JOSHUA LEDERBERG, PH.D.

GENETIC ENGINEERING, OR THE AMELIORATION
         OF GENETIC DEFECT

FEW SUBJECTS pose as many difficulties for rational
discussion as does the bearing of genetic research on
human welfare. It is monotonously coupled with such
inflammatory themes as racism, the decline of the spe-
cies, overpopulation, hidden genocide, religious debates
on abortion and contraception, the plight of the indi-
vidual in mass society, and "how many generations of
idiots is enough." Apart from these cliches of social
controversy, we also face serious problems in clarify-
ing the technical context in a field where scientific in-
novations have far outpaced their technical application
and applicability to man. Should we spend much time
worrying about the ethical implications of the genetic
findings of the next century, when we must do this on
the basis of a set of assumptions about the human con-
dition that will surely change dramatically in every
other way?

The gap between elementary principle and practical
realization poses many dilemmas for a fair-minded
evaluation, and a brief commentary cannot do justice
to all of the relevant issues. The scientist who concen-
trates on exposing the technical possibilities will be
castigated for ignoring the ethical implications; and, if
he goes further afield, he will be accused of sermoning,
and indeed may be overreaching his particular area of
competence.

According to journalistic accounts, we will shortly
be writing prescriptions for human quality to order.
"Do you want your baby to be eight feet tall, or have
four hands? Just tell the geneticist, and he will arrange
it for you," goes this line of advertisement. But the
most sophisticated geneticist today is baffled by chal-
lenges such as Huntington's disease. Will the son of an
afflicted father be afflicted later in life? What can he
do to assure that his own children will not have it?

Perhaps some year soon we will know enough at
least to recognize the genotype before neuronal degen-
eration has been irreversibly set in motion. But our
failure to be able to provide significant help today is a
humbling reality next to the effusive (though just&
able) predictions about future accomplishments.

What then of the bold claims for a brave new world
of genetic manipulation? Their substance is grounded
on the recent solution of many fundamental mysteries
of genetic biochemistry. Many of the obstacles to ge-
netic engineering, apart from the moral and political
questions that may be posed, are technological; which
is to say that their solution is consistent with our basic

scientific knowledge of the gene. But this is as if to say
that "merely technical obstacles" prevent building a
land bridge from San Francisco to Honolulu. It is safe
to predict that this enterprise will never eventuate-
not merely because it would be a million times more
costly than previous bridges but, rather, because other
challenges will compete for the energies and resources.
And the presumed benefits will be achieved by other
routes: the image of the trans-Pacitic bridge will per-
sist as a metaphor, reminding us of technical achieve-
ments in other fields of transport and communication
and of the political prodigy of the evolution of a Pa-
cific island from dependency to statehood.

Dr. Lederberg# a Nobel Laureate in medicine,
is Professor and Chairman of the Department of
Genetics and Director of the Kennedy Labora-
tories for Molecular Medicine at the Stanford Uni-
versity School of Medicine. As a columnist for the
Washington Post syndicate, he is an important
bridge between the scientific community and the
citizens of this country at large.

Construction works, like bridges, are open to evalua-
tion and judgment by common sense widely shared.
Biotechnical projects are more likely to be cloaked in
an esoteric jargon that defeats common sense justifica-
tion. We may then hear the most absurd generaliza-
tion, such as "whatever is technically feasible tends to
get done."

Anyone who has actually labored to "do" anything
knows that the more appropriate slogans are: "almost
nothing ever gets done, especially if it costs money";
or, "when a need is generally perceived, articulately
formulated and wisely analyzed, the technical problems
will be surmounted. But this will happen much sooner
if a mass advertising campaign can be built around it."
Iff* transoceanic bridges become fashionable (as might
happen incidentally to an arms race), they will be
built, and probably the same can be said for genetic en-
gineering. Our foresight about the future will prove to
be right or wrong more on the basis of the predictabil-
ity of fashion than of the scientific basis to technical so-
lutions. I do not venture to foresee the directions that

* Computerese for "if, and only if."


such fashion may take. This is more the realm of the
political theorists or of authors such as John Brunner
("Stand on Zanzibar").

Where then does the scientist fit into such a discus-
sion?

