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253  Risks and Rewards 
     "World Health"   June 1976

     Kaplan: Professor Osuntokun, in which fields of public health
do you feel that research is most important for the diseases that
you encounter in West Africa?

     OSUNTOKUN: In the developing countries, particularly in the
tropics, we face severe problems from communicable diseases aggravated
by malnutrition.  These are the areas in which research into public
health can contribute tremendously towards ameliorating morbidity
and mortality in these countries.  It has been calculated that if we
can eradicate or limit the morbidity and mortality imposed by 12
named diseases, we can reduce the mortality and morbidity in these
developing countries by 95 per cent.

     KAPLAN: Here is a group of diseases in which research has been
going on for many years, and yet it is apparent that we are far 
behind in having the available tools to combat them effectively.  We
have been attacking malaria, for example, for the last 10 or 15
years with insect control and have made great inroads, but we have
come up against a very difficult problem in Africa where social and
economic conditions preclude using such means.  If we had a vaccine
against malaria, it would be a very marked improvement.  How can we
go about developing such a vaccine?

     LEDERBERG: I would not want it taken for granted that vector
control is not part of our strategy.  The situation requires much
more careful examination to determine just what measures might be
used.  However, it is true we have tended to place almost excessive
reliance on one simple technological solution.  DDT was going to be
the miracle that would solve this problem once and for all, and
while it did for a time have nearly miraculous results in some parts
of the world, it is now apparent that a much more complex approach
is necessary.  I would agree that until we can be sure that we have
alternative approaches by vector control, a direct attack on a malaria
parasite and an understanding of its biologies is an extremely
important step to take.  One reason for the relative neglect of the
biology of parasites during the past 20 years has been the temporary
success of methods based on vector control.  Only now when we see
these have not worked out effectively do we realize that we must go
back to much more fundamental approaches.

     KAPLAN: Professor Monod, your work in the field of molecular
biology won you the Nobel Prize, yet it is difficult for many people
to see how this can be directly related, or what promise it might
hold for solving such fundamental biological problems as parasitic
diseases.

     MONOD: Let me begin with a field that is not mine, namely 
parasitic diseases again.  I think all approaches must be used at the
same time and I agree with Dr. Lederberg that, for instance, vector
control might be sought for or achieved by means other than chemicals.
There is much more to be done in developing preventive means, such
as vaccines, but recent work in our Institute suggests that parasites
have very special ways of defending themselves against the
immunological defenses or organisms which are successful for, say, 
viral diseases or microbial diseases.  Some very important advances
may be made in this field in the next five years.

     KAPLAN: Suppose we did have effective vaccines: the problem is 
how to apply our knowledge under difficult local conditions such as
one finds, for example, on the African continent.

     OSUNTOKUN: The greatest constraints in applying knowledge and
improving the delivery of health care, as far as the African continent
is concerned, are constraints dealing with the availability of
manpower, and of course, ignorance which can be corrected by health
education.  In most of the developing countries, you just don't have
the manpower to go around and apply things like immunization.  This
is an area in which we have to do something fairly quickly if we are 
going to benefit from the rapid advances in medical knowledge.

     KAPLAN: Lack of manpower is certainly one of the most severe
constraints, and particularly the lack of research manpower.  That
is one of the reasons why we in the World Health Organization have
launched a special programme of research in tropical diseases (see
article by Dr. D.S. Rowe in this issue) to try to build up a 
research manpower base in the developing countries.

     LEDERBERG: Very much depends on the time scale that you feel is
important to achieve significant progress, and all these problems
are interconnected.  The health status of the country influences its
economic productivity which in turn influences the availability of
capital for investment, in human resources as well as other industrial
resources.  These matters are all completely interlinked.  Now
you can view parasitism with malaria as a well-established ecological
equilibrium.  It is not a very satisfactory equilibrium from the
human standpoint, but we have the mosquito, we have the parasite, we
have the people; they have found themselves in a particular circumstance
which will be stable (to the human detriment) over a considerable
period of time, unless we do something about it.  Any large-scale
disturbance that we make of that equilibrium involves some risk.
It is hard to think of any method of altering the situation which 
might not have some side-effects.  Certain side-effects followed the
introduction of DDT, for example, but I am sure the hazards to human
health of DDT are much less than the benefits in those zones where
it has been effective as a public health programme.

