Sun Nov 1 16:00:34 1987

THE SECOND CENTURY OF LOUIS PASTEUR:

A GLOBAL AGENDA FOR BIOMEDICAL RESEARCH

JOSHUA LEDERBERG

The Rockefeller University, New York, NY 10021

INTRODUCTION: Louis Pasteur and the Pasteur Institute

   Nothing could have given me 9reater gratification than this
invitation.  For me,  as for my entire 9eneration of
sclentiflcally inclined youth,  Louis Pasteur was a global culture
hero.  The Pasteur Institute was an exemplar that inspired the
foundatlo" of the Rockefeller Institute in 1901.  In 20th Century
America, Pasteur's work reached popular attention largely through
the writings of Paul de Kruif - "Microbe Hunters".  The author
was a mlcroblologlst who began his career at the Rockefeller.
Rene Dubos,  a" important admirer and biographer of Pasteur, was
my colleague at the Rockefeller -- and long before that one whose
work and writings I looked up to.  Starting in 1946, figures like
Andre Lwoff, Elie Wollman,  Jacques Monad and Francois Jacob have
towered at the very top of those scientists who worked in fields
closest to my own interests,  who made important discoveries
correcting and enlargln9 my own,  and whose criticism and esteem
counted the highest in extracting the fullest meaning from my own
work.  When there was occasion to plan spaceflight missions to
Mars,  the search for chiral molecules presented itself as the
most universal of indicators of extra-terrestrial life.  I was
presumptuous enouqh to label that '+The Pasteur Probe." Many of my
closest friends and colleagues have had the good fortune to be
able to spend a slgnlflcant tlme working at the Pasteur
Instltuto,  to their lifelony advantage.  Today,  the Institute has
continued In souls Pasteur's tradition of providing new
scicntlflc knowledge in infectious disease that is our only hope
of fending off a pandemic that is already a global catastrophe.

   These lmapes of Pasteur and hls Institute complicate my task
In seeking a worthy topic for such a" occasion.  He has been the
subject of many biopraphles;  yet there is much more to be learned
about the hlstory of his ideas and their reception, and how they
related to hls contemporary architects of scientlflc revolutions:
epltomlzed by names like Gregor Mendel, Charles Darwin, and
Friedrich Mlescher.  The Institute itself deserves a formal
hlstory in more detall than my own scholarship could encompass.
You are fortunate to have many other celebrants who will look up
from thelr excitinq work at the laboratory bench, and by
descrlblng what they know so elegantly, give you a perspective of
the contemporary science that proceeds throughout the world in
these tradltlons.

   As a" introductory speaker, I claim a different canvas. My
questions ~111 Include:  what can we hope from the next century
of research In the Pasteurian tradition?  What old and new
problems "111 we face?  What do these tell us about our aqenda
for today?  I "111 also comment on the social milieu in which
science "OH functions,  and some of our challenges in sustalnin9
the utmost creativity and Intellectual boldness of the young
minds who are our most important hope for the future.

   PROPHECY:  as Cassandra told, is a perilous profession.  Why
do it?

1

   The best justification I owe to Alex Keynan: that .a Vision
of the possible motivates many social actions; and our policies
are already permeated by much false prophecy, if only that tacit
one that the future is static.  I have committed a few
lamentable, spasms of technological forecastinp, starting some 25
years ago.  They are lamentable not so much because they were
wrong -- for the most part they were accurate -- but because it
is hard for me to see any difference that it made to enunciate
them.  One can urge on any scientist that he will influence the
future far more by what he puts into the permanent record of
scientific experiment and discourse than by what he articulates
to the public.  Nevertheless, eloquent writers like Lewis Thomas,
the late Peter Medawar, and your own Jacques Monad and Francois
Jacob have had a" important impact on the public mind.

   A ceremonial occasion as formidable as this still invites
some reflection.  And I will have some excuse to mix in some
prescription.

   If we try to look ahead to foresee the development of
science for the next century,  we encounter first of all the
overwhelming impact of compound interest, of the exponential
acceleration that already impressed Henry Adams at the beginning
of thls century.  As Derek Price pointed out we have experienced
a 62 growth rate -- a Il-year doubling time -- in Western science
throu9hout the modern era.  We have indeed assimilated a JOO-fold
increase in the first Pasteurian century. Can we imagine a like
multiple in the second?  Probably not for Western Europe and
America: eve" before we reach the physical limitations of a
growth rate exceeding that of the GNP, we already experience
painful constraints.  On the other hand we must consider the
potential development of science in China, India, Eastern Europe
(as it throws off the shackles of Lysenko and his nepotic
offshoots), Latin America, perhaps some of Africa.  Recall where
Japan was in 1887 (for that matter the U.S. in medical science)
compared with today.  The cultural space for science is in the
process of a tenfold augmentation.

