operate across a broad range of activities concerning tropical diseases, from monitoring their occurrence to biomedical and clinical studies, epidemiology, and the development of preventive and therapeutic measures to protect members of the armed forces. They create a career corps of active specialists in tropical medicine within the military, and are able to dispatch trained teams on short notice to remote areas of the world. They are generally welcome additions to the American presence abroad in the countries where they are located. The chief reservations concerning the system seem to be that the vast potential benefits of these overseas installations may not be currently realized due to limitations of funds and the narrowness of their scientific mandates. In the future, it may be anticipated that the military nature of the facilities could become a liability, particularly if efforts were made to expand their functions.