COLLABORATIVE RESEARCH ON TROPICAL DISEASES (1985)    p. 1 of 12

         This commissioned draft paper was prepared by Courtney Nelson for the Board on Science and Technology for International Development, National Academy of Sciences.  It is based largely on secondary source material and interviews with several key participants in some of the programs described.  A final version of the paper will be prepared as an annex to the Academy’s Study of U.S. Capacity to Address Tropical Disease Problems.

I.  INTRODUCTION

          Tropical diseases seem to many of us like tribal warfare: difficult to understand, definitely to be avoided, and not really our business.  It turns out, surprisingly perhaps, that American science has much to offer in the struggle against these diseases, and that our national interests combine with our humanitarian impulses to make a strong case for doing more about them.  

 

Benares, India        1955

          The National Academy of Sciences is conducting a study of the U.S. capacity to address tropical disease problems.  The study will look at manpower available to deal with clinical, public health/disease control, and basic science aspects of tropical diseases.  It will also include profiles of the major institutions in which these people work.

          This paper, which will serve as annex to the main study, describes some of the programs and overseas facilities through which American capacity is or has been directed to combat tropical diseases.  Emphasis is placed on collaborative processes and relationships because it seems clear that access to endemic areas, so vital to the maintenance of an experienced cadre of experts, must be based on genuine collaborative research with Third World scientists.

          The creation and maintenance of a cadre of experienced researchers is, however, a minimalist objective for a country such as ours, possessing such a disproportionate share of the world’s medical research capacity.  The programs described below illustrate the ability of American individuals and institutions in some circumstances to ease the disease burdens of thousands or even millions of people at rather minor cost.

          The following account is written in non-technical language in the hope of attracting a wider audience than would normally attend to esoteric diseases.  Let us look first at cholera, an unfinished story of combat with a disease that terrified mankind.  Many of the programs and institutions we will scrutinize later are seen in action here. (1) 

(1)  The following section is based, unless otherwise noted, upon Cholera:  The American Scientific Experience, 1947-1980, by W.E. van Heyningen and John R. Seal. 

II.  THE CHOLERA STORY

A.  ORIGIN AND NATURE OF THE DISEASE

          Cholera is a disease with a definite home base and only an occasional urge to travel.  The base is the Ganges delta, northeastern India around Calcutta and areas of Bangladesh.  Cholera is always present in this area, thriving in the warm, moist climate.  Exactly why it bursts out into the rest of the world in brief but terrifying raids is still not known.  Curiously, cholera pandemics seem not to have occurred before the nineteenth century, and to have occurred at all only seven times; once in this century.

          A cholera pandemic must have been a horrible thing because of the suddenness of the incursion, the high mortality rate, and the grisly impact it had almost immediately on its victims.  The fourth pandemic of 1863, for example, which reached Europe by means of pilgrims through Mecca to Egypt, Constantinople and thence to Italy and France, killed a half million people on the continent.  It also reached the United States for the third and last time, where it killed about 50,000 people.  Earlier epidemics in 1829 and 1849 left approximately 100,000 dead each time.  Later pandemics, in 1881 and 1889, reached Europe, but affected many fewer people.

          Cholera was not the greatest killer of the time -- many more died in the United States of malaria and tuberculosis -- but it wondrously focused the medical mind because of the panic it spread.  The onset of the disease is abrupt, involving diarrhea and vomiting to the point of severe dehydration.  Victims appear “cadaverized” in a short time, their bodies drained of water so that their eyes sink into their sockets, the flesh sags and wrinkles, and the skin color becomes leaden.  Yet the mind remains clear, fearfully aware of the deterioration of its surroundings.

          The sudden appearances of the disease in Europe, where it was considered the worst thing to happen since the plague of the Middle Ages, led to observations and experiments of remarkable acuity which sometimes faded from the scene like the disease itself, having to be rediscovered or re-observed at a later date.  The bacterium that carries the disease, for example, was observed by the Italian Filippo Pacini around 1853, but it was discovered anew by the great German bacteriologist Robert Koch in 1883.

          Koch supposed that the cholera bacterium sent a poison into the body that acted in some systemic way on the patient, as was known to be the case with tetanus, diphtheria and botulism.  This turned out to be an error: the poison acts on the walls of the small intestine, inhibiting the absorption of water into the system and facilitating the flow of water into the intestine.  The discovery of the cholera toxin took another 75 years after Koch began the search. Then an Indian scientist, S.N. De, conclusively demonstrated that the damage to the body was caused by an exotoxin, rather than an endotoxin as Koch had supposed.