    How does such a forecast inform us?  TO extrapolate for,
say, 20 years may be a reasonable exercise.  There will be
surprises, but our baseline is numerically a third of the
estimate; and most of the technology in use In 2007 will be based
on scientific fundamentals now visible.  TO guess at the
substantive content of science for another century is not
forecasting but divination.  Hardly just technology, the very
fabric of global human affairs is subject to the most
unpredictable of perturbations -- a truism that should temper the
assertion of absolute categorical prescriptions about what should    !
or should not be ethically permitted, based on a projection of
contemporary circumstance.  Geopolitics aside, will we take the
same view of death and dying when it is no longer at the whim of
"natural causes"? Leo Szilard would say that an optimist is one
who belleves the future Is uncertain: I will proceed with that
admonition.

   Forecasts about the kinetics of science are more credible
than about Its substance.  Apart from its impact on the social
yield, the process of growth is part of the vitality of science:
it has given us the luxury of trying new people, new projects
without making painful choices about the relicts; it has been an
important factor in the youthfulness and audacity of temperament
of its practitioners.  As growth slows down we face almost
i-evitably a graying of our culture -- a side-effect of the
control of population growth and of the prolon9ation of lifespan


Sun Nov 1 16:00:34 1987

that we urge as a fundamental policy for Western society. We
should also antlclpate that 1) science will be far more broadly
distributed among cultures "nd polities of the world, and 2) ever
more attention will need to be given to the integrative measures
needed for some coherence of the research enterprise - matters
rarely attended to in the highly specialized training offered our
Young scientists today.

   These inteqrative measures are both external and internal to
science.  At one extreme, they speak to a broadening of the
educational base, at least for some professionals, towards
undnrstandlng of the soclo- cultural framework of vast
technoloplcal expansion: how to stay abreast of accumulated
information, and relate it to the needs both of the professional
discipline and of humanity.  These are not the same skills needed
for bench research, though they overlap it as do the
qualifications for teaching,  We do not have a" appropriate
balance in our academic status and reward system today.  At the
other extreme, we urgently need innovations in mathematics and
computer-science to cope with the complexity of scientific
descrlptlon Itself.

LOOKING BACKWARDS INTO THE FUTURE (which is, so I am told, the
Chinese perspective)

   100 years ago,  Jules Verne and other science-fictional
utopians gave us fairly accurate premonitions about mechanical
technology: space travel and submarine warfare.  He had little to
say about biology.  For Pasteur, the microbe was the concept that
revolutlonired medicine.  Today,  the structure of DNA is the
paradigm Lhat informs every aspect of contemporary biomedical
science.  Worklnq out the full detail of DNA structure, its
diversification on the evolutionary landscape, in Individual
variation, in the development of the organism is already the
undisputed agenda that may well occupy us for much of the next
century, in the way that the microbe did for the first.

   Such clarity of opportunity for exploitation is a rare good,
and It ~111 have enormous technoloqlcal fruits.  We have also to
guard against being so dominated by the opportunity that we close
off acts and thoughts that deviate from the mainstream: the very
idols or paradigms that inspire rapid progress.  Did thls occur
in 20th Century microbiology?  I can think of a few possible
examples that (needless to say) warrant further debate.  The very
success of the establlshed paradigms in the early conquest of
Infectious disease qave llttle encouragement to challenqe them.
As Kluyver and Van Niel have pointed out, the view of bacteria as
enemies of humankind helped to obscure the closer examlnatlon of
their biology.

  1. Skepticism about genetic variation in bacteria: this was
too often discounted as contamination, the horror to be avoided
In mlcrobioloqical techntque.  Here,  Pasteur was conceptually
correct In the face of skepticism about his attenuated variants;
though he resisted the pure culture methodology of hls teut.onlc
competitors.  A further consequence was a long lastlnq muddle
atmut adaptive phenomena, where bacteria were long retlarded as
refuges of Lamarcklan biology.

   7.  The deflnltlon of hacterla as Schlzomycetcs, namely
flsslon-funql devoid of sexual processes, and therefore beyond
the paif? of Mendelia" qenetics.  This idol stemmeti In part. from
Lrpuwenhoek's orlqlnal description of bacterle, as the slmplcat.
or9anlsms In the Scala Naturne, barely resolvahlr with t h[?

2

microscope.  (Unfortunately, even the best microscopes are still
of little help in understanding genetlc exchange in bacteria.)
The cleavage of bacteria from genetics persisted for a half-
century after Pasteur.

1'

   3.  The discouragement of anti-bacterial chemotherapy,
despite sporadic observations of antibiosis long predating
Fleming.  Even Fleming was daunted from pursuing penicillin after
1928 by the expectation of failure.  The toxicity of Ehrlich's
arsenicals and dyestuffs did furnish empirical foundation for
those negative beliefs;  but they were prematurely canonized, in
favor of the virtues of serotherapy.

