L.'

May-June 1964


A Visit with

Joshua Lederberg

by John E. Pfeiffer

We call on one of the world's foremost biologists, a leader in the field of biological engineering who at the
age of 33 was awarded a Nobel Prize for his studies of heredity. He discusses spare-part medicine, the
evolutionary crisis, mental retardation and modern man's need for a plan to shape his own destiny.

16                                                                           THINK


T HE PAST DECADE OR so has

    seen an enormous increase in

    our understanding of living
matter. Research on the master sub-
stance of heredity, deoxyribonucleic
acid (DNA, for short), has brought
fresh insights into the nature of im-
munity, protein synthesis, virus ac-
tion, memory and other basic bio-
logical phenomena. The next step
will be nothing less than a revolu-
tion in medicine, as doctors start ap-
plying the new knowledge. Coming
advances promise to surpass, soon
and by a wide margin, everything
that has been achieved previously,
from the days of Hippocrates to the
present.

A number of researchers realize
that such things are definitely on
the way. But few of them have con-
sidered the full implications as care-
fully as Joshua Lederberg, director
of the Kennedy Laboratories for
Molecular Medicine at Stanford Uni-
versity and one of the world's fore-
most biologists. The son of a rabbi,
Lederberg entered Columbia Uni-
versity at 16 and became an assist-
ant professor at the University of
Wisconsin six years later. Since then,
he has won practically every scien-
tific honor worth winning, includ-
ing a 1958 Nobel Prize for studies
of heredity-transmitting mechanisms
in bacteria.

Today, at the ripe young age. of
39, Lederberg can hardly be con-
sidered an elder statesman. But as
a member of various President's
panels and special committees he
has already helped shape national
policy involving space exploration,
research in mental retardation, the
dissemination of scientific informa-
tion and other problems. He is also
very much concerned with the even
broader problem of predicting and
preparing for expected medical
breakthroughs which, in the absence
of adequate plans, could easily be-
come mixed blessings.

I talked with Lederberg not long

"We simply cannot continue to ignore an-
ticipated . . . changes in man's biological
constitution. . .  If we . . try to mud-
dle through somehow, our world could
well become a nightmare world. Tech-
nically, we have the ability to solve prac-
tically all our present-day problems. . . ."

ago in his office at the Stanford
Medical Center. He is small and
soft-spoken, with an impressive no-
nonsense quality in the tone of his
voice and in the way he looks at
you -clearly a man who is impa-
tient with trivialities and does not
intend to become more patient in
the foreseeable future.

"About two years ago, I was in-
vited to present a paper at a sym-
posium on the future of man. As a
geneticist I had to give special
thought to the prospects of eugen-
ics. For a long time now we have
been hearing about the possibility
of breeding superior people as we
breed livestock, the idea being that
superior men and women would
have superior offspring and that the
species could thereby improve it-
self by artificial selection. Another
eventual possibility is directed mu-
tation, the production of `desirable'
traits by deliberately modifying the
chemical structure of our genes.

"Such developments may come,
and they might even be wished for
-provided, of course, that we can
agree on the wide diversity of de-
sirable traits and avoid thinking in
terms of master races. But I do not
think that they will come in a hurry.
Eugenics affects human populations,
which take many generations to
change appreciably, and it seems
to me that our greatest advances
will involve individuals, at least as
far as the near future is concerned.
Instead of tinkering with the heredi-
tary material and influencing the na-
ture of future generations, we can
work with existing people and help
them make the most of what they
already have, the physical constitu-
tions they inherit from their par-
ents."

Lederberg has coined a word for
this form of biological engineering,
"euphenics," which refers to the im-
provement of the individual and
contrasts with the species-improving
viewpoint implied in eugenics. Eu-
phenics is closely related to the daily
progress of medicine but is con-
cerned with those aspects of "human
modification," especially during de-
velopment, that produce fundamen-
tal changes in the character of the
organism. I wanted to know how

such changes would affect medical
practice.

"Making prophecies is a risky
business," Lederberg remarked cau-
tiously, "especially in science, where
practical applications depend to such
a large extent on the unpredictable
course of basic research. But some
developments are already well under
way. For example, it is only a mat-
ter of time before we learn to re-
place diseased organs with healthy
ones. Current attempts to replace
kidneys represent a beginning which
hints at far more successful pro-
cedures in the future. Also, we
should learn to reduce the failure
of blood vessels, and to improve
brain function."

Evolutionary Crisis

"Before discussing specific cases,
however, it should be emphasized
that we are totally unprepared to
accept the consequences of our suc-
cess. We simply cannot continue to
ignore anticipated and inevitable
changes in man's biological consti-
tution. The population explosion is
one example of what can happen
without planning and, as of now,
there is no striking evidence that
we have learned our lesson. We
have policies for foreign aid. civil
defense, television programming, ad-
vertising campaigns, and so on. But
as far as the most important thing
of all is concerned, what man him-
self is going to be, we have no pol-
icy.

