Biomedical Research:
Its Side-effects and Challenges

by Joshua Lederberg, Ph.D.

Reprinted from Stanford M.D., October 1967, Series 6, Number 3.
Copyright 1967 by the Stanford Medical Alumni Association.
Biomedical Research:
Its Side-effects and Challenges

We are approaching the ultimate scientific revolution-
the precise control of human development.
But the payoffs in terms of human betterment will depend
on how wisely, boldly, and quickly we can act in the coming years.

by Joshua Lederberg, Ph.D.

the major expressions of the aspirations of West-

ern culture is a milestone in human intellectual
history. It represents for American achievement a move-
ment no less creative than the renaissance of the arts
was for Europe after the Middle Ages. Starting with
physics and chemistry, the wave of scientific insight
has reached biology and medicine and is beginning to
enrich our understanding of the most important aspects
of human personality. Medical research is a major
branch of this movement: specific applications to dis-
ease problems rest on man’s fundamental understand-
ing of his own nature and of his relation to the universe.

The scientist, however, is not necessarily the best
judge of the social utility of his own work, or of that
of science in general. His motives in doing research
are irrelevant to the consequences of his work for the
community. In fact, it is fair to say that society exploits
the poetic fascination that motivates many academic
scientists, eventually capitalizing on applications that
no one could have foreseen. It may even be that research
work loses rigor and sharpness of focus if the research
worker himself is too sensitive to the unpredictable im-
plications of what he is doing.

It is important that such utilities be discovered as
soon as they can be useful. This discovery, though, is a
function of a whole community of basic and applied
scientific effort. To place the burden on individual proj-
ects would be the surest possible way of stifling the
most creative and the least predictable advances in sci-
entific understanding. From my own experience, I do
not know any scientific or technical advance of im-
portance that did not make utterly unexpected demands
on knowledge from unpredictable sources.

This is all a preface, and the statesman might reply:
“I have heard all this before; I might almost be willing
to believe it. Nevertheless, are we making the most
effective allocation of our resources for the public good?
Are we doing all we can to ‘make sure that no life-saving
discovery is locked up in the laboratory?’, as President
Lyndon B. Johnson has put it. How can we achieve the
President’s expressed wish for the most constructive

Riven of basic scientific research as one of

‘payoffs in terms of healthy lives for our citizens?’ ”

These are questions of technological development, not
of basic science. Many discoveries in physical science
have resulted in practical utilities rather quickly. Only
six years passed from the first observation of nuclear
fission to the first demonstration of man’s ability to
make the earth uninhabitable, and a hardly longer time
intervened between enunciation of the principle of the
transistor and the actuality of portable TV. Can we not
emulate such rapid progress in biomedical research?
What are some of the difficulties and challenges? Can
we also foresee some of the stressful and unwanted side-
effects of some branches of biomedical technology?

May I first comment on some of the difficulties and
obstacles. Some of them reach far beyond biomedical
science; they are among our most pervasive social prob-
lems. We cannot consider the manipulation of human
nature in a vacuum that ignores religious and political
controversy over the proper bounds of what we propose
to do; we cannot evade poignant ethical and moral con-
cerns for life and death.

The homeliest examples may be the most instructive.
It takes very little biological science to know that babies
who do not get enough to eat are unlikely to develop
into healthy, socially well-adjusted, and economically
productive adults. Throughout the world—even in this
country—there are at least a few children who are not
getting the benefit of this scientific information, because
their parents can’t afford it. As important as I believe
the furtherance of basic science to be, if I had to choose
between it and the applied science of feeding hungry
children, I would choose the latter. But I would also
ask why that particular choice was obligatory; why is it
not made over a wider range of priorities?

Only a question of scale distinguishes this question
from many others of economic allocation. Some hun-
dreds of patients with kidney disease are still dying
each year essentially because they can’t afford an arti-
ficial kidney. It is also true that we might be unwise to
sink all of our resources into this year’s technology,
when the technology is advancing rapidly. But, mean-
while, there is a simple economic discrimination for the

13
 

Dr. Joshua Lederberg, a native of Montclair, New
Jersey, and a product of New York City public schools,
Columbia University, and Yale, won a 1958 Nobel Prize
“for studies on organization of the genetic material in
bacteria.” Dr. Lederberg is professor of Genetics and
Biology and executive head of the Department of Ge-
netics of the School of Medicine. He is also director of
the Lt. Joseph P. Kennedy, Jr. Laboratories for Mo-
lecular Medicine, dedicated to basic research in ge-
netics, developmental biology, and neurobiology for
a broad attack on the problem of mental retardation. He
has related responsibilities for research programs in in-
strumentation, computers for laboratory use and in
study of mechanized intelligence, and the detection of
planetary life. The article on these pages was adapted
from testimony he gave to the U.S. Senate Committee
on Government Operations, Subcommittee on Govern-
ment Research. The text originally appeared in the Sat-
urday Review and is reprinted by permission. Dr. Led-
erberg also writes a weekly column titled “Science and
Man” in The Washington Post.

chance to live. Is this a problem chargeable to biological
research? If we deal with it on the customary scale for
basic research, the cost will inevitably be several hun-
dred more lives than if we gambled a few hundred mil-
lions of incentive money to distract some mechanical
engineering inventiveness away from washing machines
into kidneys.