    4.   In related fashion, the mystique attached to antibody
globulins -- do but recall the jargon of "lysins, apglutinins,
opso"ins, ablastins,  amboceptors,  . . . II -- supported the
presumption that they were infinite in variety, and helped
sustain the instructive theories of their specificity that
dominated the field until 30 years ago. We could not have
monoclonal antibodies, nor the conceptual framework of modern
immunology, until those idols were superseded by contemporary
insights based on cell selection. One must admit that English
invention, Occam's razor, the precept of minimizing new
suppositions, has been a poor guide to discovery of the divers
cell types involved in the immune response.

    5.  The concept of a "toxin" as a lethal weapon -- the
military jargon itself accents the idol  -- long obscured the
recognition of cholera exotoxin as a substance that "merely*
promotes the intestinal secretlon of water.  It took the cllnlcal
acumen of a far-from-mainstream  Indian pathologist, S. N. De to
overturn the Kochian ikon, no longer ape than 1951.

   These iconoclasms are no mere academic exercise.  Tens of
millions of human lives have been hostage to the intellectual
confusion of the prior mythology.  Is there a common thread to
them?  Dimly I see some vestiges of vitalism, a refusal to
recognize mechanistic explanations of llvin~ cells' behavior, and
a resistance to Darwinian theory.  Pasteur himself, in his
quarrel with von Liebig, denying cell-free fermentation,
exempllfled that tendency.  Even when they repudiate vitalism in
principle, some biologists still act as if life is so complex as
to be beyond the scope of the human intellect.  There is also the
idol of the "Dragons of Eden", that the tree of life is Quarded
by sacred guardians that humanity dare not challenge.  Do not
smile: in Washinoton, suits have been flied against the US
Department of Agriculture for infringements on the "Telos* of
barnyard animal species. In some quarters, "Evolution" has been      !

deified.  (Not that we dare disregard the delicacy of evolved
ecological webs.)  If that pod prevail, we should not rely,on the
human species having any privileged place in its purposes for the
future of the planet.

  Other fields, most notably genetics and neurobiology, have
been impeded in similar fashion.

   6.  It 1s a" extraordinary anomaly in the history of biology
that the human chromosome number was erroneously recorded, as 40,
until 1956.  The human cell was simply not a place one probed.
Until that number could be accurately rectified, 22 pairs of
Jutosomes and one pair of sex chromosomes, the field of human
cyhoqenetics could hardly be initiated.  PrompCly after 46 was
undr~rstood came the reports that illuminated Downs syndrome as a
r,~l ,ndant 71' chromosome, and WP pm,lrl horrl II t l,- m>n r,rn r-n* 1~*-


Sun Nov 1 16:00:34 1987        3

set.

  7. When Johannsen introduced the term "9ene" in 1909, he
promptly cautloned against assuming it had a material basis.
Further, he insisted that many genes might influence a given
character and vice versa.  At a time when "protoplasm" was widely
assumed to have vital properties (rather scantily veiled
Vltallsm), he was perhaps defending against the expected
crlticlsms of others rather than exposing his own convictions.
Those cautions were justified for many characters that are
manifest as the end results of a long splgenetic chain of
cellular events.  They were nevertheless an unwonted source of
resistance to the ideas finally enunciated by Beadle and Tatum in
1941, that all enzymes are primary products of chromosomal genes.
Data to support that view had been tabled long since by Garrod,
but he barely hinted at a like theory of 9e"e action.  I believe
that as a physician he felt lntlmldated by the world-view of the
genetic profession.

  Mechanism 1s now firmly in the saddle In contemporary
biochemical research.  Thls is no guarantee against mythical
errors.  I confine myself to biological studies.

   8.  The presumption that only proteins could have enzymatic
activity has made even more excltlng the recent flndlngs of
rlhozymes -- RNA molecules that mediate their own chemical
transfonnatlons.

    9.  Who would have doubted the dependence of terrestrial
life on erlergy inputs from the sun -- until the recent discovery
of the thermal vents on the ocean floor, and a rich hi&a that is
fueled by chemical seepage from primordial sources beneath the
crust.  These findings may give additional credit to Tom Gold's
qeoloqlcal iconoclasm that some natural gas and petroleum may not
be of paleoblolo9lc origin.

  10. Have we dlscovered all the major taxons on earth? We
thoupht so until Carl Woese's increasingly persuasive arguments
for elevating the archebacterla to major phyletlc status.  Should
we believe that is the end of natural historic discovery?

SOME SPECUW\TIOtIS ABOUT CURRENT RESEARCH DIRECTIONS

  Keeping in mind these historical repudlatlons of common
wisdom, I offer some unconventional and speculative challenqes to
how we think about some lar9e problems in contemporary biology.
Most of them are not new thoughts,
been refuted.              hut to my knowledge have not
        I know they are mostly wrong; hut I am not sure
all are.  They "111 surely be addressed, and most of them solved,
durln9 the next century.  If I could foretell exactly how, I
would be wasting no time petting to work o" them 1" the
laboratory.

