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SCIENCE KNOWS NO COUNTRY:
THE CONTRIBUTIONS OF THE NATIONAL INSTITUTES OF HEALTH

TO TROPICAL MEDICINE RESEARCH

"SCIENCE KNOWS NO COUNTRY because knowledge belongs to
humanity, and is the torch which illuminates the world."

Louis Pasteur, 1876

By

Richard M. Krause, M.D.
Director, National Institute of Allergy
and Infectious Diseases, NIH

Bethesda, Maryland

Presented at
The Anglo-American Conference on Tropical Medicine
12-14 December 1977
The Royal Society of Medicine

1 Wimpole Street, London
In 1876 at the International Congress of Sericulture in Milan, Italy,
Louis Pasteur gave a toast at the banquet. In that toast Pasteur said, "Science
knows no country because knowledge belongs to humanity, and is the torch which
illuminates the world. ul In a sense these remarks enbody the theme of this
Conference. They are also the philosophical foundations on which the National
Institutes of Health is basing its strategy for future research on tropical
diseases. |

This position has also been embraced by President Carter who in his message
to the Thirtieth World Health Assembly in Geneva last May, supporting the WHO
Tropical Diseases Research Program said, "these efforts will bring us closer to
our goal: a world in which all people can live free fram fear of crippling and
debilitating diseases." And more recently, Dr. Peter Bourne, Special Assistant
to the President for Health Issues, reiterated the President's position ina
speech to the American Public Health Association. He refers to "the new aware-
ness of global interdependence and a commitment by the President to a new world
partnership directed toward meeting the basic human needs of people everywhere. n3

At this Conference we have focused primarily on malaria and schistosomiasis,
and rightly so. These diseases are among the most seridus, widespread and
intractable problems in tropical medicine. Surely our future research strategies
for malaria and schistosomiasis will be a model for the larger task embracing

health in all its aspects.

lrranslated by Professor René J. Dubos.

“president Carter's Message to the President and Members of the Assembly
Meeting in Geneva, Switzerland. Dated May 5, 1977. Released 9, 1977.
3y.S. Global Health Strategies in an Age of Interdependence. Address of
Peter Bourne, APHA Annual Meeting, October 31, 1977.
In these remarks on the contributions of the United States' National
Institutes of Health (NIH) to the strategies of the future concerning tropical
medicine, I shall limit myself primarily to the research programs of the
National Institute of Allergy and Infectious Diseases (NIAID). This Institute
ig responsible for the bulk of the research at the NIH on the diseases of the
WHO Tropical Diseases Research Program. I should note that we also have
responsibility for a broad range of other infectious diseases which are peculiar
to tropical countries and the developing world, and while this falls heavily on
the Institute of which I am the Director, other components of the NIH are also
engaged in these areas. So I am speaking today for the NIH as a whole.

Furthermore, what the United States Government does about tropical medicine
will not be done by the NIH alone. For those of us, like myself, who have just
been introduced into this world of overlapping government agencies - and I am
certain it must be true for those of you who view the American scene from afar -
there seems to be a display of divergent objectives and a cacophony of dissonant
voices. There is, fortumately, less thrashing about inside the system than
appears to be the case from the outside. Over the years there has amerged a
reasonable, although certainly not perfect, delineation of responsibilities.

For exampie, the NIH has primary responsibility for the generation of new medical
knowledge; the Center for Disease Control has primary responsibility for implemen-
tation of procedures and programs to monitor, detect and control the occurrence
and outbreaks of disease; and the Agency for International Development has respon-
sibility for the development of health resources in the developing world.

So the business of the NIH is the generation of new medical knowledge through

biomedical research. Such new knowledge must then be applied by a process now
called technology transfer. It is at this very point that a major policy issue
arises throughout the health enterprise. That policy issue concerns the distri-
bution of the resources between biomedical research on the one hand, and the
application of knowledge to prevent and treat disease on the other. And this

is being intensely debated in the scientific and medical community both within
and without the United States' Government. We should not minimize the divergence
of views which prevails on this issue. The divergence prevails in Congress, it
prevails in the Executive Branch of the Government, it prevails in the Institute
of Medicine. It is not surprising, therefore, that this policy debate on the
distribution of resources between biomedical research and the application of
knowledge colors discussions concerning the future objectives of our policies
pertaining to tropical medicine.