He can fairly justify his life and work in terms of
fundamental knowledge about nature. Studies on the
implantation of nuclei into eggs of different genotypes
are a rewarding approach to learning how genes func-
tion and how this relates to how the egg develops.
Were they done for the purported purpose of learning
the technology of cloning in man, we would then be
obliged to set a priority (positive or negative) on it
from the standpoint of the human values that might
justify or repudiate the investment. A small amount of
"scientific" effort is, unhappily, biased by the expecta-
tion of the publicity that will attach to spectacular dem-
onstrations of "behavior control," or "gene control,"
or "moon-walking" for its own sake; the scientific com-
munity can seek to impose criteria of scientific validity
for the funding of such projects; or, failing this, to dis-
sociate itself from the responsibility when (as is cus-
tomary) it does not have the authority to make the
critical decisions.

Alternatively, the scientist can function as the actual
or effective member of a technological team that will
address itself to the solution of grave problems that en-
cumber human welfare. Then we must and usually do
insist that the problems are real ones and that technical
solutions are credible. What is more often obscured is
the need to examine all the side effects, to inhibit the
premature exploitation of new cures that may be far
worse than the disease, to assure that as much sophis-
tication goes into looking for the side effects as was
eagerly purchased for the primary solution. The haz-
ards of suboptimal solutions are well appreciated for
drugs; but we are just now feeling their full force in
such disparate fields as pesticides and auto transport.
Pesticide-poisoning and air pollution have been figured
as technological jinn. It would be fairer to lay the
blame on technological idiocy and the refusal to make
the economic investments needed to develop all the sci-
ence required for the safe and healthful utilization of
the new tricks.

What then are the problems to which genetic science
can be applied? Some may think of rescuing man from
the prospect of nuclear annihilation by recasting the
genes for aggression-or acquiescence-that are sup-
posed to predestine a future of territorial conflict. Even
if we postulate for sake of argument that we know the
genetics of militarism, we have no way to apply it with-
out solving the political problem that is the primary dif-
ficulty to begin with. If we could agree upon applying
genetic (or any other effective) remedies to global
problems in the first place, we probably would need no
recourse to them in the actual event.

The converse argument applies to the gloomier pre-
dictions of totalitarian abuse of a genetic technology.
The scenario of Brave New World is well advertised
by now, and no one doubts that a modern slave state
would reinforce its class stratification by genetic con-

trols. But it could not do so without having instituted
slavery in the first place, for which the control of the
mass media presents much more immediate dangers
than knowledge of DNA. It is indeed true that I might
fear the control of my behavior through electrical im-
pulses directed into my brain, but (possibly excepting
television) I do not accept the implantation of the elec-
trodes except at the point of a gun: the gun is the prob-
lem.

So much for the grand designs of genetic engineer-
ing. There remain the very real tragedies of genetic
disease. The societal interest in preventing or amelio-
rating mental retardation and other forms of congenital
malformation is obvious. (The true cost of lifetime
maintenance of a 21-trisomy approaches a megadol-
lar). It is also entirely congruent with the needs of the
family and, if we believe in the nobility of man and the
worth of human life, also of the afflicted child as well.

The most effective avenues of preventing genetic dis-
ease include (1) the primary prevention of gene muta-
tions, and (2) the detection and humane containment
of the DNA lesions once introduced into the gene pool.
The "natural" mutation process in man results in the
introduction of a new bit of genetic misinformation
once in every ten gametes. Most of the human cost of
this "mutational load" is paid during early stages of
fertilization and pregnancy, where it makes up a fair
part of the total fetal wastage. But about 2 per cent of
newborns suffer from a recognizable discrete genetic
defect. This is just the tip of the iceberg; the heritability
of many common diseases suggests that from one-
fourth to one-half of all disease is of genetic origin, for
there are important variations in susceptibility to the
frankest of environmental insults.

Not all of this health deficit can be attributed to re-
current mutations. An unknown proportion results
from the selective advantage that is paradoxically as-
sociated with the heterozygous state of many genes,
even some with lethal effect in the homozygote (such
as sickle-cell hemoglobin). Nevertheless, a significant
part of medicine-much more than most practitioners
overtly recognize-is in fact directed to lesions that are
inherently preventable, if we could control the mutation
process in the background.

