Stanford M.D.

Spring 1973 Vol. 12, No. 2

STANFORD MEDICAL ALUMNI ASSOCIATION

 

 
 

 

The Perfection of Man

Social and ethical factors will be increasingly important in
determining the application of new genetic advances.

by Josuua Leperserc, Ph.D.

T HIS ESSAY is intended to be a glimpse of the future
as a way of celebrating the history of an exciting
era in biological science. The hazards of prophecy (not
least to the prophets) are well known. Still, it would be
a relatively simple task to post lookouts at the frontiers
of contemporary insight and knowledge in fields like
genetics and molecular biology. If, mercifully, our
range Is confined to the next 25 years, shrewd observers
may miss no more than half of the significant ques-
tions that will unpredictably emerge and may score
even better in outlining the solutions to some of the
major problems that are clearly recognized—like the
structure and development of the nervous system, im-
munity, or neoplasia. We should, however, be uneasy
(or delighted, according to one’s temperament) about
the prevalent mood that tells that most of the really
exciting fundamental questions have been answered—
for history teaches that this often foretells a new scien-
tific revolution that could shake our beliefs to their
very roots.

This purview is based on an autonomous model of
science that has uncertain durability. Perceived igno-
rance (or error) is postulated to be the main orienting
influence in scientific activity. Paradoxically, the more
we know, the better we perceive what we do not; hence,
the process is inherently autocatalytic. We should, then,
be able to judge the main directions of scientific de-
velopment as the exploration of the known unknown.
The main uncertainty is the liability of all autocatalytic
processes to burgeon unexpectedly in scale, or in direc-
tion, in response to imperceptible fluctuations.

A glance at the national research budget over the last
five years is enough to deflate the political plausibility
of this model. The overall growth of science is clearly
not autocatalytic, and, increasingly, other issues of po-
litical and social choice override the opportunity pre-
sented by perceived ignorance as determinants of in-
vestment and support.

On the one hand, the central flow and apportionment
of research funds is increasingly tied to specific techno-
logical missions, like cleaning up the environment or

From Challenging Biological Problems, Directions Toward
Their Solution. Edited by John A. Behnke. Oxford Univer-
sity Press, New York, 1972. © American Institute of Bio-
logical Sciences. Reprinted with permission.

12

curing cancer. On the other, the autonomy of the re-
search laboratory is increasingly caught up in irresist-
ible pressures at the periphery for social goals that are
orthogonal to scientific knowledge: equal opportunity
in education and employment for minority groups and
women, amenities for the local community, and the
ideals of participatory democracy. (The laboratory, of
course, did serve other masters in the past—viz., the
ego-aggrandizement of the chief Forscher, or the central
motifs of the industrial-capitalist culture.) Specific re-
search projects are also under increasingly severe scru-
tiny by polarized cults of critics on issues like the ex-
ploitation of human subjects, relevance (intended by
the investigator or not) to the military capability of
the country, or potential abuse in conflicts over welfare
assistance and population policy.

‘These pressures are bound to impinge on the conduct
of science through their influence on institutional sup-
port but, of equal importance, on the recruitment of
students and perhaps, above all, on the morale of the
investigators themselves.

It follows, then, that the future course of biological
research will be influenced only in limited measure by
its technical opportunities, even as far as they can be
observed from the existing frontier. The prophet must
also foresee the outcome of complexly interwoven
trends in the ethics, politics, economics, and social struc-
ture of the entire culture in which science is embedded.
No contingency more dreadful than large-scale nuclear
warfare can be imagined. If even this can hardly be
dismissed with the confidence of a logically-rigorous
demonstration, how much more precarious are our pre-
dictions that bypass many other tempests.

I am scarcely qualified to enlarge the reader’s pre-
visions of the larger scene. What is manifest is that
scientists will be less and less indulged as innocents, that
they will be increasingly bewildered if they do not at-
tend to the social forces that rive our milieu. Indeed,
we may have to take a more positive role in leading the
culture through the religious crisis that scientific skep-
ticism has done much to edify. To understand how
“society” will deal with science demands a deeper un-
derstanding of how science is perceived by the public,
and how scientific progress influences the welfare of
everyman. The noisiest grievances about science (or
technology) have to do with weaponry and with en-
vironmental ravagement. An even more durable com-
plaint may be the Luddites’-—that new machines de-
prive men of a sense of worth in their work by unregu-
lated technical progress that outpaces human adaptabil-
ity.

Scientists should also seck a deeper understanding of
their own profession—what inspiration and discovery
really consist of and the forces that mold the choice of
rescarchworthy problems. They may then be more
likely to face up to the rationalization of their work
(even in ways that may lead to their own technological
displacement); for example, through more efficient dis-
semination of research literature or through the devel-
opment of computers to undertake lower level ‘“ccre-
bral” functions (Feigenbaum et al., 1971), Can we
believe that we have an ideal understanding of the
innate talents and learned skills required for most
effective performance in different fields or that the dis-
ciplines themselves are most effectively and adaptively
organized?