  Eobioloqy (oriqln of life):  Conventional theory makes this
a photochemlcal process of the early atmosphere of our own earth.
nut the cosmic condensation necessarily involves preeminently
llqht elements, lncludlnq H, C, N, 0. The aggregation of stars
and planets Is already a" exercise in orqanlc chemistry.
larqn molecules have now been observed in space.        Many
                                      Should we not
look there for early chemIca1 evolution, perhaps even of the
rudiments of nucleic acids and proteins or their predecessors?

  Exobioloqy ("are we alone In universe").  The cost of radio
r~celvers and of computation may finally he reachlnq an asympLote

that would justify some modest investment -- if not now, in the
next decade or two -- in acquiring and processing potentially
lntelllgent sipnals.  We have no way to assess the probability of
their occurrence.  As to the solar system, the 1975 Viking
mission gave a discouraging report on Mars; but it is wrong to
foreclose the possihllity of microhabitat refuges -- especially
at modest subsurface depth -- perhaps from a more hospltable
epoch in that planet's history.  The thermal vents on our ocean
floors offer an interesting analogue of such habitats.

The Epigenetic Dilemma.

   The central model of cellular differentiation must
reconcile:

a) the orderly delimitation of gene expression in embryonic cell
lineages.
b) the clonal inheritance of these self-sustaining differences,
c) the apparent reversibility of these effects in some stages.

   On account of (c), we usually assume the genetic uniformity
of all somatic cells, and therefore that epigenetlc cell changes
are epinuclelc, i,.e., they do not alter the primary
informational sequence of the DNA, but involve secondary
structures or lateral attachments like methylatlon, histones,
etc.  However, the dogma of genetic uniformity of somatic cells
was overthrown with modern concepts of antibody formation.  This
is unlikely to be the only exploitation of nucleic
diversification of somatic cells.  Many mechanisms of reversible
nucleic differentiations are now known in prokaryotes.  Should we
abandon the search for eplnucleic explanations?  I favor an
eclectic perspective; but we have still to find a robust example
and rationale of epinucleic transmission.  We seek a consensually
accepted experimental model, not just of modulation of gene
expression, hut also of its quasi-stable inheritance without
nucleic alteration.  The field might look for a Wax Delbruck who
would establish some discipline about the models to be pursued,
as he did in plying phage T2 forty years ago.

  More attention should he given to grossly obvious
histological differentiation of nuclear and chromosomal
structures -- the bands in polymorphs, the dimples in monocytes
must he eplphenomena of underlying chemical differentiation; and
I will be rather surprised if they are not associated with fairly
specific segments of DNA information and their current
expression.  The recent explorations of human fragile-x
chromosomes show the value of correlating morphological and
molecular-biological observations.

Aging

Here too, we have yet to establish a consensus on "ha;,
phenomenon we are investigating, what would constitute an
explanation.  I suggest we use as a standard the difference in
lifespan between human and mouse: are there any cellular
attributes that can be correlated with that outcome?



cancer

  The paradigm of the oncogene is properly taking hold, and I
do not dlsputo it.  My remarks are on another tack: to ask
whether chemotherapy or radiotherapy can really be explained as
eradlcatlon of all tumor cells.  This seems very doubtful, and
the collaboration of endoqenous hloloqical defenses must be
involved.  If so, it has been mischievous to focus on modlflers


Sun Nov 1 16:00:34 I.987

like interferons or interleuklns as sole therapeutic aqents to be
tested as s1n91e agents.  They must be examined as adjuvants to
cytocidal aqcnts.

Heart Disease

    The flDL/LDL (IIpoproteLnl ratio has been established as the
best predictor of atherosclerosis.  Almost no therapeutic
j  research is founded on efforts to modify this ratio, which is
certainly a question of dlfferentlal 9ene expression under
metabolic regulation ln the liver.

Psychiatric disease

  Our ONLY leads are a) psychotropic drugs' mode of action,
and b)genetlc influences In dlsease.   We are beginning to see
important studies on DNA probes for polymorphisms linked to
disease susceptibility.  However, almost "oone is looking at
polymorphism in drug metabolism, although there are many clinical
hints of It.  Thls would reflect the handling of endogenous
metabolites.

On Human Intelliqence

  Arc we too wedded to the prewired switchboard model?  There
1s abundant evidence for extensive cell migration, durin9
development.  Could this continue throughout adult life, be part
Of learning?  There Is recent evidence of cell turnover, at least
In song nuclei in birds.  Is human cerebral function merely a
numerical extrapolation of the neurobiology of lower mammals, or
are there higher orders of differentiation of neuronal types in
the human brain?  Else, Why is so much nucleic information
uniquely expressed in the brain?

Physiology, Anatomy -- Some orphans.