"Furthermore, the pressure is in-
creasing. Scientific knowledge has
been doubling every 10 or 1.5 years
and the rate is still increasing ex-
ponentially. Perhaps even more im-
portant, our culture has learned the
benefits of supporting research on
an unprecedented scale. Thus our
potential leverage encourages a new
confidence that any scientific or
technological problem can be solved

- merely provided it can bc formu-
lated in precise terms. In biology
and medicine this realization, eu-
phenics, is an evolutionary leap of
the same dimensions as the original
divergence of man from the pri-
mates, and the discovery of agri-
culture, language and politics. Pre-

MAY-JUNE 1964

17


"Studies of mental retardation need not
apply to afflicted persons only.  The
more we learn about . . . this condition,

dictions of the ultimate significance
of biological advance are not new;
what should be stressed now is
`there is less time than you may
think.' "

What are some current examples
of intensive research in such areas?
Lederberg cited studies involving
tissues and organ transplants, stud-
ies which show that immunity may
not always be a beneficial thing.
Most grafts fail to take because the
body mistakes them for dangerous
invaders. It fights back by produc-
ing the same sort of proteins which
help neutralize the harmful effects
of germs and viruses.

"Currently this fighting back is
the major obstacle to spare-part
medicine. But the solution suggests
itself. If we could prevent the for-
mation of specific proteins which
cause the rejection of specific grafts,
if we could inhibit immune mecha-
nisms with selective drugs, the way
would be clear for the large-scale
use of substitute tissues. Consider-
able progress has indeed been made
in the use of such drugs, and we
should soon reach the point of con-
fident reliance on them."

Lederberg indicated that hearts,

18

the better we . . . understand . . . normal

. * . tissues-and the greater the chances
of artificially enhancing intelligence. . . ."

lungs and livers may be obtained
from human cadavers and eventu-
ally from genetically pure, inbred
strains of chimpanzees or cattle. A
contrasting approach is the use of
artificial organs made out of plastics
and other materials. (Already, spe-
cial transistorized devices built into
the chest wall can take over one of
the heart's functions, that of pace-
maker, and produce regular rhythms
in defective hearts that cannot beat
regularly on their own.)

"Because of difficult technical
problems involved in overcoming
immune reactions," Lederberg ex-
plained, "the use of artificial organs
might well become practical before
the use of natural organs. Unfor-
tunately, however, this line of attack
is receiving only a fraction of the
support it deserves, especially in re-
lation to the benefits of bypassing
serious problems of allocating natu-
ral organs."

He went on to point out that
even more serious problems lie
ahead. As soon as medical inves-
tigators learn how to provide pa-
tients with substitute organs, natural
or artificial, we may expect real
trouble.

"We cannot sit back and leave
everything up to the customary prac-
tices of the marketplace, as if spare
parts for sick people were household
appliances or television sets. De-
mand is certain to outrun supply
for several years or more, and you
can imagine the macabre nature of
a black market under such circum-
stances. We should establish rules
for allocating organs in a humane
and systematic fashion and thereby
avoid the obvious abuses that might
occur. At the very least, transplants
should be formally registered to help
an orderly evolution of legal and
surgical procedures.

"You can see that euphenics is
neither abstruse nor remote. As long
as organ shortages prevailed we
would be faced with, and forced to
make terrible decisions on a broad
social basis. Imagine a national
roster of 30,000 patients, all of
whom would die within a year un-
less they could be furnished with
new organs. Suppose further that
the entire supply for that period
amounted to just 1,000 of the spare
parts. How would you select among
the patients? Would you choose a
brilliant surgeon in his early 50's
over a young student of uncertain
future, or vice versa? A school-
teacher over a housewife? A wealthy
elderly widow who might donate
money for a new laboratory or hos-
pital wing over a young electri-
cian?"

According to Lederberg, compa-
rable decisions are already being
made on a small scale. Doctors at
the University of Washington Medi-
cal School in Seattle, for example,
have developed an artificial kidney
center, which supports a machine
designed to remove toxic waste
products from the bloodstreams of
persons suffering from advanced
kidney diseases. Patients are kept
alive by visiting the medical center
once or twice a week to have their
blood cleaned by passing it through
the  "mechanical kidney." These
people are lucky. They were chosen
by a special jury; for every one of
them two to three other patients had
to be rejected. It costs about $lO,-
000 a year to treat a patient, and at
present there is not enough money

THINK


to treat all those who need help.
"All this is merely a faint hint
of things to come," Lederberg con-
tinued,  "a kind of rehearsal of
problems which may become wide-
spread. Sooner or later, and prob-
ably sooner, we must be prepared
to weigh many lives in the balance
- and who will do the judging?
Research advances are being made
at a breathtaking rate. Organ trans-
plantation will be perfected as a
reliable procedure certainly within
five to ten years -but where is the
system for preserving and allocating
precious organs?"