This preamble may be summarized with a presump-
tuous assertion that limits to the development of sci-
entific knowledge of life are no longer technical ones.
The elucidation of the “secret” of heredity, the replica-
tion of DNA, leaves no doubt that the basic principles
of many other mysteries of biology are also tractable by
similar methods. We have no need to invoke an élan
vital, other than sheer complexity of organization, to
account for the special attributes of life. (That com-
plexity remains, however, an effective and formidable
guardian of the freedom of the individual will in any
practical test.) It follows that further advances in biol-
ogy will be dictated by the problems that biologists
choose to attack; this, in turn, will be enforced by social
policy to a far greater degree than in the past. An in-
evitable corollary is exposure to the crossfires of polit-
ical conflict over the definition of the social good. There
are many signs to justify Aron’s (1968) prediction that
the fundamental conflict may be between relative-
egalitarian versus absolute-efficient conceptions of ethi-
cal utilities. (Which is preferable: to live in a levelled
society free of disparity or a stratified one, whose pyra-
mid may rise from a higher base?) Biologists, as imputed
experts on the diversity of organisms, will face many
dilemmas over this social conflict of equality and
efficiency (Lederberg, 1972).

The long-run possibilities of biological technology
are unbounded—even mortality may become a matter
of definition of the rate of change of memory and per-
sonality (converging, then, with the consoling reassur-
ances of the great religions), as we contemplate the
gradual but increasingly foreplanned replacement of
outworn molecules. But, in the short run, everyone
still dies, and too many die prematurely according to
any ethical standard. Futuristic pretensions about ge-

netic engineering are a mockery to a mother who has
delivered a trisomic child. And we are still unable to
tell the offspring of a Huntington’s choreic whether
he will transmit the disease to his children or, indeed,
whether he will in some few years succumb himself.
This disparity between present-day reality and eventual
potentiality may arouse deep-seated resentments against
that rosier future and even against contemporary scien-
tists who are not quite able to bring it off—in time.
Perhaps this is an argument against advertising the
future, but too much indispensable planning hangs on
clarifying the picture the best we can. The remainder
of this essay will, however, focus on the challenges and
horizons of the near future.

According to popular legend, “anything possible will
be done” if the technologists get their hands on it. Any-
one who is trying to do anything substantial knows that
the opposite is usually true. Absent the incentives of
military applications, the more sophisticated the science
the greater is the distance between its conceptual oppor-
tunities and reduction to practice. One of the most
egregious gaps between scientific potential and human
needs is in agriculture. Formidable technical compe-
tence and human importance attach to the new intro-
ductions of dwarf wheat and rice which have promoted
the green revolution. Nevertheless, the scientific foun-
dations of these breeding ventures go little beyond the
rediscovery of Mendelism in 1900. Shrewd agronomic
insight, and meticulous attention to detail in the selec-
tion of parent stocks and intermediate hybrid lines,
rather than innovational genetic theory, were the roots
of these successes. It is likely that Many more oppor-
tunities await. the intelligent application of the most
straightforward techniques of plant breeding. They
will, in fact, be indispensable, merely to retain our
present position in the face of the evolution of parasites
adapted to new and homogeneous genotypes.

In principle, the cell- and molecular-genetics devel-
oped in the last 25 years could make even more incisive
contributions, but it has yet to make any significant
impact. Some of the fault must be laid at the door of
the agricultural research establishment. But the United
States Department of Agriculture must, in turn, be
responsive to a community that now puts increased
crop efficiency very low on its list of priorities, since
bumper crops prove to be economic disasters. We are,
then, relatively backward in fundamental biochemical
and genetic investigations of the development of seed
proteins compared to their importance in human nu-
trition. Until recently, the National Institutes of Health
have been hard put to justify research grants on the
amino acid sequence of zeins in different varieties of
corn. But if we had information of this kind, to the
depth of, say, our knowledge of human hemoglobins,
we should be much further along in designing more
efficacious sources of plant protein.

13
iP

This remark does too little credit to the empirical
development (International Atomic Energy Agency
Panel, 1969) of hi-lysine corn. The nutritional advan-
tage of these mutants, which have visibly altered sceds,
evidently depends on the diminution of zein content
and substitution by other proteins. However, the de-
velopmental mechanisms involved are still poorly un-
derstood, and we are still very far from a rational design
of a seed protein optimized for human nutrition. With
a more detailed analysis of gene-controlled protein
sequences, we would have a firm basis for the stepwise
accumulation of point mutations or recombinants
toward that optimum. The substitution of threonine
for serine, or of lysine for arginine, in a seed protein
would be expected to have little impact on its function
for the plant compared to its utility for man. Plant
breeding is, of course, burdened with logistic problems
of assessing intact seedlings as the units of genic ex-
pression and with the traditional problems of diploid
inheritance (need for back-crosses and multiple progeny
tests). These might be averted by more attention to
artificial haploids and to the manipulation of plant
ceHs in culture, including cell fusion. Similar tech-
niques have greatly advanced our knowledge of the
genetics of a species, man, which few would have ex-
pected to outstrip maize two decades ago.

Viruses (as an exemplification of plasmagenes) may
also play a role. (Indeed, they already do; for example,
in the control of male fertility for the production of
hybrid corn.) An example of genetic engineering of a
virus that may eventually be important for improving
the quality of plant protein is suggested by the claim of
Rogers and Pfuderer (1968) of the engineering of a
tobacco mosaic virus variant to which poly-A was ap-
pended, with the concomitant production of excess
polylysine. Well-defined clones of such variant viruses
have not, however, been reported.

