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MEDICAL SCIENCE (and the UNITY of HUMANKIND
Joshua Lederberg
The Rockefeller University

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The ravaging AIDS epidemic has shocked the world. Still not clearly
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understood 3 that 1s a natural phenomenon/ We will face similar catastrophes
again and again if we do not come - to, grips with the realities of man’s place in
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nature -- a conception with the existing political organization of national
sovereignties, and a reality that stresses many deeply cherished myths about the

autonomy of each individual.

We look back today over a century of biological science that has been
impelled by the iconoclastic insights of Charles Darwin and of Louis Pasteur.
However, Darwin never quite rectified the anthropomorphic view that man has a
privileged place in nature. Man’s intelligence, his culture, his technology has of
course left all other plant and animal species out of the competition. Pasteur
taught, and we should have learned, the hazards of insouciance about the
remaining vital kingdoms, the microbes, as our competitors of last resort. Many
medical scientists, like Theobald Smith and Rene Dubos have offered us broad
perspectives of the natural history of infectious disease -- perspectives that leave
no illusions about the infeasibility of eradication of our scourges, of the need for
an ongoing struggle. Some of the great successes of medical science, including
the "miracle drugs", the antibiotics of the 1940’s, have inculcated premature
complacency on the part of the broader culture. Most people today are grossly
overoptimistic with respect to the means we have available to forfend global
epidemics comparable to the Black Death of the 14th century, (or on a lesser
scale the Influenza of 1918) which took a toll of millions of lives! We have no
guarantee that the natural evolutionary competition of viruses with the human
species will always find ourselves the winner.

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I eften Visualize human life on this planet as mirrored in the microcosm of a

culture of bacteria: betweentwo_fingers one_can-easiy held a viayve) 5 billions
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of cells. In 1911, d’Herelle discovered that bacteria have their own virus
parasites, the bacteriophages. It is not unusual to observe a thriving bacterial
population of a billion cells undergo a dramatic wipeout, a massive lysis, a
sudden clearing of the broth, in consequence of a spontaneous mutation
extending the host range of a single virus particle. The bacteria will be
succeeded by a hundred billion viruses -- whose own fate is now problematical,
as they will have exhausted their prey (within that test tube). There may, or
may not, sometimes be a few bacterial survivors: mutant bacteria that now resist
the mutant virus; if so these can repopulate the test tube -- until perhaps a
second round, a mutant-mutant virus appears.

Is there any reason to believe that such processes are unique to the test tube,
that life in the large is exempt from them? Of course not! Only the time scale
is certain to be different, by a factor of years to minutes, the disparity of
generation time of human to bacteria. The fundamental biological principles are
the same. The numerical odds may be different, by a factor hard to estimate.

As crowded as we are, humans are more dispersed over the planetary surface
than are the "bugs" in a glass tube, and we have somewhat fewer opportunities
to infect one another, jet airplanes notwithstanding. The culture medium in the
test tube offers fewer chemical and physical barriers to virus transmission than
the space between people -- but you will understand why so many diseases are
sexually transmitted. The ozone shield still lets through enough solar ultraviolet
light to make aerosol transmission less hospitable; and most viruses are fairly
vulnerable to desiccation in dry air. The unbroken skin is an excellent barrier to
infection; the mucous membranes of the respiratory tract much less so. And we
have evolved immune defenses, a wonderfully intricate machinery for producing
a panoply of antibodies, each specifically attuned to the chemical makeup of a
particular invading parasite. In the normal, immune-competent individual, each
incipient infection is a mortal race: between the penetration and proliferation of
the virus within the body, and the development of antibodies that will dampen or
extinguish the infection. If we have been previously vaccinated or infected with
a virus related to the current infection, we can mobilize an early immune
response. But this in turn provides selective pressure on the virus populations,
encouraging the emergence of antigenic variants. We see this most dramatically
in the influenza pandemics; and every few years we need to disseminate fresh
vaccines to cope with the current generation of the flu virus.

Many quantitative mitigations of the pandemic viral threat are then inherent
in our evolved biological capabilities of coping with these competitors.
Mitigation is also built into the evolution of the virus: it is a pyrrhic victory for
a virus to eradicate its host! This may have happened historically, but then both
that vanquished host and the victorious parasite will have disappeared. Even the
death of the single infected individual is relatively disadvantageous, in the long
run, to the virus -- compared to a sustained infection leaving a carrier free to
spread the virus to as many contacts as possible. From the virus’ perspective, its
ideal would be a completely symptomless infection, in which the host is quite
oblivious of providing shelter and nourishment for the indefinite propagation of
the virus’ genes. Our own genome carries hundreds or thousands of such
stowaways. The boundary between them and the "normal genome" is quite
blurred; intrinsic to our own ancestry and nature are not only Adam and Eve, but
any number of invisible germs that have crept into our chromosomes. Some
confer incidental and mutual benefit. Others of these symbiotic viruses or
"plasmids" have reemerged as oncogenes, with the potential of mutating to a
state that we recognize as the dysregulated cell growth of a cancer. As much as
99% of our DNA may be "selfish", parasitic in origin.