     KAPLAN: Your point about possible risks recalls one of the most
heated controversies of recent years, concerning the so-called genetic
manipulation of micro-organisms; there have been some horror
stories thrown around that this has untold dangers for mankind.  We 
would like to know more about this procedure and how you view its
future possibilities.

     MONOD: These hazards exist.  Whenever a new powerful tool is
developed in fundamental science, new knowledge is new power, and
new power can be put to good use or to ill use.  But there is
nothing specific about this particular development, in fact I think 
that it is far less hazardous than many that we have seen or will be
seeing in the next few years.  Microbiologists around the world have
learned over the past 100 years or so since Pasteur's work to handle
extremely dangerous pathogenes in complete safety.  The kind of 
hysteria that has developed recently--simply because the public has
been poorly informed--reminds me of what happened when the Pasteur
Institute was first built in Paris.  A number of articles appeared
at that time treating Pasteur as a sort of Frankenstein monster who
was going to spread horrible foreign diseases around the city.  It's
the same story today.  Frankly, there is much less danger in most of
the research programmes now under way in this field than there was at
the time microbiology began, and we have only to look at the benefits
of microbiology.  These new techniques of genetic engineering
have a wide variety of application, not only in medical therapy, or
prevention, but also in zoological technology and agronomy; they may
contribute considerably to solving some of our nutritional problems.

     KAPLAN: Professor Lederberg, you are a geneticist.  Can you give
as simple an explanation as possible of what is genetic manipulation?

     LEDERBERG: All the findings of molecular biologists for at
least the past 25 years focus on the way in which genetic information
is represented in a chemical substance at the centre of a cell.
This chemical substances is DNA.  And while we have had a revolution
in our biological understanding of the nature of life, the cell,
reproduction and the mechanism of evolution, up to now this
has had very little actual medical application.  DNA,
deoxyribonucleic acid, is the substance in which the genetic information
is represented and forms the material basis of the gene.  It is a
chemically defined structure of considerable complexity, the
blue-print of the cell.  If you put the DNA into a animal, or inject
it into a man's veins, unless there were some very special circumstances
where the DNA was taken directly from an infectious virus, it would
have no biological activity whatsoever.  Only in experiments with
micro-organisms, with bacteria and with certain curious particles
found in bacteria called plasmids, have we found operationally
effective ways of demonstrating that DNA does have biological 
specificity in revealing the information which is present in that DNA.
This means that the focus of technical application of our basic
scientific knowledge about the structure of DNA is still limited to
those cases where DNA can be used as a reagent, having some effect
on the biological outcome of the system into which it is introduced.

     KAPLAN: What benefit has medicine had so far from this molecular
engineering in terms of prevention of disease?

     LEDERBERG: So far, very little.

     MONOD: As Professor Lederberg says, there are still few ways of
applying the basic knowledge and concepts of molecular genetics, of
molecular biology.  On the other hand, great benefits have been
derived from technical advances stemming from this work, for instance,
most of what we know and understand about virus replication
structure and so forth comes from this work and it has been very 
important in the development of modern viral vaccines.

     LEDERBERG: What are being developed--which in the long run will
totally transform the picture--are methods whereby DNA from one
cell, from one source, can be implanted into the genetic structure
of a totally different kind of cell.  Thus it has been possible to
move DNA not only from one strain of a common bacterium escherichia
coli, into another of the same species, but even very different
strains of bacteria, and even totally unrelated organisms.  For
example, one can take DNA from the cells of a toad, and certain 
special kinds of DNA in such cells can be implanted into a bacterium
and used there in order to manufacture large quantities of products
that originally came from the toad.  This opens possibilities for 
very important applications in just the sphere that we are talking
about.  Many of the parasites against which we are trying to produce
vaccines, whose life-cycle we need to understand in order to control
them, are very difficult to deal with in the laboratory, precisely
because they are hard to cultivate.  It has been a major obstacle in
the study of malaria that we do not have a pure chemically defined
system in which the malaria parasite can be grown in the way that we
can grow bacteria.  We have to grow it inside the living red cells
of certain hosts, and even then, there are severe problems.  One 
possible method of producing purified vaccines, which I am sure will be
attempted in the very near future, would be to isolate fragments of 
DNA from the malaria parasite and implant portions of that DNA into
bacterial clones.  Those clones (identical progeny of a single cell)
would then be examined to see whether any of them produce products
that can be used as vaccines against malaria.  This would be a 
prototype of a wide variety of experiments that are available to us now
and simply could not have been done two years ago.