A control long-run objective for molecular agrobiol-
ogy is the maximization of protein yield at the expense
of polysaccharides. The plant will have to be engi-
neered into a kind of lactating organ in which just
enough structural cellulose is invested to sustain the
primary utility of protein synthesis. The dwarf va-
rieties, indeed, exhibit this very principle.

Human consumption of photosynthetic product
amounts to about 300 M (3 « 108) tons of fixed carbon
per year. This is only about 5 percent of the total crop
yield, most of this being waste tillage. Crops, in turn,
make up only 10 percent of land-cover photosynthesis;
ic will be at least as difficult to expand this ratio as to
improve the efficiency of already cultivated lands. A ris-
ing population will have few alternatives more palat-
able than the use of chemically recycled cellulose or
fossil carbon for human, as well as industrial, fuel.

The salvage of the world food resources is by all odds
a mixed blessing, according to well-known Malthusian

14

 

reasoning. It is dificult to see how striving countries
will be induced to limit their population growth so
long as the weight of numbers is a political, and even a
military, weapon in interstate competition. The tech-
nical means of contraception are improvable, but
scarcely lacking now. We have little basis for optimism
except the hope that world order and economic mod-
erniziattion may advance in spite of the population drag,
and that these factors will encourage a demographic
reversal, The natural and man-made disasters that have
afflicted Bengal are visions of the alternate paths.

Another crushing affliction of most of the world is
infestation with animal parasites, especially malaria,
blood flukes, and worms. Environmental sanitation,
directed at vector control, has been the most effective
public health measure to mitigate these debilitations,
but tropical countries are likely to remain burdened
with them for many years nevertheless. The well-de-
fined life cycle of these parasites should make them
biologically fascinating, as well as humanely rewarding,
targets for more profound study with modern methods.
The attenuated mutant already plays a central role in
prophylaxis against virus infection by vaccination with-
out the benefit of deep insight into the mechanism by
which the parasitism is frustrated. With the flukes and
worms, well-defined morphogenetic stages are involved
in the progress of an infestation, and with the malaria
plasmodia, it should be even easier to superimpose bio-
chemical analyses of the critically altered stages of at-
tenuated mutants which could confer analogous bene-
fits in the form of virus vaccines for the control of cor-
responding diseases. The genetic engineering of Plas-
modium falciparum vies with that of Oryza sativa asa
further target of molecular genetics.

From the standpoint of scientific and technical ac-
cessibility and of clarity of ethical consequence, para-
sites and domesticated animals and plants are clearly
the most attractive targets for genetic design. However,
utopian aspirations for the “biological improvement”
of man were appended to the development of genetics
even before its emergence as a rigorous experimental
discipline. The eugenic aspiration, of course, conflicted
head on with theological doctrines of the origin of man
in original sin and alternative recipes for salvation. It
is refueled today by doctrines of the inevitability of evil
in human nature that are fallacious deductions from
ethological research.

The most telling argument for eugenics is the fear
that the existing human species is doomed to self-de-
struction. But a culture that cannot evolve the political
machinery to contain its weapons will hardly improve
its competence for survival by adding biological engi-
neering to its repertoire.

Like many other messianic visions, eugenics is faulted
by a confusion between the needs of an abstract man-
kind and those of individual men and women. In many
arenas, utopian aims for the ordering of human affairs
might be achieved at the sacrifice of individual liberties.
In the economic sphere, “from each according to his
abilities” is a plausible humanitarian ideal, but it can
be enforced only with the apparatus of a police state
and an arbitrary determination of what cach has to
contribute. Apart from the already fatal obstacles of
political implementation, genetic planning faces frus-
trations analogous to the failures of planned economies,
both with respect to technique and to the validation of
consensual purposes. In the real world, social move-
ments will continue to have much more incisive effects
on the human gene pool than any conceivable technical
advances that could be labelled as “tampering with the
genes.”

Geneticists, in the main, have been so critical of large-
scale cugenics that they may forget that the allegation of
seeking to breed Supermen will be renewed in every
popular discussion. Some of my own efforts to outline
the difficulties and paradoxes of genetic design have,
for example, been misquoted (Ramsey, 1970) as advo-
cacy. I will plead guilty to withholding categorical
anathema on issues that are amenable to deeper ex-
ploration, both technically and morally. Social atti-
tudes on questions like contraception and abortion
have changed too dramatically in one or two genera-
tions to reinforce the posture of sempiternity of our
ethical pronouncements, above all in human biology.
This is no assurance of ever-increasing permissiveness—
the history of the tides of moral fervor shows more dis-
placement than dissipation, and they may return once
again to now-abandoned shores.

Let it be clearly posited, nevertheless, that the re-
making of man is an illusionary goal for the application
of genetics in a liberal society.

The principal task of genetics is scientific under-
standing; the principal target for its applications to
man is the alleviation of individual distress—which
the physician cannot repudiate no matter what the gen-
eral state of the world. In pursuing his goals, it should
go without saying that the geneticist is bound by the
same set of ethical restraints that apply to other inno-
vative branches of medicine. The surgeon does not use
his scalpel by whim, and even in the chase after poten-
tial knowledge, he is, above all, accountable by law
and ethical tradition to the needs of his patient.