          For tetanus and diphtheria, the discovery of the toxin led quickly to production of a vaccine to ward off the disease.  This has so far not occurred for cholera, although efforts have continued since the toxin was discovered.  Prevention of cholera in Europe followed the demonstration by John Snow of Britain in 1853 that the disease was transmitted through water contaminated by sewage.  This led throughout Europe to important improvements in sanitation.

          The idea of treating the disease by rehydration was also conceived during the early pandemics.  In Moscow in 1830 or thereabouts, two German expatriates, Jaehnichen and Hermann, had the idea, based on the chemical analysis of the blood and stools of cholera patients, of injecting water and acids into the blood stream.  Their attempts to do this were, however, unsuccessful.  In London, in 1831, a young physician named O’Shaughnessy proposed injecting water and salts into the blood stream, rejecting Hermann’s notion that acids were lost from the disease.  O’Shaughnessy took a job with the East Indian Company and worked no more on cholera, but his ideas were tried in 1832 by a Scottish physician named Thomas Latta.  Latta succeeded in reviving an aged female patient who seemed at death’s door.  Within a half hour she was free of discomfort, her features restored, and convinced that all she needed was a little sleep.  Latta himself needed rest and retired.  The patient soon again experienced vomiting and diarrhea and died before Latta was informed of her change in condition.  He was convinced that she could have been saved if the rehydration had been continued.

          These early attempts at rehydration, while promising, could not easily have succeeded.  Intravenously injected water, alone or with acetic acid added, as proposed by the expatriate Germans, did not replace the essential minerals also lost from the blood.  The use of unsterilized saline and undistilled water by Latta could have led to septicemia and high fever.  Latta died the following year, and cholera retreated from Europe of its own accord.  The medical community became convinced that rehydration merely postponed the effects of the disease and prolonged suffering.

          The virtual disappearance of cholera from Europe and the Americas by the end of the nineteenth century meant that Western medicine had little concern for the problem, except for those few physicians and scientists working in the Orient.  One of these, Sir Leonard Rogers, a professor of pathology at the Medical College of Bengal in Calcutta before the First World War, had the idea of using an intravenous solution twice as salty as normal when rehydrating cholera patients, in order to restore circulation while preventing a recurrence of diarrhea.  His reasons for trying this solution have since been faulted, but the fact is that his method cut the fatality rate in half, from 60% to 30%, of those treated in the hospital.

          In Manila about this time, Andrew Watson Sellars, an American, experimented with sodium carbonate and sodium bicarbonate solutions similar to those proposed by O’Shaughnessy and tried by Latta in 1832.  Sodium bicarbonate proved effective, and using it in Calcutta Rogers was able to bring the fatality rate down to 20%.  There the death rate remained, for those fortunate enough to have access to intravenous treatment in sanitary conditions, until after the Second World War.

B.  AMERICAN INTEREST IN THE DISEASE

          American medical science had not yet come of age in the mid-nineteenth century.  Despite three serious cholera epidemics, no major contributions to knowledge arose from the painful experience.  The Marine Hospital Service dispatched Dr. Joseph Kinyoun to Europe to find ways of studying cholera and other infectious diseases.  He visited the famed Professor Koch, and returned home with Zeiss’ latest microscope to set up The Hygienic Laboratory, the precursor to our National Institutes of Health, on Staten Island in 1887, but its concerns soon shifted from cholera to other diseases. (2) Corning, pp 11-15

          A significant chance encounter between cholera and one of the key figures in our story took place in Cairo.  Robert A. Phillips, a medical scientist, joined the Naval Reserve in 1940 and was assigned in 1944 to work at a newly established Naval Medical Research Unit (NAMRU) at the Rockefeller Institute in New York.  Among his colleagues were several scientists who became important to the cholera story in later years.

          Phillips, NAMRUs, and Rockefeller Institute scientists weave in and out of the cholera picture for the next 30 years, but at that time they were working on problems of body fluid balance in connection with transfusions.  These studies required a reliable method of determining the specific gravity of blood that could be carried out under field conditions with minimal equipment.  The techniques they devised later played a critical role in determining the degree of dehydration in cholera patients.

          Later in 1944, Phillips was assigned to an American facility in Cairo to work on typhus.  After the war, this laboratory was turned over to the Navy and designated NAMRU-3.  Phillips returned to Cairo to become its first head in 1947.  His return was followed within three months by the first outbreak of cholera to hit Egypt since 1919.

          The disease raged through the delta to Cairo and up the Nile Valley, causing 30,000 cases and 20,000 deaths in under three months.  Phillips and NAMRU pitched in.  Using the field-tested specific gravity techniques and biochemical analysis to determine the amounts of rehydration necessary and appropriate, they reduced the death rate of those treated from the 20% achieved by Rogers to 5 to 7 1/2%, a relatively quick return on the transfer of technology.