About a tenth of the "natural mutation rate" can be
attributed to background radiation-from cosmic rays
and from radioactive potassium and other isotopes in
our natural environment. Therefore, doubling the back-
ground, which would correspond to the "maximum per-
missible standards" now advocated by federal agencies,
would add another 10 per cent to the existing mutation
rate: one-ninth rather than one-tenth of our gametes
would carry deleterious mutations. This is an enormous
impact in absolute terms; a modest increase in relative
terms. We must, nevertheless, pay careful attention to
the benefits that would be connected with this level of
radiation exposure to be sure we are getting a fair bar-
gain,

It must be pointed out that industrial nuclear energy
activities today add less than 10 per cent to the average
background (hence, less than 1 per cent to the muta-


tion rate); medical x-rays add 50 per cent and 5 per
cent, respectively. The same question applies: the now-
more-prevalent standards for the judicious and cost-
effective use of diagnostic x-rays do not necessarily or
automatically excuse the dispensable residue.

A significant portion of "spontaneous" mutations
must be attributed to environmental chemicals, many
of which are clearly established as mutagens in labora-
tory experiments (for example, the peroxy compounds
that characterize smog). The extent to which such ma-
terials reach the germ cells is absolutely unknown at
present. There are good reasons to believe, however,
that ( 1) the induction of mutations, in germ cells and
of cancer and in somatic cells, are fundamentally sim-
ilar processes-most chemical carcinogens being also
mutagenic when properly tested; and (2) a large part
of the incidence of cancer is of chemical-environmental
origin, cigarette-smoking being only the best-known
and best-advertised example. It therefore follows that
enviornmental mutagenesis is equally prevalent. If the
relative effects of radiation in the two systems are any
hint, the cryptic penalties of the mutations are likely,
in the long run, to exact even a larger price in human
misery than the short run cancers.

The direct observation of human populations for evi-
dence of changes in mutation rates is an almost hope-
less task. We have no way of managing the tangle of
known and unknown environmental influences that
bear on different individuals. Nor do we have tractable
assays for the occurrence of new mutations, whose
manifestation may be delayed (by transmission through
heterozygotes) for many generations, or confused with
malformations due to pre-existing mutant genes, or to
non-genetic causes. If we had to rely upon epidemio-
logical evidence, we would still lack persuasive evi-
dence that radiation, even in barely sub-lethal doses,
was mutagenic in man.

Our only recourse is the laboratory experiment, with
a convenient mammal such as the mouse, and some-
times even more efficiently with viruses and micro-
organisms. Even so, only the most potent mutagens can
be identified with mice, and many uncertainties will re-
main that cannot be resolved given possible differences
in metabolism and transport, cell selection, intrinsic
sensitivity, and the duration and style of life of the hu-
man versus the experimental species. Very recently, we
have been able to look deeper into the mechanism of
chemical mutation, at the level of the structure and re-
pair of the DNA molecule, and new procedures may
be developed that can give us more reliable informa-
tion on the susceptibility of the DNA of human cells
to environmental insults. They may also give us clues
to ways of neutralizing mutational lesions, either by
blocking the primary effects of mutagens on DNA or
by bolstering the natural mechanisms of "editing" and
repair of DNA information.

Once a mutation has been allowed to occur in a ga-
mete, and this then participates in fertilization and the
production of a new individual, we face a much more
difficult problem in any effort at genetic hygiene. For
now we must deal with the destinies of human indi-

viduals, not merely the chemistry of an isolated seg-
ment of DNA. Our problem, seen in the large, is com-
pounded by every humanitarian effort to compensate
for a genetic defect, insofar as this shelters the carrier
from natural selection. So it must be accepted that
medicine, even prenatal care (which may permit the
fragile fetus to survive), already intrudes on the ques-
tion "Who shall live?," the challenge so often thrust at
rational discussions of policies that might influence the
frequencies of deleterious genes. It is so difficult to do
only good in such matters that we are best off putting
our strongest efforts into the prevention of mutations,
so as to minimize the heavy moral and other burdens
of decision once the gene pool has been seeded with
them.

We still cannot evade an evolutionary legacy of ge-
netic damage that would remain with us for genera-
tions, even if all new mutation could be stopped by
fiat. Our fundamental resources remain very feeble: in
a few cases, we can diagnose the heterozygous carriers
of recessive mutations, and the genetic counselor can
then advise the prospective parents of the odds that
they will have affected children. Where voluntary child-
lessness is unacceptable, it is also sometimes possible
to monitor a pregnancy by sampling cells from the am-
niotic fluid. This can then enable the mother to pro-
ceed with confidence, or to request an elective abortion,
on the basis of firm knowledge of the genotype of the
fetus. We can expect a rapid extension of technical fa-
cilities for such diagnoses. At present, they are limited
to examination of the chromosomes (for gross chromo-
somal abnormalities, such as Downs' syndrome), and
to enzyme assays on cultured cells, which can diagnose
a few dozen rare diseases with varying degrees of re-
liability. We will surely be learning, during the next
decade, how to use much more sophisticated ap-
proaches to the structure of the DNA and RNA of such
cells for more basic diagnostic methods.