Table 1 catalogs a number of potential techniques
that may relate to the prevention or therapy of genetic
disease or which may influence genetic constitution.
This is not a well-bounded arena, for all of medicine
—indeed, all of culture—is potentially euphenic and
eugenic. That is, they may (1) ameliorate the actual
development and expression of genetic predisposition,
and (2) thereby, indirectly influence the relative fre-
quency of different genes in the population.

The boundaries of what should be called “genetic”

disease are also uncertain, for every pathology must
have both a genetic and an environmental component.
Many common diseases, as well as overall longevity,
have a significant heritability. About 5 percent of over-
all morbidity can be related to specific genetic defects
with a relatively simple basis; if we also take account
of the heritable component of prevalent diseases, like
schizophrenia, diabetes, cardiovascular disease, and so
on, at Ieast a fourth of total morbidity (in medically ad-
vanced communities) must be attributed to genetic im-
perfections.

Genetic Load, Mutagenesis, and Environmental Hygiene

The genetic load is, therefore, a formidable part of
the problems that must be faced by medical practition-
ers and their patients. Plainly, preventive measures
should have a high priority, if we could, thereby, pre-
vent the intrusion of genetic defects in the first instance,

 

This may not always be possible—an unknown part of
the genetic load is “segregational’; i¢ derives from
heterosis; Le., an advantage of the heterozygote over
either homozygote. Natural selection, then, tends to
keep both of the alternative alleles in the population,
notwithstanding the inevitable quota of impaired
homozygotes that must recur at every generation.

Heterosis is important to framing reasonable expecta-
tions for genetic improvement since no freely breeding
population can then be composed exclusively of the
healthiest (heterozygous) phenotypes. The production
of high-yielding corn is based on the careful nurturing
of a number of rather weak, highly inbred strains as
parent stocks which are then crossed to produce vigor-
ous hybrids. The farmer who tries to use these, in turn,
as seed corn courts disaster—a fact hardly in keeping
with racist mythology or with the naiver forms of eugen-
icism.

Furthermore, the heritability of different diseases
gives no assurance that a single optimum genotype can
exist. Susceptibility to cancer may reflect a low excita-
bility of the immune mechanism; allergy the converse.
Total freedom, both from cancer and allergy, may be
physiologically unattainable. We have only provoca-
tive data about mutual exclusions in predisposition to
disease, but we can still be fairly sure that we have more
choice about how, rather than whether, to die.

These aspects of disease genetics are relatively inde-
pendent of the mutation rate, responding mainly to
natural selection. They offer some room for genetic in-
sight, short of total amelioration, since the existing
gene pool has evolved in a historical context of medical
and other cultural determinants that haye changed far
more rapidly than gene frequencies can have respond-
ed. Furthermore, Darwinian fitness, or reproductivity,
is becoming less and less congruent with the standards
of somatic quality by which we judge ourselves and our
peers.

 

15
 

 

 

ee 0 Th MeN he

Table J

Potential Technologies of Eugenics and Euphenics
(Not Confined to Man)*

A. Selective mating:

1) By phenotype of parents (assisted by biochemical and
cytological assay)

a) negative — distracting, discouraging, or sterilizing
the “unfit”

b) positive—

i) encouraging select pairs
il) with artificial insemination, donor (“rational
germinal choice’)
iti) with oval or ovarian transplant
iv) both ii and iii, or fertilization in vitro, followed
by implantation
extracorporeal gestation (test tube baby)—see
also euphenics
(i-v are not very different in their genctic conse-
quences)

2) By genotype of parents—as above, with deeper analy-
sis of parental constitution. Except for specific aberra-
tions, very little can be said at present about genetics
of desirable traits.

<
—

 

3) By relationship of parents
a) inbreeding—The main impact is to expose reces-
sive, usually deleterious, gencs: increase phenotypic
variability of F,; decrease the genotypic variability
of later generations.
b) outbreeding—antithesis of (a). Most cultures strong-
ly encourage outbreeding.
4) By age of parents—to forfend accumulation of dele-
terious mutations and chromosome anomalies which
increase with parental age

5

mS

By phenotype or genotype of the zygote or of the fetus
(antenatal diagnosis and voluntary abortion)—Earlier
selections would avoid the trauma of aborting an es-
tablished fetus.

6) By genotype of the gametes: e.g., separation of X from
¥ or normal from defect-bearing sperm

7) With sperm of other species (compare [1] [b] fivJ)—
Nothing is known of the consequences among primate
species (possibly in vitro). All contemporary races of
man appear to be freely infertile. Cross-pollination is,
of course, a crucial technique in plant breeding.

. Innovations in Zygote Biology — Vegetative (asexual)

propagation. Cloning. (Almost universal among plant

SPP.)

1) Parthenogenesis—development of an unfertilized egg.
(This might be genetically identical to the mother, or
might be a product of meiosis, which would be an in-
tense form of inbreeding.)

2) Regeneration — development of a whole individual
from somatic tissues (as in some plants and lower ani-
mals like earthworms)

3) Differentiation of gametes from somatic tissues pre-
viously subject to extensive genetic manipulation

. Adjuncts from somatic cell biology

4) Somatic reduction in gamete-forming cells in culture
(somatic inbreeding)—would allow predictable out-
come of further matings from a given parent which is
not now assured.

wn
eed

Nuclear transplantation—renucleation of a fertilized
enucleated egg. Genetically equivalent to cloning from
the source of the nucleus.

a

Embryo—splitting to produce twins or multiplets. Not
to be confused with multiple ovulation (occasionally
induced by fertility-promoting drugs). About one-third
of spontaneous twins are monozygotic, i.c., arise from
the splitting of one embryo. Note also the opposite
phenomenon.