  That exercise Influences muscle hypertrophy is an everyday
observation.  To understand it and other banalities at a
molecular level could have great practical application: not just
for Olympic competition, but for maintenance and rehabilltatlon
of the heart and of that organ so uniquely vulnerable In the
human,  the intervertebral disk.  To refer to "compensatory
hypertrophy" of muscle or any other organ as a response to
functional demand is hardly to explain its mechanism.

Toxicolo9y

  Toxic "side effects" are no longer incidental in the process
of adoption of new drugs, pesticides and other chemicals: they
are the central issue.  Toxicology must be elevated from a
stepchild of pharmacology to a central position in the health
sciences, as one of the most important applications of
fundamental molecular blologlcal lnslght.  Most of our
expenditure on empirical toxicology Is wasted, would better be
,Icvated to mechanistic analysis of toxic effects, especially the
lnleractlo" of exogenous chemicals with oncogene mutation and
1~XpteSSlOII.

  The paradigm of comparative toxicology would seek a
tundamcntal understandln9 of the similarities and differences oC
luman responses to chemicals compared to other species.  WC Cl"
Irotcct human health only by well founded extrapolation from
Implcr models.  HistorLcaLLy,  toxic substances lmctaholtc
:\hlhitors) had been central to thr \lnra\r*lJ', c

4

pathways.  The study of colchicine helped uncover tubulln;
neurotoxins did the same for synaptic mechanisms. However,
metabolic inhibitors have been displaced by more sophisticated
tools of microanalysis, tracer methodology, genetic lesions for
pathway analysis, and the direct isolation of enzymes.  These
have left a generation only dimly aware of that history.

Public Health and Epidemiology:

  We have no good alternative to the blind clinical trial: but
this 1s devoid of mechanistic content. Therefore it tests only
the narrowest of hypotheses: the efficacy of the specific
treatment, conducted precisely according to the protocol.  Its
conclusions could be quite misleading about the most minute
variations, unless a sensitivity criterion can be established,
But blind trials are prescribed today as the essential criterion
of adoption of therapeutic regimes.

Parasitology:

  When I started compiling this list a decade ago, I felt it
important to press not only the humanistic importance but the
scientific excitement that would attach to intensified research
on protozoan and helminthlc parasites.  That lesson is one I
would hardly have needed to bring to the Pasteur Institute. It
was a privilege to work with Jacques Monad and many others on the
advisory committees to the WHO that helped support the Tropical
Disease Research initiative, and with financial support from many
foundations there is now a global scientific network devoted to
these problems.  The effort still needs much more support and
especially from governments.  There is no doubt that the field
will be one of the most challenging and effective for the
application of the modern tools of molecular biology.

The bio-political myth of aggression versus altruism.

  It is commonplace to hear how human evolution has not kept
pace with and therefore cannot properly control the technologies
of destruction in modern warfare.  The "ghost in the machine" is
purportedly the aggressive lnstlnct, lnsufflclently tempered by
altruism.  I can scarcely challenge the problematic6 of today's
human condition; but I challenge the blopolitical model so
presented.  The root problem may be too much altruism, too little
individual aggressiveness, as deepseated human instincts.  The
main technologies of warfare entail mass mobilization in response
to threats to the defined group.  Some of the most altruistic
self-sacrifices in historical record are those of combatants on
behalf of their fellows.  It is beyond imagination that organized
warfare could be conducted if each recruit aggressively pursued
his own narrow self-interest.  I offer, further, the gloomy
speculation that emergence of altruism, intelligence and '
mythopoiesis -- the signatures of humanity -- had, as its primary
selective driver in human evolution, the pressures of intra-
specific conflict, viz., warfare with other human groups.  This
Is not a cheerful contemplation; but if we are to seek remedies
for the psychic roots of qlobal problems, better that they be
correctly diagnosed.  One answer is of course the global
cultlvatlon of human Intelligence, and the accumulation of a
culture of socializing traditions, to harness a9gression and
transcend misplaced altruism.  The prescriptions are futile,
however, until they can be symmetrically applied to competing
groups.


Sun Nov  1 16:00:34 1987        5

   Partly on account of the anxieties raised by international
economic competitiveness we are experiencing a new debate about
the optimal styles of orqanlzatlon of science.  This is a
reflection of old controversies about needs for relevance or
early application,  "hlch have caused much prief in many
countries,  perhaps most of all in the U.K.  Rlomedical science
has been stressed by such demands, but far less than, say pure
chemistry or mathematics.  The debate no" has a new wrinkle: the
avallabillty of intricate but costly technology -- like the
supercomputer -- has raised questions about the need to
restructure even basic research.  It is said that existing
academic departments interfere with cooperative work across
disciplines, and that reQroupin9.s are necessary to share in the
justification of costly equipment. This is not controversial for
"Dip Science" instruments like particle accelerators or large
telescopes.  But there is an itch to invoke similar principles to
establish new "cent.ers" devoted to particularized objectives for
science on a smaller scale than the national laboratories.