          Phillips had wanted to do more accurate balance studies on the patients, which would have required limiting fluid intake to intravenous means so they would not induce vomiting, and the loss of fluids could be carefully measured.  His colleagues considered it inhuman to deny drinking water to patients, so this experiment was delayed until 11 years later in Bangkok, when Phillips, assisted by Raymond Watten, balanced intravenous input with measured fluid output and reduced the mortality rate to .6%.  Here again, work on cholera benefited from a transfer of technology.  Watten had worked in San Francisco on one of the first artificial kidneys, which required very careful studies of the balance of intravenous input of electrolyte and fluid and output by the kidney, and losses through respiration and perspiration, with nothing given by mouth.

          The possibility of bringing knowledge and experimental techniques developed for other purposes to bear on tropical diseases is of course one of the main reasons US involvement can be so beneficial.  Two other notable examples occurred in Bangkok in 1959.  Eugene Gangarosa had worked with Colonel W.H. Crosby in the development of a device that could be passed through the mouth, the esophagus and the stomach into the small intestine and there obtain a biopsy sample of the lining that could be used for microscopic and biochemical studies.  Use of the Crosby capsule helped settle the debate over what actually happened to the wall of the intestine during active purgation.

          The other example is that of Robert Gordon, an NIH scientist who had been studying the permeability of the intestinal tract to proteins in a variety of diseases.  By the intravenous injection of a radioactive molecule about the size of a protein molecule, he was able to show that the wall of the intestine remained sufficiently intact to block passage of proteins.  The conclusion of Gordon’s and Gangarosa’s work was that the lesion of the intestine that occurred in cholera was biochemical and invisible.

C.  WHY THAILAND?

          But what brought all of these knowledgeable people to Bangkok in 1958 and 1959?  Certainly not the size of the outbreak, nor its rarity.  Cholera outbreaks occurred every year in the Ganges delta, often twice a year, and of greater magnitude, but they attracted little Western scientific attention.  The Bangkok outbreak, in two seasons, killed 2,372 people, a significant but not startling number.  The previous incursion of cholera into Thailand, a decade earlier, had resulted in 13,000 deaths.

          Van Heyningen and Seal offer clues to the motivations of several of the actors in the Bangkok outbreak, but no satisfactory explanation of the magnitude of the US response.  It is clear, however, that the events of the day heralded the beginning of an explosion of knowledge about cholera and other diarrheal diseases, and revolutionary advances in therapy.  It may, therefore, be worth reviewing who was there from the American medical establishment and how they came to be present.

          The first year, 1958, Phillips and his NAMRU crew were there, and the renewed outbreak in 1959 brought teams from the Walter Reed Army Institute of Research (WRAIR), the National Institutes of Research (NIH), and the Jefferson Medical College of Philadelphia.

          Phillips’ motivation is fairly clear; he had been interested in cholera since his first exposure in Cairo.  In the mid-1950s he went to Taipei to set up a Pacific NAMRU to work on tropical diseases.  There was no cholera in the area of interest at the time, but in 1958, the year after the unit was commissioned, Dacca experienced an unusually heavy outbreak, which was expected to and did spread to Thailand.  NAMRU-2 was ready to move when cholera hit Bangkok on May 23, and the team, in collaboration with the staff of Chulalongkorn University, quickly succeeded in learning rehydration procedures that reduced the mortality rate of those treated to .6%, as discussed above.

          There are differing versions of how the other organizations came to Bangkok when the disease broke out.  Phillips is reported to have alerted other federal services to the recurrence and invited their participation.  The Army perhaps felt their unit in Malaysia should have been involved in the first place because it was closer to the scene than Taipei.  A personal friendship between Kenneth Goodner of the Jefferson Medical College and one of its graduates, who was then a high official in the Thai Ministry of Public Health, prompted an official invitation for assistance.

          Who invited whom is thus a bit unclear, but perhaps the more important questions are who authorized the expenditure of time and money, and why?  The answer to the first question takes us back to the Rockefeller Institute, where Phillips got his start.  The talented group of medical researchers working there during World War II went on to become influential policy-makers and administrators in the Washington medical research establishment.  Seal refers to them as The Inner Circle, a group held together by common experience and interest in tropical diseases.  They included James Shannon, Director of NIH; Joseph Smadel, Associate Director of NIH for Intramural Research; Colin McLeod, then a professor at the University of Pennsylvania and later Deputy Director of the White House Office of Science and Technology; Theodore Woodward, professor at the University of Maryland; and Goodner.  Tangential to the Inner Circle were Richard Mason, Director of WRAIR, and several members of the Armed Forces Epidemiological Board.