At evolutionary equilibrium, we would continue to share the planet with our
parasites, paying some tribute, but even deriving from them some protection
against more violent aggression. Such an equilibrium is unlikely on terms we
would voluntarily welcome: at the margin, the comfort and precariousness of
life would be evenly shared between the parasites and ourselves. No theory lets
us calculate the details; we can hardly be sure that such an equilibrium for earth
even includes the human species. Many prophets have foreseen the contrary,
given our propensity for technological sophistication harnessed to intra-species
competition.
In fact, innumerable perturbations remind us that we cannot rely on
"equilibrium" -- each individual death of an infected person is a counter-
example. Our defense mechanisms do not always work. Viruses are not always
as benign as would be if they had the intelligence to serve their long term
advantage.

The historic plagues, the Black Death of the 14th century, the recurrences of
cholera, the 1918 influenza, and now AIDS, should be constant reminders of
Nature’s sword over our head. They have been very much on my mind for the
past two decades. However, when I have voiced such fears, they have been
mollified by the expectation that modern hygiene and medicine would contain
any such outbreaks. There is, of course, much merit in those expectations: the
plague bacillus is susceptible to antibiotics, and today we understand its
transmission by rat-borne fleas. Cholera can be treated fairly successfully with
simple regimens like oral rehydration (salted water with a touch of sugar).
Influenza in 1918 was undoubtedly complicated by bacterial infections that could
now be treated with antibiotics; and vaccines, if we can mobilize them in time,
can help prevent the global spread of a new flu. But we have been lulled into
complacency only recently jarred again.

Technology’s impact is not all on the human side of the struggle.
Monoculture of plants and animals has, of course, made them more exposed to
devastation. In like fashio » the 3 increasing density of human habitations,
inventions like the Cubway ha the jet sftplane’ bli add to the risks of spread of
infection. Paradoxically, improvements in sanitation and vaccination leave the
larger human herd more innocent of microbial experience, and may in the long
run make us the more vulnerable.

Technology, exercised in the opening of wild lands to human occupation, has
also exposed people to unaccustomed animal viruses, to zoonoses. Yellow fever
has sustained reservoirs in jungle primates, and the same source is the probable
origin of the HIV virus in Africa. It is mystifying that yellow fever has not
become endemic in India, where competent mosquitoes and susceptible people
abound. We will almost certainly be having like experiences from the "opening"
of the Amazon basin.

Our preoccupation with AIDS should not obscure the multiplicity of
infectious diseases that threaten our future. It is none too soon to start a
systematic watch for other new viruses before they become so irrevocably
lodged. The fundamental bases of virus research can hardly be given too much
encouragement -- and they have made extraordinary leaps, particularly with the
help of recombinant DNA technology. Such research should be done on a broad
international scale, both to share the progress made in advanced countries, and to
amplify the opportunities for field work at the earliest appearance of outbreaks in
the most afflicted ones.

The most promising answers to these grievous challenges, the afflications
that today beset so much of the world’s populations, and the horrors Nature still
has up her sleeve, come from recent research on DNA, and especially its
application to infectious disease. "Recombinant DNA", still a scare word in
some quarters, is our most potent means of analyzing viruses and developing
vaccines.

The basic principles of vaccination were established long ago, but practical
means of production of vaccines for viral afflictions like polio had to await the
cell and tissue culture advances of the 1950’s. The most celebrated example,
smallpox, also has the oldest historic roots. Political determination and
operational know-how were of equal or greater importance compared to recent
laboratory investigation for the success within this decade of the world campaign
to eradicate smallpox. Most important for any further efforts at eradication of an
infectious disease is an understanding of its natural history to calibrate the
feasibility of the goal. This will strain our basic knowledge of the genetics and
evolution of most virus diseases.

As one species, we share a common vulnerability to these scourges. No
matter how selfish our motives, we can no longer be indifferent to the suffering
of others. The microbe that felled one child in a distant continent yesterday can
reach yours today and seed a global pandemic tomorrow. How can we
procrastinate any further, or have any reservations, about a common cause -- one
that responds to every outbreak of disease anywhere as a challenge to all of us.

"Ask not for whom the bell tolls ... it tolls but for thee.”
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