7) Embryo fusion (chimerism) — so that one individual
comprises two or more genotypes. ‘This grades into
tissue transplantation at later stages. It should allow
different genotypes a new latitude for mutual comple-
mentation, ¢.g., mens sana in corpore sano, Somewhat
less than 1/1000 live births are spontaneous chimeras,
but some of these arise by other mechanisms.

 

For cugenic applica-
tions, these would be coupled with procedures like B(5).
For euphenic effects, altered cells can be grafted back to
a host or some manipulations done directly on his tissues.

1) Algeny—directed alterations of genes

a) controversial claims of effects of DNA uptake in
mammalian cells following a long tradition of ge-
netic work with DNA in bacteria

b) incorporation of viruses

1) experimental tumor viruses
ii) use of specially modified viruses
1) vaccination to induce immunity to viruses
2) virogenic therapy to replace missing genes
3) virogenic enhancement for superior per-
formance—if we but knew the biochemistry
thereof

¢) incorporation of chromosome fragments transmit-
ted by cell fusion

d) specifically induced mutations — No plausible ap-
proaches are now apparent.

2) Random mutation and specific selection of cells with
altered properties—has full precedent in strain selec-
tion in microbes. Many uncertainties relating to pos-
sible cancer potential of such implants.

 

3) Gell fusion to form somatic hybrids—These cells may
then lose various chromosomes to give many new
forms. Extends scope of (2). Can be readily applied to
fuse cells from “distant” species, e.g., fish and human.

4) Development of symbiotic strains of lower species, with
habitats that grade from the external world (e.g., crops)
to internal to intracellular—Parasitic worms in man
have evolved in this direction with the help of adapta-
tions to thwart immunological rejection. In principle,
they might be domesticated. So also might algae be
trained to an intracellular habitat in man where they
might photosynthesize essential nutrients, if not bulk
calories, as they already do in primitive animals.

* From Lederberg, 1971); see also Davis, 1970.

 

16
However, the “mutational” part of the genetic load
must be considerable, and this is related to the rate of
mutation (informational deterioration) in the genetic
material. A certain level of mutation is an inevitable
byproduct of molecular accidents in cell metabolism.
However, if we argue from the relative incidence of en-
vironmental, compared with intrinsic, carcinogenesis,
which may be parallel phenomena, we may judge that
four-fifths of our ambient mutation rate is of environ-
mental origin and could be eliminated by environ-
mental hygiene (relating to drugs, food additives, and
possibly some natural foods, water, and air pollutants,
certain virus infections). About 10 percent of that quota
can be attributed to the natural radiation background,
which is essentially not avoidable, and an equal propor-
tion to artificial radiation. At one point, nuclear power
development appeared to be the main source of in-
creasing environmental radiation, but the newly adopt-
ed standards of the AEC promise to keep this to a negli-
gible proportion of the background. The major source
of artificial radiation today, by far, is diagnostic X-rays
which approximate half or more of the natural back-
ground. Our increasing sensitivity to genetic hygiene
will raise agonizing issues of the costs and benefits of
medical X-rays. These can hardly be answered by point-
ing to the overall benefit which is irrefutable. They do
demand an examination of the dispensable margin, be
this 10 or 80 percent of the total level of manrads now
dispensed. Many physicians believe that ‘defensive
medicine,” that is, the anticipation of lawsuits for mal-
practice, is responsible for a needless volume of caution-
ary X-rays. The present legal framework compensates
the single patient who might have been benefited by a
routine X-ray that was negligently withheld. It does
nothing for the 10,000 others or their progeny who must
eventually pay some price for having been X-rayed with
unimportant results. Our skills at matching these costs
and benefits can only be sharpened if we are first edu-
cated to asking such questions in economic, rather than
diabolic, terms.

The same issues confront us in the formulation of
policy about chemical additives to the environment—
solvents, drugs, food additives, and so forth. It is not
very uscful to assert that a compound is mutagenic with-
out proceeding to a more quantitative evaluation of its
impact, and our data on human response to chemicals
is even more fragmentary than to radiation. Before
joining the bandwagon against synthetics, the geneticist
must caution that natural foods need a similar exami-
nation. The first authentic publication about chemical
mutagenesis (Auerbach and Robson, 1944) concerned
allyl-isothiocyanate, a constituent of horseradish and
mustard, (This compound has, moreover, been found to
induce skin tumors after local application in mice.)
Mustard has not, however, been subjected to the rigors
of evaluation according to the Delaney Amendment,
perhaps for fear that this would overturn our simplistic

approaches to a problem that is as complex biologically
as it is vulnerable to the bias of vested interests. En-
vironmental hygiene may be the most fruitful area of
application of more sophisticated molecular genetic
analysis.