But I, personally, take comfort in the vigor of this debate. It reflects
a genuine concern for the complex issues pertaining to medicine and health.

And we should recognize too, that this disagreement is an old argument. Science
has lived with it from the very start of our modern age, and in my view, we
should not get hung up on the technicalities of the issue. I will, in the
course of my remarks, make a case for both biomedical research and the applica-
tion of knowledge in instances where both are clearly necessary. Then I would
suggest we let the middle ground sort itself out.

When this controversy produces more passion than reason, I myself take
reassurance from the wisdom of men of the past who also were caught up in this
argument. Many of you know that Benjamin Franklin - in addition to his career
as a printer and a writer and a representative of the colonies to the Courts

of England and France - was also a bit of a scientific tinkerer. We learned
as school children about his experiments to probe the mystery of electricity

by flying a kite during a thunderstorm. On yet another occasion, when describing
a series of experiments, he was asked at the end of a lecture, what good could
there possibly be in such knowledge? Franklin's immediate response, "What is

the purpose of a newborn babe?"

Faraday was involved in a similar exchange shortly after his discovery of
electromagnetic induction - not too far from here actually, at the Royal Insti-
tution. He was demonstrating this new phenomenon to the Prime Minister. The
Prime Minister asked the question, "What is the possible purpose of your new
discovery, Dr. Faraday?" To which Dr. Faraday quickly replied, "Mr. Prime Minister,
some day you will use it as a source of taxes." And indeed, this has came to
pass with heavy tax rates on electrical utilities.

During his life Pasteur, too, was drawn into the vortex of the argument
over basic research and the application of new knowledge, and spent much time
circulating this dipole. But he was content with his belief that "there are
science and the applications of science, linked together as the fruit is to the
tree that has borne it." .

In these comments I shall make two points concerning the NIH strategy for
the future. The first point concerns an inventory to determine the tropical
diseases which are currently controlled by existing public health measures and
those other diseases which will require additional biomedical research before
control is achieved. My second point deals with what I have termed the syner-
gistic application of new discoveries of biomedical research to conventional
public health measures for the control of tropical diseases. I shall then close

with four specific proposals on NIH initiatives for the future.
Last April, when I gave the Annual Geographic Medicine Lecture at Case-
Western Reserve University School of Medicine, I discussed what in my judgment
was the first order of business in overall strategy for an attack on tropical
diseases. With no claim to originality, I suggested that we examine tropical
diseases from two points of view. First, identify those diseases for which
application of known social, economic and public health measures would provide
effective control now; and second, identify those other diseases for which
there is little’ likelihood that in the foreseeable future application of socio-
economic and public health measures will have any appreciable, beneficial
impact. In these latter cases, we must be prepared to devote research manpower
and research resources to develop new diagnostic procedures, new therapy and
new preventive measures. I recognize of course that complex diseases such as
those that occur in the tropics do not break out neatly into one category or
another. Few things are that simple. It is also true that because of social
and other environmental factors it may not be possible to apply the same scheme
for any single disease on a worldwide basis.

It is entirely likely that a tropical disease controllable in one country
by currently available means would be impossible to contain in another. Let me
illustrate. We have been told that in China, intensive application of public
health and sanitation procedures has gone far to eliminate the problems of
schistosamiasis. Similarly, schistosomiasis has decreased dramatically in
Puerto Rico. But in Egypt, on the other hand, a lifestyle dating back to the
time of the pharaohs, is so ingrained - so keyed to the rise and fall of the Nile
and the irrigation of the canals - that one suspects it may be difficult, in cur

lifetime, to put into effect what we think of as good public health and sanitation
 

practices, or to put into effect a new way of life that would go a long way
towards the control of schistosomiasis... For the foreseeable future, it may
be that the only alternative is an intensive research program focused on the
development not only of new public health measures, but also of new drugs, new
treatment programs, new molluscicides and perhaps even vaccines.