Can we provide economic incentive for such a new
industry? If so, how? And how do we relate federal
seed-money for technology affecting human life and
health to a body of talent embedded in profit-oriented
commerce?

In the long run, skilled manpower is the limiting
factor in making the best of existing knowledge freely
available, though better techniques could be developed

14

to make more effective use of the scarcest kinds of peo-
ple. The education of the patient population is also of
utmost importance in evoking intelligent avoidance of
quackery and encouraging use of preventive facilities
when they are available—for example, prenatal care
and survey screening for cervical cancer.

The discrepancy between existing scientific knowl-
edge and public availability and acceptance of that
knowledge is immediately visible in attitudes on nar-
cotics. The medical case against alcohol and tobacco is
overwhelming. Yet these agents are tolerated by the
Establishment. This might seem to reflect a principle
that the law hesitates to intervene against determined
self-abuse by legally competent adults, despite the enor-
mous social problems generated by easy availability of
these commodities. In this context, the savage recrim-
inations against marijuana are incomprehensible, ex-
cept insofar as the pronunciation of any synonym of
“hashish” amounts to spitting in the face of organized
society. The failure of the law to follow pharmacological
science and discriminate carefully among different
drugs in some relationship to their actual hazards en-
courages defiance of the law in far more damaging
ways, such as taking LSD and opiates. In general, the
law on narcotics remains the despair of rational medical
science, and is a testimony to the power of symbols of
conformity.

The situation is even more complicated where con-
flicts of religious belief still enter into public policy.
For a long time the importance of birth control for the
health of the family has been universally conceded, but
a militant religious minority nevertheless has opposed
the spread of the appropriate knowledge and only
grudgingly acquiesces in its availability now, even to
members of other faiths. Since contraception has been
practiced throughout this period by the whole middle
class, the practical consequences of this perverse class
discrimination have been to deepen the gulf between
rich and poor, by class and by race.

The Johnson Administration has finally gathered the
courage to insist on a rational policy in furnishing birth
control information. Perhaps we need not resuscitate
what may be a settled controversy. However, a similar
conflict is following a similar course in the related
field of therapeutic abortion. A scientific understanding
of man is of the utmost importance for social policy
here in several ways.

Most important is the discovery of a number of
catastrophes where the continuance of a pregnancy can
be predicted to result in a deformed child, or in serious
physiological or psychiatric injury to the mother, Tech-
niques for safe interruption of pregnancy are now well
established. More to the point, biological science offers
no support of the theological speculation that fertiliza-
tion of the human egg immediately results in a “human
being.” On the one hand, the fertilized human egg dif-
fers from that of an ape in a finite number of DNA
components; on the other hand, any tissue of the human
body, including cells of the menstruum regularly dis-
carded by every woman, has in it the same hypothetical
potential to participate in a developmental process. The
egg does eventually develop into a human being, but
only gradually does it become differentiated from the
forms of other animals. By the time a viable infant is in
being, we have no doubts about enfolding him into the
species; but every scientific observation shows his de-
velopment to be a gradual elaboration of the potentiali-
ties ultimately inherent in every cell.

If we are to ask honestly about impediments to utiliza-
tion of scientific knowledge for human benefit, we must
include these strictures despite their relationship to reli-
gious controversy. The consequence of a dogmatic posi-
tion on therapeutic abortion has not been to prevent the
practice. Instead, abortion has been forced under-
ground. Perhaps a sixth of all pregnancies are now
terminated illegally under conditions that are a serious
medical and psychological hazard to a million women
every year. Judging from trends around the world, we
may hope for a gradual transition of authority in this
area from the penal code to private morality, where it
has a place I would not presume to intrude upon. Our
political problem is how to respect the conflicting pas-
sions intensely held by different groups of constituents,
giving the utmost latitude to individual liberty where
it does not intrude on the welfare of the whole group.

trate the complexities of applying merely sci-

entific attitudes to human problems. Allocation
of resources is likely to remain subject to the same com-
plexities.