In many cases, a deeper understanding of the causal
chain by which a DNA alteration leads to pathology
may help us devise new forms of therapy to compensate
for the genetic defect. This may be as crude as the use
of insulin in diabetes, or as subtle as the use of con-
trolled diets in phenylketonuria. (Both approaches are
valuable; neither is entirely satisfactory.)

Another approach to constructive therapy, which
may mitigate a variety of diseases, is an extension of
the existing uses of specific virus strains. At present,
their role in medicine is confined to their use as vac-
cines, for the provocation of immunity against related,
wild viruses. This is a specialized example of the modi-
fication of cell metabolism by inoculated DNA, discov-
ered empirically by Jenner, and still quite imperfectly
understood (our ignorance being concealed by the con-
ceptualizations of clinical virology which still fail to ex-
plain just how a vaccine works-e.g., to state just
which cells of the vaccinated individual are carrying the
viral genetic information, and in what form). We can
visualize the engineering of other viruses so that they
will introduce compensatory genetic information into
the appropriate somatic cells. to restore functions that


are blanked out in a given genetic defect. As with vac-
cine viruses, this presumably will leave the germ cell
DNA unaltered, and therefore does not attack the de-
fective gene as such. If we can cope with the disease,
should we bother about the gene? Or may we not leave
that problem to another generation?

There has been much to-do about another theoretical
possibility-"cloning" a man, as might be done by the
renucleation of a fertilized egg with a somatic cell nu-
cleus from an existing individual. Similar experiments
have been successfully completed with frogs and are be-
ing attempted with mice. Such experiments, with lab-
oratory animals, will surely be very fruitful of basic sci-
entific knowledge if the technique can be developed. It
would also have enormous value in livestock breeding,
just as cloning (propagation by cuttings) is a mainstay
of horticulture. Until such experiments have been pur-
sued in some depth, with other animals, it is merely a
speculative game to discuss applying such reproductive
novelties to man. There is no urgent social problem to
be addressed by such a technique. It does serve as a
metaphor to indicate that future generations will have
infinitely more powerful ways than we do to deal with
whatever they perceive as [the] socially urgent issues of
human nature. We can therefore focus, more confident-
ly, on dealing with the distress of individual human
beings in the immediate generation. The cloning issue
shows that intrusive genetic engineering, if it is pur-
sued for any other reason, will have plenty of policy
problems to digest even before the "technology" has
reached the point of detailed synthesis of genotypes by
design.

Finally, medical scientists in general well appreciate
and usually respond to ethical concerns about the
application of new techniques in man, by contrast to

experimental animals. For a long time, it has been
known that one could operate on the brain, in such
"interesting" ways as dividing the corpus callosum,
with the possibility of the development of autonomous
"intellects" in the two hemispheres. It would be un-
thinkable to apply such surgical technology to man
without the persuasion and conviction that it would be
for the benefit of the patient-subject. We will not be
given the benefit of the doubt in public discussions of
such questions; there are many influential people who
really believe that "anything feasible will be done," and
we may have to restate the obvious many times in re-
viewing the ethical constraints on possible experimen-
tation.

To return to the "clone-a-man" metaphor: in my
view, we simply do not know enough about the ques-
tion, at either a technical or an ethical level (and these
are intertwined), to dogmatize about whether or not
it should ever be done. Certainly it cannot be thought
of, within the framework of our generally-accepted
standards of medical ethics, unless (1) we can make
and communicate a reasonably confident prediction of
the outcome, and, more important, (2) it has the in-
formed consent, and serves a reasonable humanitarian
purpose, of and for the individuals who are involved.
In genetic matters, this must include the interests of the
prospective newborn, as well as of his parents, and of
the community. If we demand that he be represented
in person, then no one could reasonably be allowed to
be born, whether by "natural" sexual fertilization, by
the design of his parents, or otherwise. The specific
question of "cloning-a-man" is almost the least impor-
tant one I can think of; the one it opens up-who must
be held to account for the next generation, and how-
may be the most.

                   Reprinted from
   THE PHAROS OF ALPHA OMEGA ALPHA
       January 197 1. Vol. 34, No. 1, Pages 9- 12
Copyright. 197 1. by Alpha Omega Alpha Honor Medical Society