The overall strategy which I have suggested — in a sense applied to
schistosomiasis at the recent Edna McConnell Clark Foundation meeting at
Bellagio, Italy. The purpose of the meeting was to discuss the current state
of the measures available for the control of schistosomiasis. A review of
recent work on this disease revealed several general conclusions: well designed
studies of various methods of control of schistosomiasis have been campleted
and evaluated; studies on morbidity of schistosomiasis in nearly every case
reveal a correlation between the intensity of infection and the extent of disease;
and while immunological studies of this disease have uncovered a great deal about
immune mechanisms, the possibility of a vaccine remains remote for the present.

These general conclusions lead to several specific points in regard to the
future efforts in schistosomiasis control.

1. In most cases the aim of control programs should be the sustained
reduction of prevalence and intensity to a point at which clinical disease
is of low public health importance in relation to other diseases in the area.
Parasite eradication is not a goal of schistosomiasis control.

2. Campleted studies of single methods of control that were reviewed
indicate that chemotherapy may be the most cost-effective method of reducing
prevalence, incidence, and intensity of infection at present. Highest priority
should be given to operational research involving improved delivery systems of

these new drugs.
3. New methods of chemotherapy delivery systems such as selective cheno-
therapy or subcurative single dose therapy may substantially decrease egg
contamination of the environment and thereby decrease transmission, cost of
control, morbidity and mortality.

4. Despite the advances in chemotherapy, in many epidemiologic situations,
control will require the use of secondary methods such as molluscicides, and
management of water supplies and sanitation.

The NIH will conduct research on these specific points where there is still
insufficient knowledge to implement them. And we do not take lightly the con-
tinuing need for applied research on existing control measures. But I must
say we have a responsibility to go one step further. And that one step further
takes us right into the importance of biomedical research as a strategy for the
future.

The most powerful argument for biomedical research on tropical diseases
stems from the unanticipated reemergence of medical problems for which we had
earlier developed solutions. Over and over again in medicine we are faced with
the reemergence of old problems in new garments. An example is the recent and
alaming occurrence of antibiotic resistance among pyogenic bacteria such as
gonococci, pneumococci and H. influenzae B. Widespread occurrence of plasmid-
mediated resistance to antibiotics among pyogenic bacteria has forced us to
reassess our research strategies for the disease control which was thought to
have been achieved with antibiotics.

Indeed in the United States in 1964, because of the emergence of sulfanamide-
resistant organisms, we made a deliberate public health decision to embark on

meningococcal vaccine development for the control of meningococcal meningitis.
In the face of the subsequent worldwide dissemination of sulfanamide-resistant
meningococci, there was no alternative to control epidemic meningitis but the
development of a new vaccine, and that vaccine required resources, basic researc,
brains, and new ideas.

In 1968 I made a special unsolicited trip to Geneva to urge that WHO give
meningococcal Group A vaccine field trials the highest priority in the meningo-
coccal belt of Africa. Dr. Karel Raska, then the Director, Division of Comuni-
cable Diseases at WHO, seized the Opportunity, and meningococcal Group A vaccine
is now a public health measure in Africa. I just recently returned from Zambia
where the vaccine had been used widely during the past two years in the northern
provinces around Ndola.

The reemergence of malaria as a Major disease problem - one more directly
related to the focus of this conference - also underscores the continuing need
for basic research. Malaria was thought to have been solved. The application
of traditional public health measures using more recent tools such as DD? and
chloroquine - the legacies of research incidentally - was believed adequate for
the control of this disease, throughout the world and for all time. What
complacency. And how wrong we were. The emergence of chloroquine-resistant
malaria parasites and DDT-resistant mosquitos has laid bare our smugness.