Medical molecules are even more valuable fruits of
biomedical investigation than are elegant medical ma-
chines like the artificial kidney. It would be highly de-
sirable to subject the whole process of drug research to
an operational systems analysis and attempt to ratio-
nalize it once for all. Under the impact of federal sup-
port for research in medical schools, and an aggressively
defensive patent policy connected to that support, fun-
damental biochemical research is becoming less and less
effectively coupled to the actual development of useful
drugs in the pharmaceutical industry. Indeed, with
more effective regulation of drugs, and appropriate de-
mands for more rigorous testing, and with legislative
interest in drug pricing, there is serious danger that risk
capital for drug development will be choked off, that a
larger and larger proportion of capital investment in
that industry will be devoted to the promotion of exist-
ing agents—the few that have passed the scrutiny of
an agency pressed to assure impossible goals of abso-
lute security and perfect efficacy. Attention to promo-
tion versus research is also encouraged by the growing
bewilderment of an over-busy medical profession un-
able to maintain its own ability to assess new drugs dis-
criminately, and therefore increasingly reliant on the
drug industry’s slick ads and detail men for expertise.

Here the ultimate problem is the inability of the medi-
cal profession to keep faith with the demands of the
times. By failing to maintain its own capacity to judge
the merits of new agents, it has abdicated its responsi-
bility to a federal agency that inevitably must follow the
most cumbersome procedures towards monolithic judg-
ments about drug safety and efficacy. In the process, a

Te Questions I have just discussed help to illus-

great deal of flexibility is lost; only those drugs can be
allowed even on the ethical market which are safe for
the average practitioner, who is assumed to be guided
by the fine-print disclaimers and precautions in the
manufacturer’s literature. To the extent that only an
enlightened minority of practicing physicians remains
in contact with modern medicine through systematic
postgraduate training, the profession as a whole will
remain at the mercy of self-interested advertising, which
does have to be policed by a regulatory bureaucracy.
The profession itself must accept the responsibility of
qualifying its membership; the government could, how-
ever, accelerate the process by recognizing a gradation
of responsibility that can be assumed by practitioners
with more sophisticated training—an end toward which
the roster of qualified drug-experimenters is a useful
step.

The expertise of the medical profession is, however,
so vital to our national well-being that we should be-
gin to consider more far-reaching measures, The most
essential is the reinvigoration of our centers of medical
education to encourage the training of many more phy-
sicians over a wider variety of skills and specialties,
Some of these centers must also be dedicated to the
continuing education of mature physicians. We have
modern techniques of dissemination at our fingertips—
wideband communications, computerized information-
retrieval, videotape libraries, but we have not yet
learned to apply them to this vital use, more out of per-
plexities of economic policy than because of technical
limitations. One of the fundamental difficulties is that
the time of the mature physician is so valuable he can
hardly afford even his preseni efforts at continued self-
education. The organized profession’s tacit attitude that
every physician is equally and identically perfect offers
the most limited encouragement to his self-improve-
ment.

It should be possible to devise tax incentives or even
more direct subventions to encourage a more positive
trend. Consider, for example, the career scholarship pro-
posal. A meritorious fraction of medical students should
be offered full scholarships covering their own living
expenses and the cost of their education throughout
their initial training period, which usually runs at least
seven years after the college degree. These scholarships
would, however, be loans rather than gifts: means of
repayment would be not in cash but in credits earned
through 1) later national or community-oriented ser-
vice, 2) regular intervals of postgraduate education, the
credits partly compensating for time taken from prac-
tice, or 3) time spent in clinical teaching, as is now gen-
erously volunteered by many of our finest specialists. If
the prorated cost of education were included in the
stipend, the system would already provide a big step
to funding the needed expansion of medical education,
and the students themselves would constitute a very
broad selection committee for allocation of support to
beneficiary institutions. Such a program is undoubtedly
self-liquidating in terms of the tax yield from improved
earnings, but even if it were not, the social interest even
exceeds the personal interest of the physician in his
own continued education.

15
courage the most creative deployment of the

resources of the drug industry. In view of the
restraints on profiteering on drugs, secondary incentives
for risking capital in research are essential. The opera-
tions of FDA ought to be financed by a manufacturer's
excise tax on drugs amounting to, say, 25 per cent of
their wholesale value, or about 10 per cent of the con-
sumer price. However, the company’s research and test-
ing costs (its investment in innovation) should be
credits against that tax. Furthermore, companies that
contribute matching funds to university research should
be able to participate fairly in patents in which the gov-
ernment now would retain a preclusive interest, and
even worse, a vaguely defined bureaucratic involve-
ment. The lack of clear definition of the scope of gov-
ernment interest in patents that bear any relationship
whatsoever to federal health research support is an in-
tolerable barrier to industrial-academic cooperation.
Perhaps we might altogether bar patents for the more
fundamental aspects of drug innovations, and leave the
patenting privilege open only to the fruits of the later,
costlier development work for which industry is better
suited. For example, a drug might be patentable only at
the stage where it could qualify for FDA approval. The
interested drug company might be allowed some period
of time after preliminary registration during which to
pursue the development work, for the registration itself
entails a substantial commitment of effort.