Options for Genetic Therapy

Among these options, a few stand out for offering the
most realistic opportunities for health benefits. They
include:

Antenatal Diagnosis

An increasing number of diseases will be reliably
diagnosed by cytological and biochemical studies on cell
cultures derived by amniocentesis (Dorfman, 1972). We
already have exciting advances in the understanding of
several neurochemical disorders which rely upon the
identification of specific enzyme defects. The tech-
niques of cell-fusion and of chromosome identification
with fluorescent stains will strengthen our ability to
trace mutant genes, and similar methods will also help
identify high-risk parents. We can visualize more direct
assays for specific information content of DNA with
techniques for the isolation of specific messenger RNA
and, then, the homologous genes. The DNA segments
can then, in principle, be tested in cell-free systems for
protein synthesis or, perhaps, even subjected to direct
analysis of their nucleotide sequences.

This level of sophistication in the analysis of gene
effects should, in many cases, lead to deeper under-
standing of the disease and may provoke explicit thera-
pies. Meanwhile, our main recourse is voluntary abor-
tion of the impaired fetuses to allow a mother the best
chance available to her of delivering a child free of
malignant defect.

Our experience with the antenatal diagnosis of sex
should help correct overanxious predictions about the
anticipated misuse of “genetic engineering.” This has
allowed a reliable method of voluntary control of the
sex of offspring for some years. Whether the sex of the
fetus has ever been a controlling factor in a decision
about abortion, without more persuasive indications,
simply has not surfaced as a significant social problem
to warrant any special regulatory controls. The com-
mon sense and patient-oriented values of the medical
profession remain the most effective bulwark against
nonsensical distortions of its tools.

Actually, voluntary control of the sex of offspring
might encourage a limitation of family size (c.g., one
boy, one girl) consistent with the social interest in over-
all moderation of population growth. Then, a balanced
sex ratio could be maintained even under voluntary
choice.

Transplantation

Many genetic defects involve cell populations as
metabolic units that could be supplanted or restored

17

Ameren a mE RE
 

 

 

eel A, A A SO la i Ae A ras

by transplantation. For example, complete transfusion
plays an important part in the therapy of Rh-hemolytic
anemia (but is associated with a danger of graft- vs host-
immune disease when applied to the fetus). The scope
of tissue transplantation should not be judged by its
present limited application which is constrained by
the hazard of graft-rejection. Specific ways of mitigating
rejection are bound to appear as a fruit of immunobio-
logical and immunogenctic research. We will then have
a simple, practical way, for example, to deal with sickle-
hemoglobin disease — namely, by transplantation of
normal erythropoietic marrow to the newborn or, per-
haps, the fetus. We will also surely find that many other
diseases, genetic or not, are amenable to relief by tissue
and organ transplants—e.g., hepatocytes for PKU and
for galactosemia, or insulin-secreting cells for diabetes.
The Jast example illustrates the opportunities for
therapy even where the transplanted organ may not
be the primary seat of action of a defect.

The growing popularity of transplantation of hair
(auto- today; homo- tomorrow; hetero- yesterday [the
obsolete fur coat]) attests to the same principle.

‘Transplanted immunocytes are also likely to play a
key role in the treatment of auto-immune disease (per-
haps, after systemic elimination of offending cells) and
in the prevention and treatment of neoplasms.

In cell biology research, we have just begun to move
into the arena of systematic work on the genetics of
somatic cells. The discovery by Henry Harris (1970) of
Oxford of powerful methods to induce the fusion of
cells has attracted enormous interest in the conse-
quences of mixing chromosomes of different genotypes
and species and in their reassortment in various combi-
nations. The way is, then, open to genetic analysis (and
genetic engineering) of mammalian and human cells in
a way that would have been technically and ethically
impossible otherwise. We can also expect that domesti-
cated lines of somatic cells will be important inputs to
therapeutic applications of transplants.

Vaccination and Virogenic Therapy

Since 1798, vaccination has constituted an important
medical application of the genetic modification of so-
matic cells by viruses, though its practitioners to this
day are often oblivious to its mechanism. Jenner found
that inoculation with infectious lymph caused a mild
disease, cowpox, immunity to which also protected
against the dangerous smallpox.

Many aspects of vaccination are still scientifically
obscure, but we can now describe the process in terms
of molecular genetics. The DNA of the cowpox virus
is purposely introduced into certain cells which adopt
the genetic information contained therein. These cells
thereupon produce new gene products, encoded by the
viral DNA, which stimulate other body cells to produce
antibodies against them. The cross-immunity is then a

18

 

byproduct of the virogenic alteration of some cells of
the host.

Live viruses are now widely used for vaccination
against many other diseases, including polio, measles,
and—in special cases or in the near future—rubella,
mumps, rabies, and so on.

Vaccination can be regarded as if it were a therapy
to replace the functions of hypothetical genes not nor-
mally present in the human organism, those that would
endogenously stimulate the formation of antibodies.
This idea can be extended, in principle, to other gene
products, for example, enzymes that may be missing in
certain gene-defect diseases like phenylketonuria and
perhaps diabetes. Laboratory models for this kind of
virogenic therapy are being perfected and rational trials
for human disease can be anticipated shortly (Rogers,
1970). Although basic genetic principles underlie this
technique and the genetic apparatus of somatic cells is
altered, it is classified as euphenic because the germ
cells are left unchanged, and there should be no effects
in future generations. This is a matter of empirical ob-
servation rather than necessary principle in biology,
and it is quite conceivable that some inoculated viro-
genes might also be inherited, as has already been pos-
tulated for certain tumor viruses in rodents. This res-
ervation applies with equal force to vaccination against
infectious diseases about which we have little informa-
tion in proportion to the enormous numbers of chil-
dren involved.