  This is not the place to prolong a parochial discussion of
one country's science policies; but I do wish to register my
concern that today's solutions may be tomorrow's larger problems.
Some of the root difficulties of inter-disciplinary effort and
other innovations are that, in the US, support for science is too
much tied to specific, pre-approved projects.  If we could just
identify the most creative people and 9lve them the freedom to
make their own affiliations, they will do a better job than
lmposinq fixed structures on them.  There are mega-projects
loomlnq that will, nevertheless,  impinge directly on how we 90
about the pursuit of molecular bloloqy during the next century:
in particular the proposed sequencing of the human genome.

  This is a structure of formidable complexity: 3 billion
nucleotide pairs of DNA,  a full three meters of double-helix if  a
unravelled from a sinqle cell.  If, as is widely assumed, about
one percent of that total length is transcriptionally active,
about 100,000 gene products will have to be accounted for.  The
ultimate reductionism would be to build an analytical factory
that could complete the readinp of all 3 billion units as one
technical exercise.  A price tag of a few billion dollars Is
cited, perhaps less if there is prior investment in new
technology to automate the task.

   Is lt worth the cost?  Undoubtedly.  Is it the wisest use of
that level of expenditure?  I have very grave doubts.  Part of my
reservations have to do with the style of research it encourages,
part with a misunderstanding about what we need to learn in
"mapping the qenomn".

   We have by no" profound information concerning a score or so
human proteins;  each of them Is at least a life's work.  At a
modest $10 MM each,  that would amount to a trillion dollars for
the full set; and ohvlously we must make dlscrlminatinq
selections of targets hcfore committing to the task.  About a
hundred human proteins are no" discernable as agents of important
biological activity; that number will soon qro" to perhaps a
thousand, these should be the priority list for further lnqutry.
It "111 be far more important and more feasible to learn in depth
about that percent.lle of the human c)enome than to have an
cxhaustlve listing of a sequence of 3 billion nucleotides.  For
these, we "111 look In detail into regulation, three-dimensional
structure,  qenetlc variability withln and between species,
physloloqical interrelationships and therapeutic applicat.ions.

To pursue such enquiries will take much more than the enqineerinq
mentality that would apply a sinqle methodology for a sinqle
*weep.  It will need a sense of the organism, and a focussed
expertise on, even fascination for the parts under scrutiny.

   This meqa-proposal is, however, a plausible extension of the
"project mentality" I mentioned before.  It is most approprlate
to what I call the exploitative phase of discovery.  Exploratory
research engenders revolutionary breakthroughs with new
perspectives: the agenda for exploitative science then becomes
fairly obvious.  Exquisite technical skills are to be recruited,
but not too much imagination.  Such projects can then be fairly
readily judged by objective reviewers.  There is little
likelihood of plans being disrupted by totally unexpected
discoveries -- though this may happen even in the best regulated
laboratory.  Precisely because the DNA-sequence paradigm is so
central to modern biology,  it does set the agenda for almost all
of the foreseeable, the plannable research at least of the next
couple of decades.  My fear is that it may also submerge new
revolutions,  not unlike the ones that initiated us into this
phase of the history of biology.

   DNA-sequencing is, however,  so central to biotechnology that
I have little concern whether it will be adequately supported
over the next few decades.  I heartily agree that desperate
exigencies like AIDS and the need for vaccines for third world
disease require a large public investment as well.

   My recipe is that we not overlook exploratory research,
often best done in the context of natural historical observation
-- the field of view may be under the microscope, or at the
hospital bedside,  as well as the open countryside or the oceans.
Such research is often not informed by a prior theory (or one not
much more than a hunch, like my own 40 years a90 that bacteria
might in fact be crossable).  It must of course be supported by
much the same conceptual intricacies and instrumental methods as
is exploitative work; but it takes the past less for granted; it
waits for Nature to show new tricks.

   For many years we have taught that advances in medical
practice would be the fruit of prior scientific progress.  This
"as surely the Pasteurian lesson, and it had much truth in
deallnq with infectious disease through its culmination in
vaccines and antibiotics.  Sometimes forgotten "as the historical
fact that much scientific advance, much of the foundations of the
germ theory for example,  eventuated from feedback from clinical
observation raisin9 scientific questions and offering some clues
to their solution.  The epic instance Is the discovery of the
genetic function of DNA by Avery, MacLeod and McCarty in 1944.
This was a product of a research program that had its roots in
seekin serotherapy of pneumonia.  That in turn required lookinq
at antiqenlc variation in the pneumococcus, and an inspired
stroke by Griffith to trying transforming one variety with
extracts of another.  Only the medical significance of the
pneumococcus could have justified so much attention to its
natural history.  But if Avery had been obliged to defend his
proup's quest for the transforming factor, it is doubtful any
group of experts, reviewing such a research proposal, could have
forecast its significance.