Every possible measure should be considered to mini-
mize the commercial value of a brand name on a drug
in favor of the actual merit of the innovation in the drug
itself. Another way to approach this problem might be
to relax the law that requires a prescription to be filled
by the brand-specified product, so as to encourage the
use of generic names. Physicians must, however, be left
the discretion to specify a particular formulation and
manufacturer.

A new superstructure of precepts and institutions
needs to be consolidated for the rapid and orderly ex-
trapolation of fundamental biological research findings
to human problems. This realm has seen most extraor-
dinary advances within the last decade, especially in
elucidation of the genetic material, DNA, and the chain
of events that links DNA to the synthesis of the proteins
from which cells are made.

Clinical research on human beings is incredibly
slower and more expensive than comparable work on
microbes and laboratory animals. It is also fraught with
grave moral problems. Whenever any one of us gets
effective medical treatment, he benefits from the risks,
inconveniences, and sacrifices of others who have par-
ticipated in the clinical trials to prove the efficacy of that
treatment. Knowing consent must regulate the repay-
ment of this moral debt to our predecessors. Moreover,
risks to patients in clinical experimentation should be
covered by a new form of insurance. It is enough that
the subject volunteers his body. Financial redress for
bad luck should be charged as an explicit cost of the re-
search and not be confined to consequences of culpable
negligence.

But the most stringent bottleneck at present is in

Asi ocous approaches are worth considering to en-

16

trained people. The very clinicians who might be best
able to do this kind of research are the busiest people
in the community, working overtime in the care of pa-
tients. If we are to get good clinical research, these men
need relief. Our medical schools must have financial
support adequate to enable the hiring of two in place
of one person to do the work of three. And we must take
a new look at the manpower goals of, and recruitment
for, medical education.

suffers from serious difficulties in the collection

of data on the life-histories of human beings. For
example, in 1955, at least 4,000,000 children were in-
advertently inoculated with a virus, SV-40, that con-
taminated some polio vaccines. Subsequent studies on
the geographic incidence of various diseases have
shown no relationship to the distribution of SV-40 ex-
posure, and we can possibly breathe a sigh of relief that
this was not the worst medical catastrophe of modern
times. However, our health data management is so bad
that it would be almost hopeless to correlate individual
cases of future disease with past exposure to this virus.
We are confined to rather general comparisons of time
and geographic trends, which would be quite insuffi-
cient to detect risks which, while far short of cata-
strophic, would generate considerable alarm if attached
to other drugs.

The same concern attaches to other drugs now in
widespread use. For example, the oral contraceptives
as a group have been exonerated from any acute, sub-
stantial risks—compared, for example, to the hazards
attached to the normal pregnancies they are intended
to avert. It is very difficult to evaluate very low-level,
long-term hazards—or, for that matter, incidental bene-
fits—with our existing techniques of population study.
A number of different agents and dosage forms are al-
ready on the market, and after ten years are past it will
be quite useless to get reliable information on exposure-
history by retrospective interrogation of a woman who
may turn up with some or other disease which might
or might not be within the range of average expectation.

Situations like these cry out for definitive registration
of patients and their treatments. But there would be a
justifiable outcry of potential invasion of privacy if data
like contraceptive prescriptions were centralized. The
concept of the computerized data bank has already been
introduced before Congress, and vigorously criticized.
Within the existing legal context, I would have to sup-
port such criticism. Compulsory registration of personal
information has already reached the margins of abuse,
and it makes little difference whether the data are man-
aged by a computer or not. However, so long as transac-
tions within the Executive branch of the federal govern-
ment are virtually insulated from judicial overview, the
private citizen would have little recourse against po-
litical blackmail. I believe the dilemma may be soluble
through legal definition of the rights of privacy—by
making the divulgence of personal information from the
data bank a crime that can be punished by the courts.
Since the courts will not act against the President, the

Bu the manpower shortage, clinical research
data bank should be confided to a semi-public corpora-
tion, which would be vulnerable to judicial oversight
according to the law established by Congress for pri-
vacy. It would not be difficult to construct computer-
coding techniques to ensure the registration of every ac-
cess to privileged information. The Bureau of the Cen-
sus has in fact operated under a system of privileged
information for many years, with no known example of
abuse. Like the Census, a data bank would have a
purely statistical function and should never be used
without consent to impinge in any way, good or bad,
on the life of an individual citizen.