The recent discovery of “reverse transcriptases,”
which copy RNA information back to DNA, promises
to simplify some of the technical problems of develop-
ing virogenic agents. Differentiated cells should, under
certain conditions, produce multiple copies of active
messenger RNA molecules, and it will be easier to
purify and test these than to attempt to dig out a single
DNA gene from the complete chromosome set. (In due
course, however, this should also be facilitated by know-
ing the chemical signals that distinguish the active from
the inactive genes in a given cell.) Reverse transcrip-
tion would then allow the recoding of the RNA message
into DNA which would then be spliced to a virus for
facilitated re-integration into chromosomes.

Virogeny will be in competition with cell transplants
for the replacement therapy for genetic defects, but
each may have special advantages in particular cases.
For example, the transplantation of neurones is not
likely to be very helpful except at the earlier stages of
development.

Proposals for virogenic therapy reawaken many other
questions about the use of live virus vaccines for mass
prophylaxis —a public health measure that involves
most of the world’s population in contrast to the few
subjects of experimental approaches to gene therapy.
Inevitably, live viruses will carry a residual hazard of

 

atypical reactions, and of passenger contaminants, al-
though these could be mitigated by more attentive re-
search. On the other hand, the assumption that public
smallpox vaccination can be safely abandoned is based
on experience with the management of breakthroughs
under almost optimum conditions. The notion that
smallpox will be finally eradicated within the decade
is hindered by serious geopolitical obstacles, and we do
not know what would happen if the virus should be
reintroduced (1) in unusually virulent form; (2) into
populations who are immunologically relatively naive
with respect to other infections as well as smallpox; and
(3) under contingencies of breakdown of public health
services. The 1972 epidemic may be a fortunate tocsin.

Viruses used for prophylaxis in man have been de-
veloped and monitored with scarcely more sophistica-
tion than that available to Jenner. The molecular bi-
ologist should insist that the highest standards of chem-
ical and biological purity and characterization avail-
able in the research laboratory be applied to these
agents. This will not be possible without a recognition
that cheap vaccines will be worth what we pay. The
drug companies cannot be faulted if higher standards
are not imposed uniformly on their competitors.

Renucleation (Cloning)

From the work of Briggs and King (1952) and of
Gurdon (1968), we know that an activated egg may be
renucleated with a nucleus taken from a somatic cell of
an existing frog. From a genetic standpoint, the new
embryo is like a cutting, or clone, of a rose plant.

The question of renucleation of human eggs was first
introduced (Lederberg, 1966) to make a rhetorical
point. Many speculations had been put forward about
the possibilities of “genetic surgery’—of a kind that
would require fantastic innovations in our knowledge
of molecular genetics. Renucleation in frogs had, how-
ever, been demonstrated long before, and it was also
very plain that it would be available in man as a neces-
sary prerequisite to more incisive techniques of genetic
manipulation. It follows that, if one wishes to agonize
about the likelier directions of futuristic change, he
should attend to renucleation rather than genetic sur-
gery.

My erstwhile remarks that mice and men should not
differ from frogs in amenability to renucleation may
have been naive. Chromosome-inactivation, exempli-
fied by the inactivation of one X in normal female cells,
may play an even more important role in tissue dif-
ferentiation in mammals compared to amphibia (Di
Berardino and Hoffner, 1970). In that event, renuclea-
tion may not be technically possible until long after the
achievement of other aspects of ontogenetic control
which, in turn, may make renucleation relatively less
useful for any practical problem.

We may still discuss “cloning” if only as a speculative
exercise. If it could be done today, it is hard to see

 

where renucleation would have very important applica-
tions, but this is precisely the kind of anticipatory study
that needs to be done. On the positive side, it may give
some otherwise sterile mates the opportunity of par-
enthood, An anovulatory woman might borrow an
otherwise wasted egg cell, renucleate it with one of her
own, or her husband’s somatic cells, and have it re-
implanted into her own uterus. Or a fertile wife might
offer an intact egg for microsurgical fertilization with
a haploid spermatocyte nucleus from her azoospermic
husband.

We can properly understand the moral objections
and justifications of such procedures only if we explore
the whole continuum of technical interventions in hu-
man reproduction. Ever since primitive man discovered
the connection between sexual intercourse and concep-
tion, human reproduction has entailed deliberate cxer-
cise of purpose and intelligence, an unavoidable power
and responsibility for the next generation. The guard-
ing of such responsibilities against external intrusions
is the essence of personal freedom. It goes without say-
ing that we would abhor state-enforced reproduction of
any kind. Conversely, to what extent should individual
patients be deprived of the possibility of using techni-
cal devices they, and their professional counselors, be-
lieve to be in their own and their offspring’s interest?

Many unanswered questions remain on the ethical or
technical merits of renucleation. Popular discussion of
cloning has probably overemphasized the significance
of a common genotype: Monozygotic twins are not
copies of an identical personality, especially if they have
been reared separately. They do resemble one another
more closely than other relatives, to be sure, and re-
nucleation could be a means of avoiding certain ge-
netic defects that arise from segregation. If, for other
valid reasons, renucleation is ever practiced, we can
clear up many uncertainties about the interplay of
heredity and environment; and students of human na-
ture will not want to waste such opportunities. So many
developmental hazards may be associated with renuclea-
tion that very extensive animal studies would be the
minimum prerequisite to ethically justifiable trials in
man, and the interval gives us ample time to ponder
the values in balance.