We were complacent because we overlooked the durability of a species; a
durability for survival in changing environments; a durability arising out of
adaptability. We lost sight of the underlying evolutionary processes. Even
now at the close of Darwin's century, we too often think of biology as a static.
process, as if each species of all living things were caged in solitary confinemer.

in a Linnéan garden.
So in the face of these adaptations of nature such as drug resistance among
microbes, we must reassess our means to control malaria, and plan research
strategies for new treatment and control methods. And when we have achieved
that, make no mistake about it, if we are not vigilant, the course of evolutionary
events will again overtake us. And so our strategy includes the study of the
biology of malaria, mosquitos, schistosomes and snails. It is the course of
prudence. It is the course of vigilance.

Darwin, I suspect, would have anticipated the emergence of DDT-resistant
mosquitos or chloroquine-resistant malaria, understanding as he did, the meaninc
of selective pressure in the survival of the species. It is indeed ironic that
at the close of Darwin's century we grasp the molecular mechanisms of evoluticn,
but in the applications of modern medicine to public health we fail to recognize
the predictable consequences. The job of the NIH, as I see it, is to remain
alert to those predictable consequences.

My second point on the NIH strategy for the future concerns the practice
of what I call synergism. By synergism as a strategy, I mean the reinforcemert
which occurs between the use of conventional public health practices and the
enhancement of those practices through the additional benefits of biomedical
research. Indeed, our most immediate past experience with plagues in our own
countries reveals the importance of this synergism between the application of
conventional public health measures along with the new benefits of medical
research. What better example of such synergism than the modern control of
tuberculosis. Long before the age of antibiotics, much was done in the control.
ef tuberculesis with the isolation cf cases and improvement of nutrition, nousin«

nd

end sc on. But in the 1950's modern chemotherapy broke upon the scone as the
culmination of seventy-five years of intensive bacteriologic research. Only
then was it possible to combine public health practices synergistically with
modern chemotherapy and to control tuberculosis beyond what would have seemed
possible at the turn of the century. I mention tuberculosis, particularly,
because this remains a disease which is not yet controlled in the developing
countries.

Another example. Synergism remains an important strategy in the control
of yellow fever. When conventional public health practices were coupled with
the use of Max Teiler's attenuated vaccine - a product of laborious basic research
in virology for which he received the Nobel Prize - the beneficial effects were
synergistic rather than additive. And how fortunate it is that we can still use
this synergistic approach to yellow fever control without continuous modification
of the vaccine through basic research. We have been less fortumate, as has already
been noted, in the synergistic application of stagnant practices to the control of
malaria.

So for all of us, the overall strategy for the future will be to apply what
we know now and to apply it vigorously. At the same time, the particular strategy
of the NIH is to develop new modalities for diagnosis, treatment and prevention
through basic and applied research. We will work with our own various government
and private agencies in the United States, and we will work with other countries,
either formally or informally. In particular, we will work with all countries
through the good offices of the World Health Organization.

We most especially endorse the Tropical Diseases Research and Training (TDR)
Program of WHO. We have followed its development with interest and we have parti-~
cipated when asked in the development of its plans and objectives. Hundreds of

~ 10 -
American scientists supported by the NIH and other government agencies, are
currentiy working on the six diseases identified by WHO as of first importance.

In Figure 1 are listed 1977 estimated expenditures by United States agencies
on the six WHO tropical diseases in the TDR program. The total was approximately
24 million dollars. The NIH spent just over 7 million dollars. In Figure 2 is
presented the 1977 estimated expenditvres on each of the six diseases. Notice
that agencies other than the NIH also have a major effort in malaria.

As I said earlier, there has been much talk about new initiatives in
international health. This new intensity of interest has received widespread
notice including an editorial in Science last June written by Dr. Howard Minners
whom we have seconded to WHO to assist in the management of research.

» But the time has come to act, to act now, to take the first steps in the
“ implenantation of new initiatives, and this we at the NIH shall do. I announce
these first steps here with the approval of Dr. Donald Fredrickson, Director
of the NIH.