HEN WE COME to the problem of replacing

\ X / natural body organs with mechanical substi-

tutes, the gaps again are likely to be techno-
logical rather than scientific; that is, they depend on
great investments in design and development, with a
relatively small distance of untraversed knowledge to
cover. The artificial kidney is the outstanding example
of a device whose utility was proved long since, and for
which cost factors have been the outstanding obstacle.
No very fundamental obstacles stand in the way of
similar developments for the heart or lung, and the pay-
off is that much larger in proportion to the incidence of
serious diseases affecting the heart and lung. This kind
of engineering is, however, extremely expensive, of the
order of hundreds of millions of dollars—comparable to
the investments we make in weapons systems, nuclear
energy spacecraft, or supersonic aircraft. Our health
statesmen have yet to learn that they can think in these
terms and carry Congress’ enthusiasm into support of
the necessary gambles. Much the same can be said for
extensions of the human limbs and senses: only a rather
large amount of money stands in the way of very sub-
stantial improvements in artificial arms, legs, and fin-
gers, or in surrogate eyes and ears.

These remarks take for granted the need for sub-
stantial federal participation in the research and devel-
opment costs of medical machines. The arguments for
this need are more compelling than those which have
been put forward for the supersonic transport. There
are inordinate discouragements for private capital; the
investor would face the likelihood that even if his risk
paid off, the social attitude against “profiteering” would
keep him from making any really substantial return.
Even after a successful device has been engineered, it
must then undergo very costly certification, and after
that may still be liable to civil litigation in the event
of unforeseen shortcomings. More important, a new in-
dustry must be vitalized on a large scale to pool the
diverse talents needed for real innovation in medical
machines. The necessary combination of biomedical and
engineering skills does not exist.

The highest overall social payoff of any of the ap-
plications of system engineering now visible clearly
lies in modernization of the hospital. Following quickly
behind that is analysis of the research process itself.
There are many sophisticated instruments, or more
broadly, services—for example, the sequence-analysis
of proteins, or the calculated synthesis of known se-

quences—which now occupy an enormous amount of
routine effort in academic laboratories and belong in
just the same category. Once again, university scientists
have been too accustomed to think very small, in terms
of their individual project budgets, to specify the kind
of development support that would ultimately magnify
their efforts.

ITH THE leadership of the Department of De-
W fense, other science-oriented agencies have
begun to realize that large-scale facilities like
computers, expensive though they are, have become in-
dispensable for the full realization of the intellectual
capabilities of scientific research workers at the uni-
versities. Why is it traditionally defense, rather than
health, that commands such leadership?

Engineering support for development work is not in
competition for the same manpower needed for the con-
duct of scientific and medical research. It has, however,
been suggested that funds for target-oriented work in
health be allocated in competition with those for basic
research. The logic of this competition eludes me. As
our civilization grows more complex and its problems
more demanding, we should and do place an ever-
higher premium on intellectual attainment and our in-
stitutions for education to it. The fastest possible growth
of individual educational accomplishment remains the
most plausible goal of our efforts in that area, a prin-
ciple that could well furnish the backdrop to questions
about where we should accept a plateau in supporting
science.

When it comes to technological development, we have
a much larger aggregate investment than we do in basic
research at our educational institutions. That invest-
ment is, by necessity, spent very abundantly for national
defense. We must learn how to allocate the resources we
do have for technology—mostly contracted with indus-
try—to meet our own priority decisions among defense,
health, urban affairs, and all the other needs of our
society.

Important as it is, the optimization of our economic
resources to encompass biomedical science and tech-
nology is only part of a larger political and social prob-
lem. The application of science to biology has reached
near the fundamental secrets of life, and whether it be
twenty years or 200, we are still very close to the ulti-
mate scientific revolution: the precise control of human
development. Wise decisions about the uses of such
power can be made only in a climate of effective com-
munication between the political and scientific commu-
nities, in one of continuing mutual education about
social purpose and scientific opportunity. If we demand
narrow payoffs too quickly, we may indeed get them,
as we already have—and then find ourselves with nu-
clear weapons but insufficient means of control and in-
spection—with splendid automobiles and unmitigated
smog—with innumerable healthy babies and an inade-
quate base of population control. Our capacity to react
quickly to the next generation of technological prob-
lems, the progeny of the first payoffs, depends on the
broadest base of scientific knowledge and the tech-
niques of new discovery.

17