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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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