A continuation as well as an expansion of our current efforts in tropical
medicine will focus on four broad objectives.

li. The strengthening of tropical medicine in United States" universities
within the framework of existing biomedical disciplines, é.g., internal medicine,
pediatrics, pharmacology, biochemistry, immunology, etc. This will not only
enhance the present research effort in our universities, but will also provide
long term ~areer opportunities in the usual medical disciplines for investigators
with a specialized interest in tropical medicine.

é¢. An tension cf current United Stat>s’ research to the developing

countries through "Linkages" between United States’ investigators and tho:.e

-ll-
in the countries where tropical diseases prevail. The WHO TDR program has called
for a network among the research centers in the countries where the diseases exist.
and in the developing countries. When I attended the Donors and Participants
Meeting at WHO a year ago, I emphasized then my preference for the process of
linkage between scientific and medical groups in both regions with common goals

in biomedical research and development and training.

To facilitate this linkage we shall announce a new research grants program
for International Collaboration in Infectious Diseases Research. These grants
will require a U.S. investigator to have a defined linkage with a foreign
investigator for research done in a truly cooperative way including laboratory
and field studies in the Overseas environment. Emphasis will be given to the
disease entities in the WHO TDR Program and to those investigators who have
identified linkages with colleagues in developing African and Latin American
countries, although not to the exclusion of other locations.

3. Assistance in the establishment or strengthening of centers of
excellence in developing countries. ‘The linkages described under objective 2)
can be important in reaching this goal. Resources in U.S. public and private
sectors as well as the developing countries will be required.

‘

4. And finally, expanded Opportunity for research training in the United
States for young medical scientists and health professionals from developing
countries. This is particularly true for training related to the tropical
diseases and we have plans in process for an International Tropical Diseases
Research Fellowship Program of NIAID. It will be established in cooperation
with the WHO, and will be administered by the NIH Fogarty International Center.

This research fellowship program will focus especially on the six diseases of

~ 12 ~- .
the WHO TDR Program. The objective of this new international fellowship program
is to provide junior or mid-career health professionals and scientists the
opportunity to acquire the special skills which will be applicable to infectious
diseases in their own country.

Further information on these new programs to establish research linkages
and fellowships will be forthcoming in the near future.

In these comments I have sketched the barest outline of the NIH stratedies
for the future. Our business is the generation of new medical knowledge through
basic and applied research, and this we shall do on the tropical diseases, in
collaboration with our colleagues in the United Kingdom and throughout the worli.
We endorse the objectives of the WHO TDR Program as a sensible and realistic
beginning, recognizing that other diseases are also of major importance in the
developing countries.

I have indicated that an expansion of our current efforts in tropical medicine
will focus on four broad objectives. Included in these are: 1) a new research .
grant program to establish research linkages between investigators in the United
States and our colleagues in the developing countries; and 2) new research trainin:
fellowships for young medical scientists from developing countries to work in the
United States. ‘

Finally I have said also that the control of tropical diseases can have ar
elusive and ghostly quality. The reemergence of malaria is a notable example -”
such behavior. We had not anticipated the occurrence or the consequences of
chloroquine-resistant malaria parasites or DDT-resistant mosquitos. In our
strategy for the control of tropical diseases, we must recognize that this re-

emergence of an old problem in new gamments is programmed in the gonetic macuineryv

- 13 -
of biological evolution. We therefore must remain both vigilant and venturesame.
If we are not alert to the sovereign stream of evolution, we shall be swept away

by the inevitable consequences of biological adaptability in the microbial world.

-14-
MILLIONS OF U.S. $

24

16

12

 

 

 

 

 

 

 

FIGURE 1

1977 U.S. EXPENDITURES FOR THE 6
WHO TROPICAL DISEASES BY AGENCY

 

 

 

 

 

 

 

oe

ea

 

TOTAL

ARMY

NIH

 

NAVY

AID

CDC

HSA
MILLIONS OF U.S. $

24

20

16

 

 

 

 

FIGURE 2

1977 U.S. EXPENDITURES FOR THE 6
WHO TROPICAL DISEASES

 

Total