   Constitutional disease (heart disease, cancer, psychiatric
disorder) surpassed infection as a public health problem around
mid-century.  At that point, the teaching "science first" "as no
lon9er an accurate portrayal of therapeutic advance.  In fact the


Sun Nov 1 16:00:34 1987

science of the human constitution was hardly up to the task.  The
most important advances in practice were semi- empirical, e.9.
the drugs used in cancer chemotherapy.  To this day, we have no
insight lnto their organ speclficlty or their therapeutic index;
and I have grave doubts whether their cytocidal effects are more
than the beginninq of thelr mode of action.  From 1950-1980 most
pharmaceutical innovations were substantially empirical, the
result of vast screening programs.  The quest for antibiotics "as
rationalized by the perception that they could be found as
secondary metabolltes of soil microbes.  We still argue what
their ecolo9ical function may be;  and we learn a 9ood deal of
cytophysiology by explorin9 their mode of actlon after the fact.
Subsequently,  structures (like beta-lactams) found to be
bacterlcldal may be the subject of random synthetic chemical
variation in a quest for further activities.

   The same applies a fortiori In the development of
psychopharmaceutlcals.  Wlthout exception these were empirically
discovered; in some cases they prompted further studies of mode
of action that have contributed importantly to neuroblochemistry.

   A similar story can be told of one of our most important
drugs:  aspirin.  The elucidation of willow bark as an inhibitor
of the prostaqlandin synthetase system "as a most worthy citation
for a recent Nobel prize.

   In this decade, we are seeing a turn-around.  Just "hen
there has been accumulated skepticism about so much investment in
basic research,  it has begun to bear abundant fruit. Most recent
pharmaceuticals have been the product of calculated search for
compounds that would bind to targetted receptors, like
arlglotonsin-converting-enzylne or beta-receptors or calcium-
channels,  or enzymes In the blosynthesls of cholesterol,  Alld
biotechnology has offered the means of production, increasingly
often even discovery, of polypeptldes and proteins lmportant in
functional regulation.

   I have already offered a recipe, to sustain an eclectic
balance between dedlrctive and inductive approaches to scientific
discovery,  in some sense between the Appollonlan and Dionysian
styles.  Thls la not accomplished very well in our current
educational regimes.  The Ph. D.  degree is all too specialized:
students in a blochemlstry department even in a medical school
are unlikely ever to see a patlent:  the M.D.  students rarely
visit a research laboratory.  To wait for both de9rees is to be a
perpetual student.  In the U.S.  there are almost insurmountable
flnanclal incentives for M.D.s to enter the high-earning
specialties, and pay their educational debts, and against goin
into a research career, whose material compensation is In inverse
proportion to its fundamental significance.  Undergraduate
education is an ever narrowing stralt between remedial makeup for
the faillnqs of the seccndary schools and premature enrollment in
a graduate specialty.

   The Ph.D. graduate must look forward to a lifelong career of
seeking project grants.  His most promising years may be those in
graduate school and as a postdoctoral fellow when he at least has
the adminlstratlve and financial shelter of an established
laboratory.  We should not lose sipht of the often contradictory
demands on the scientific personality: antitheses such as
lmaglnation vs. crltical rigor; iconoclasm vs. respect for
established truth; humility and generosity to colleagues vs.
arrogant audacity to nature;  efficient specialization vs. broad
Interest; doing experiments vs. reflection; ambition vs. sharing

6

of ideas and tools -- all these  and more must be reconciled

within the professional persona.  They are intrinsic to the
nature of science.  We should work hard to avoid pilinp on
gratuitous stresses that discourage, perhaps even deter, some of
the worthiest your39 people seekin scientific careers today.

   The M.D. contemplatinp research today faces the added
complication of widespread confusion about the nature and future
of clinical investi9atlon.  Research ON patients is indispensable
for answers to many urgent medical problems; it is also very
difficult to conduct wlth the rioor and efficiency of laboratory
studies.  No wonder that the majority of papers in the Journal of
Clinical Investigation concern animal, tissue-culture, or cell-
free models I  Lamentably, many M.D.s who remain in research have
fled clinical problems altogether,  with an obvious wasta9e of
individual and social investment in their clinical education.
The ideal example Is clinically informed investigation, conducted
with the most efficient tools on the part of medical scientists
who remain involved in clinical practice, are inspired by their
observation of disease, and may return to experiments on patients
at the appropriate stage of elaboration of principles worked out
on more amenable models.

   In our role as mentors, there is one universal: we can set a
good example of not fearing to display our ignorance: In the way
we present our seminars,  and how we ask even "dumb" questions.
Some may feel that is no voluntary calculation on my part.  Too
many presentations are self-congratulation about what we have
accomplished rather than a sharing of perplexity about what
remains to be learned.