Lederbcrg is extremely effective
in communicating his deep feeling
for the urgency of things, the feel-
ing of an investigator who knows
science from the inside and knows
how fast things are happening,

"One result of spare-part medi-
cinc, and concomitant developments
in biochemical medicine, of course,
will be an appreciable extension of
the human life span. With limita-
tions of heart failure removed, many
people could already expect to live
90 to 100 years. As we deal with
the other organs, which become the
limiting factors when we reinforce
the more vulnerable organs, we
could anticipate an indefinite exten-
sion of the life span."

New Hearts, Old Bodies

I asked what good it would be to
have a new heart if the rest of the
body aged as it does now-wouldn't
we simply be extending the period
of human uselessness by a few
decades?

"That's just the point," Leder-
berg replied.  "We must scan all
problems beforehand and consider
their interrelated consequences and
establish research priorities in some
balance where they touch on such
vital applications. If we remain in-
different to such things and try to
muddle through somehow, our world
could well become a nightmare
world. Technically, we have the
ability to solve practically all our
present-day problems, but we hardly
know how to apply this power.

"For example, the next 20 years
will see enormous advances in our

techniques for mitigating the effects
of aging. My point is not the speci-
fics of the solutions, but some pos-
sible directions might help make the
discussions more tangible. Many ag-
ing effects seem to be due to a kind
of accumulated scarring. Little acci-
dents are occurring all the time.
Blood vessels become blocked, frag-
ments of nerve and muscle die, and
not all the debris leaves the body.
The increasing load of clogging tissue
takes its toll in the long run. To
counteract such tendencies we may
find custom-built enzymes, com-
pounds designed to dissolve spe-
cific types of scar tissue without
affecting normal tissues. We might
reduce scarring in the first place by
introducing into the bloodstream
special substances to prevent the
formation of tiny clots in the blood
vessels, a major cause of trouble.

"Treatment of this general sort
can be expected as we learn more
about chemical changes that ac-
company the aging process, notably
changes in the hereditary material
and the proteins whose syntheses it
controls. Some of the most impor-
tant applications will involve the
functioning of the brain. This organ
seems to be particularly vulnerable
to blood-vessel accidents and clot
formation, and anything we do to
reduce such troubles will help it op-
erate effectively longer. Euphenics
might go even further and deliber-
ately improve the brain's circulatory
system by modifying the course of
its embryological development be-
fore birth."

Lederberg has a special interest
in the workings of the brain. The
laboratories he directs were built
with funds provided by the Joseph
P. Kennedy Jr. Memorial Founda-
tion and are dedicated to a broad
attack on biological problems which,
among other applications, are fun-
damental to mental retardation-a
condition afflicting more than five
million adults and children in the
United States. This research could
have far-reaching implications for
all peoples.

"Studies of mental retardation
need not apply to afflicted persons
only. The more we learn about the
basic causes of this condition, the

better we shall understand the
chemical workings of normal brain
tissues - and  the greater   the
chances of artificially enhancing in-
telligcnce, perhaps with the aid of
appropriate drugs during develop-
ment. After all, in a very basic sense,
we are all mentally retarded in com-
parison with what WC could be if
we realized the full potentialities of
our brains."

Lederberg had reached a natural
turning point in his discussion.

A Potential Tragedy

"There is nothing sacred about
any one of these suggestions as to
possible future advances in applied
biology,"  he emphasized quietly.
"They are significant only as ex-
amples to illustrate the type of prob-
lems that will arise, and the fact that
we cannot atford further delays in
facing up to such problems. We
cannot continue to immerse our-
selves in the past, as if research were
still moving at the relatively slug-
gish pace of a generation ago.

"But above all please do not give
the impression that 1 have a pro-
gram, or that anyone else has a pro-
gram. Indeed, the whole point is
precisely that no program exists.
This is the danger, the potential
tragedy, of the situation we find our-
selves in today. To arrive at a plat-
form of carefully considered recom-
mendations, we must establish a com-
munity of opinion. Scientists should
be working along these lines? of
course, but the problem is far too
big to be left to scientists alone.

"The problem here involves the
lack of communications between the
sciences and the humanities. People
who distrust or are hostile to
science, and our educational system
still continues to produce them in
quantity, often find a strange de-
light in turning away from problems
whose solutions call for some scien-
tific knowledge-that is. from prac-
tically all the major problems of our
times. The universities can take the
initiative in defining a broader hu-
manism, and providing an atmos-
phere for provocative and produc-
tive discussions. And we desperately
need such discussions."         a

MAY-JUNE 1964

19