          The importance of the interest this powerful group took in cholera to the size of the subsequent US research effort is indisputable, but what prompted the original interest is not so clear.  Some of them had been involved in devising a cure for scrub typhus and an immunization procedure found to be highly effective against both typhoid and scrub typhus.  As participants and leaders of “the Great NIH Take-Off” after the War, when its budget was growing by 15 to 20% per year, they may have been uncomfortable with the overwhelming emphasis placed on degenerative diseases, to the near total neglect of tropical maladies.  They may have been intrigued by communications from another of the old boys from the field, Robert Phillips.  Or they may simply have displayed the quality of leadership that perceives opportunities to benefit mankind as an important perquisite to the exercise of power.  In any case, their interest in cholera, first evident in the US response to the Bangkok outbreak, continued throughout their careers.

          Leadership and vision are, alas, seldom enough to produce action in agencies of government; also required are justifications in terms of Congressional authorizations for the expenditure of funds.  It seems most likely that Thailand’s proximity to Vietnam explains the extraordinary attention paid to the relatively minor outbreak of cholera there, as compared to the indifference its annual occurrence aroused on the Subcontinent.  Vietnam split in two in 1954, and by 1958 was clearly destined to become a trouble spot.  An American build-up occurred in Thailand in 1955-57.

D.  THE SEATO CENTER

          SEATO, the Southeast Asia Treaty Organization, was a military alliance formed in 1956 to give Western backing to the Asian front-line states, Pakistan, the Philippines and Thailand, in containing communism.  In 1958, the year of the cholera outbreak in Bangkok, the treaty was broadened to include cooperation on economic and social matters as well as military.  This new clause in the treaty gave rise to a suggestion by Phillips to the State Department officer handling SEATO affairs in Thailand that a medical laboratory modeled on NAMRU be set up in Bangkok for research on cholera.  Phillips, in response to encouragement, drew up a proposal for such a center, including a budget of $400,000, half for buildings and half for equipment.

          This amount was soon earmarked by the International Cooperation Administration (ICA) for the laboratory, but some confusion arose over how in fact to spend the money.  ICA did not wish to become mortgaged to paying the recurrent costs of a laboratory for years into the future. 

          NIH, upon being informed of the existence of the earmarked sum by Clifford Pease of ICA, formed an ad hoc committee and devised a research program on cholera that would use the money over three or four years, for university-based research in the US under contract to NIH, for field studies combined with laboratory work on cholera epidemiology, and for field trials of cholera vaccines.  The fieldwork might best be done in Calcutta in collaboration with the World Health Organization (WHO).

          Two things were wrong with this idea: India was not a member of SEATO, so the funds could not be spent there, and the State Department wanted visible evidence of our concern for the disease.  The Department wanted an edifice in a SEATO country, not a research program in American universities.  In the end, the creation of an institution was almost certainly more beneficial to the struggle against the disease than a research program would have been.  Research programs can quietly dry up and disappear when the initial funds run out.  An institution, particularly a productive one, creates continuing demands of its own, as ICA had feared.

          A team of six from the ad hoc committee toured the region in late 1959 and wisely decided that the laboratory should be in Dacca, where cholera was endemic.  An excellent building was found, empty because of a fall in the price of jute, and the Pakistan Government was eager to supply the space and local personnel.  ICA funds held over from a previous year could not be spent on personnel, so three positions from the National Heart Institute were assigned to the project.  ICA, which became AID in 1961, passed its funds through NIH for administration.  The problem of recurrent costs was in part met by funds from the AID office in Pakistan, but a more important source turned out to be blocked currency, newly available to NIH through PL-480.  Thus the Pakistan SEATO Cholera Research Laboratory (PSCRL) was launched, without, it should be noted, a single dollar of SEATO funds.  SEATO deserved its spot in the title, however, because without its political/military rationale, the PSCRL would not have come into existence.

          Other SEATO member nations were invited to contribute to the PSCRL.  The UK and Australia did so, thus earning seats on the Directing Council.  The structure of the PSCRL was modeled by its first director, Fred L. Soper, on the Institute for Nutrition for Central American and Panama (INCAP), which he had earlier founded.  This created an autonomous organization with its own Directing Council and Technical Committee.

          Our friends from the Inner Circle changed hats from the ad hoc committee to a Cholera Advisory Committee, established to advise the Director of NIH on technical aspects of the project.  Smadel was the first chairman.

          Getting all these pieces to fit understandably took time, so it was well into l962 before the PSCRL was really operational.  By then, the 7th and current pandemic was spreading in Asia.



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