   My final remark about sclentlflc process: we don't
understand it very well; and we have not been much helped so far
by those few Olympian philosophers who have attempted to analyze
it.  There is little authentic descriptive data on how discovery
was actually accomplished.  Even when there has been a singular
"Eureka!",  there is usually a more complex process of
confirmation, refinement,  reconstruction of context, social,
dialectic of acceptance, resistance, and remolding.  Ina
tradition solldlfied by Claude Bernard, our publications are
recipes and rationalizations after the fact; rarely do they
describe the stumblings and false starts: so Medawar called them
lies.  They do little to teach how science is done; and they 9ive
too much inappropriate support to those who think that scientific
discovery can be planned and written up in advance in project
proposals.

SOCIAL MILIEU

   The sporadic campaigns for a return to primitive nature and
against technology notwithstanding, there is no si9n of a
diminished appetite of the world's people for the fruits of
sclentlfic and technological advance.  People are worried that
they may have to make ethically difficult choices which probe
their innermost values -- and these are often bitterly argued.
They also worry (appropriately) about the shadow of nuclear
destruction.  We have to tell them It 1s the unrepealable laws of
physics that make bombs possible -- and that would be at least
half right.  The most irrational demands are for perfect
environmental safety,  for zero pollution (In the face of the
immensity of Avogadro's number).   All of these issues are
amenable to public education about the substance of science --
much has been written about the disgraceful state of that, at
least In American schools.


Sun Nov 1 16:00:34 1987

    More deepseated are cultural changes that challenge
  authority: the secular prlesthood of scientific expertise no less
than that of abandoned beliefs In traditional rell9io".  PlXSOW31
privacy is jealously guarded eve" in the face of overwhelming
threats to public health.  Animals are bein invested with
ethical and legal rights In a" extension of democratic
principles.  Many people expect to 9et all the benefits of
medical innovation while encumbering the process with a" ever-
increasing bureaucracy; and of,course many livin9s are to be made
' by the officers and lawyers who police science and medicine. I
do not expect much amelioration in these tensions: they are
almost inevitable byproducts of the disestablishment of plven
authority.  Science will be slowed down, but it can accomodate to
these challenges.

   I am more morally troubled by the individualists' selfish
preoccupation with micro-ethical Issues.  There is enormous
publicity 9iven to the fate of one frozen embryo: the avertable
death of 3 mIllion children per year, from disease that can be
prevented with known vaccines, is all but ignored.

  Fears about the hazards of recombinant DNA are recurrently
incited, and they take ready root in a public that has a" almost
theological (or diabolical) preoccupation with DNA, and one which
especially has no competence in the assessment of risk under
uncertainty.  It should be understood that work with recombinant
DNA is not a" idle game: without it, for example, we would be
Virtually helpless in dissecting the AIDS virus.

   We can arpue that our HIV predicament has followed almost
syllogistically from our neqlect of the health problems of the
third world.  It was predictable that those populations would be
ideal foci for the evolution and seedlng of novel infectious
agents.  IiIV has a" insidious quality that transcends what anyone
could have imagined for a" emergent virus.  I am certain that it
will not be the last.

   The hazards of monoculture of our main food crops, their
consequent vulnerability to devastating plant diseases, have had
much comment (but little responsive action).  The global
conditions of modern life : the combination of crowding, a"
underclass of ne9lected people exposed to zoonotic infections,
prlmltlve health facilities,  rapid jet transport and selfish
individual behavior are almost designed for slmllar evolutionary
outbreaks of human disease.  Our enormous advances in
chemotherapy for bacterial infection are so far not matched for
VlCUStXS; we are barely beginning to learn the specializations of
viral metabolism that would provide targets, and there is no
assurance they will work.

  That the apocalyptic challenges to humanlty are hunger,
overpopulation, pestilence, and war is so truistic that one may
be shy about repeating the reminder.  We have all dedicated our
scientific endeavors to do all possible to meet them -- we do not
often get requisite political and social attention.  I am all the
more 9rateful that Presldent Mitterand and M.  Elle Wlesel will
be holding a convocation here in Paris in January for a serious
mobllizatlon of intellectual and moral concern about humanity's
needs.

  Their program would be in wonderful harmony w1t.h LouJs
Pasteur's remarks on his 70th birthday:
`...Do not let yourselves be tainted by a drprncatln9 and barren

7

skepticism, do not let yourselves be discouraged by the' sadness
of certain hours which pass over nations.  Live in the serene
peace of laboratories and libraries.  say to yourselves first:
"What have I done for my instruction?" and, as you gradually
advance, "What have I done for my country?* until the time comes
when you may have the immense happiness of thinkin that you have
contributed In some way to the progress and good of humanity.
But, whether or not your efforts are smiled upon by fate, what
really matters In the end is to be able to say: "I dld what I was
able." '