Our consensual standards of an ethical medical ex-
periment require that it serve a reasonable humani-
tarian purpose and that it have the informed consent
of the individuals concerned. The problem of renuclea-
tion sets into relief the general problem of parenthood.
Who else can speak for the welfare of the individual
not yet in being? Should parents be held in contempt
if they procreate despite the knowledge that they are
risking a significant deformity in their offspring?
Should they be encouraged to undertake artificial mea-
sures that will give their young an easier start? And
where is the boundary line between the responsibility

19

 

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A aa A Hay Ms A Mae

co i eat ale Sala: haa

at eR A i

 

of the parent and of the community for manipulating
a child’s development—the socialization or education
that predestines him to function as a particular kind of
human being?

‘These questions are properly applied to the destinies
of particular individuals born day by day. Gloomy pre-

20

 

 

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 Joseph D. Grant professor of
genetics and biology and chairman of the
Department of Genetics of the Stanford
University School of Medicine. He ts also
director of the Lt. Joseph P. Kennedy, Jr.
Laboratories for Molecular Medicine,
dedicated to basic research in genetics,
developmental biology, and neurobiology
for a broad attack on the problem of
mental retardation. He has related
responsibilities for research programs in
instrumentation, computers for laboratory
use and in the study of mechanized
intelligence, and the detection of planetary
life. Both he and Dr, Elliott Levinthal,
director of the Instrumentation Research
Laboratory in the genetics department,
are participating in the design of science
packages to carry out exploration of Mars
on Viking ’75 Project missions planned by
the National Aeronautics and Space
Administration.

dictions about the long-range future of the species
might be substantiated as a side effect of medical care
and other welfare measures that avert the pain of
natural selection. However, the pace of discovery in
genctics is so rapid, compared to that of biological evo-
lution, that we can afford to wait another 50 or 100
years before we tackle the species problem. We will
then have sharper tools and, at least, as much wisdom
about how to use them. Meanwhile, we have enough
to do in trying to minimize the enormous burden of
personal distress and anxiety that attends our genetic
load as it is manifest birth by birth, death by death.
Indeed, it is hard to see how we can make better sub-
stantial progress toward an ideal of human improve-
ment than by frecing individual families of the anxiety
and the burden of known defects. The general ques-
tions of human improvement (Lederberg, 197]a) apply
with equal force to policies of education and even to
the standards of health and nutrition promulgated by
pediatricians.

Summary

Advances in molecular biology promise to enlarge
our technical capacity to intervene in genetic problems.
Social and ethical factors are, therefore, likely to play
an increasingly important role in determining the ap-
phcation of new scientific advances in man. This is no
cause for great alarm, for the same principle already
applies to the use of surgery and of other medical inter-
ventions that could, in theory, also be applied for ex-
traordinary “renovations” of human nature.

‘The evolution of wise policies for the use of genetic
advances, and the surveillance of existing practices for
compliance with consensual ethical standards, and for
the anticipation of social injury, of course, require a
widely disseminated understanding of the probable po-
tentialities of various types of genetic intervention.

The most important influences on the genetic com-
position of the human species are likely to remain side
effects of other global policies: the movement of popu-
lations, transportation technology, the effects of war
and of discrepancies in economic development and
attention to preventive genetic hygiene, especially
through the identification and elimination of principal
environmental sources of gene mutation.

Specific options for genetic therapy include the
rapidly developing field of antenatal diagnosis (coupled
with elective abortion of threatened fetuses); cell and
organ transplantation; and virogenic therapy. The last
would entail the introduction of desired DNA segments
into domesticated strains of viruses; these would then
serve for the vaccination of patients lacking a critical
metabolic function which would then be restored un-
der the influence of the added DNA.

The renucleation of eggs (cloning) is also a theoreti-
cal possibility, likely to be of more metaphorical than
pragmatic interest. The discussion of cloning may help
to illuminate the ethical problem of parenthood, gen-
erally: What is the responsibility of each generation
for the biological and educational predetermination
of its successors?

In any event, the central responsibility of the ge-
neticist, gua physician, is to the welfare of his individ-
ual patients.

REFERENCES

I could not pretend to have mastered all of the works that
would have to be cited in a comprehensive bibliography of
the subjects of this paper. Indeed, the central issues might
be obscured more than clarified by too detailed an elabora-
tion.

A comprehensive bibliography on bioethics is maintained
by the Kennedy Center for Bioethics, Georgetown University,
Washington, D.C.

Further references may be found in the bibliographies of
the papers cited here and by using these, in turn, as keys
for a citation-index search of current literature. This list of
references has been limited to secondary sources and to a
few titles essential for the clarity of the text. The most secure
prediction that can be made about the near future is the
early obsolescence of this bibliography.

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AUERBACH, C, and J. M. Rosson. 1944. Production of muta-
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Briccs, R. and T, J. Kine. 1952. Transplantation of living
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FEICENBAUM, E. A., B. G. BUCHANAN, and J. LEDERBFR«. 1971.
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