     KAPLAN: One of the hazards that has frequently been mentioned
is that, for example, by taking a cancer virus that is known to produce
a cancer in animals and then isolating the component of the DNA
responsible for producing the tumor and putting it into a cell, we
could produce large amounts of the virus.  If it escaped from a 
laboratory, it could be spread widely among the public.  Is this a 
matter for concern?

     MONOD: This is just the kind of speculation that has tended to
frighten people.  In fact, while the remote possibility of something
of that kind happening has to be borne in mind, the techniques and 
security measures to prevent such an event or to contain any dangerous
organism that might turn up are well known and can easily be
built in at relatively little cost.  The risks involved in the use
of these techniques have been greatly exaggerated.

     LEDERBERG: I agree with Professor Monod and would like to add
that the very term cancer virus scare is a misnomer.  The public
would be misled if they thought a wide variety of infectious agents
existed which were known to produce cancer in man, in the sense that 
there is a virus for influenza, and a virus for measles, and so on.
That kind of a virus for cancer in man does not exist.  We have 
evidence that certain viruses, when inoculated under very restricted
experimental conditions into new born mice or newborn hamsters at a
time when they have no immunological protection whatsoever, can 
induce widespread tumours.  This is a very interesting biological 
phenomenon and is expected to shed light on the problem of cancer 
formation.  But the virus capable of having this effect are already
very common in nature--one or two percent of all wild rodents
already carry the polioma viruses, a large fraction of wild monkeys
carry the S.V. 40, and some very common viruses of the adenal virus
group, which cause respiratory and intestinal infection in man, have
been shown to have cancer virus-like properties and are present in 
perfectly healthy people.

     KAPLAN: And there has been no evidence as yet for the transfer
of tumour viruses from animals to man: they seem to be quite species
specific?

     LEDERBERG: They do, and we may indeed be thankful that this is
the case, because of our daily exposure to agents of that kind.
Many viruses may contribute to the possibility of cancer developing
in the individual, which makes it all the more important that we 
understand their mechanism.  The risks are there.  For example, as an
approach to dealing with the problem of cholera, one might wish to
undertake new combinations of genes, including those for the toxin
of cholera, and to put it in a different biological framework, like
that of an otherwise harmless escherichia coli.  It is quite possible
that such things could be produced and that, if they were, they
would multiply the cholera problem because there would be a variety
of kinds of organisms capable of giving the symptomology of this
disease.  But as Monod said, such a level, of hazard is already an
important part of medical microbiological research, and it would be 
madness to put a stop to such research.  It would be folly to allow 
it to continue if there were not reasonable precautions connected
with the circumstances in which it was done.  A large part of the
public outcry about research which is labelled DNA recombinant research
arises because a new community of investigators are now working in
this area.  These are people whose prior training has been in
fields other than medical microbiology and, in a certain sense, they
have now discovered it for the first time.  This is a very fortunate
circumstance.  It brings in enormous additional intellectual resources,
but there is also a certain element of enthusiasm when they
first encounter the kind of risks we are discussing.

     OSUNTOKUN: Could there be some religious tone to the fears that
maybe scientists these days are now creating life out of nothing?

     MONOD:  I am sure that is so.  In the years since the great
discoveries in molecular biology, there have been discussions in the
press about the possibility of manipulating the genetic structure of
man, and creating a monster, or what not.  Of course, what we are
talking about now has absolutely nothing to do with that, and I
think it is important to point it out.  Even the word genetic 
manipulation is unfortunate.  There is something ominous about it.  The
expression genetic engineering is preferable.

     LEDERBERG: This is not to say that there is no risks to micro-
biologists themselves.  There are heroes in the field.  And again,
there have been unfortunate incidents which we can trace to sloppy
techniques.  We have to be careful that microbiological research is
done to a high standard of care and concern, so that we don't have
a repetition of such incidents.  The risk is if we neglect elementary
precautions.  If we stop research in this direction, we shall pay
a heavy cost.  The enormous benefits from microbiological research
are already very well established.  Hundreds of millions of deaths
have been prevented by the knowledge that has accumulated during
the past century, and there are prospects of being able to do the
same by continuing this research.  And those are benefits of such
magnitude that I think no-one who examines the situation will want
to forgo them in the face of the very speculative and hypothetical
risks that have been suggested about research in this area.
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