Stanford M.D.

                    Spring 1973        Vol. 12, No. 2
STANFORD MEDICAL ALUMNI ASSOCIATION


                               I- .,"_ j   -, .~--- ----II. ., .~ ."-~-".-, _


The Perfection of Man

Social and ethical factors will be increasingly important in
determining the application of new genetic advances.
         by JOSHUALEDERBERG, 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 2.5 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 ~lnknoztin.
The main uncertainty is the liability of all autocatalytic
processes to burgeon unexpectedly in scale, or in clirec-
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, 197% @ American Institute of Bio-
logical Sciences. Reprinted with permission.

12

curing cancer. On the other, the a~~tono~iiy of the re-
search laboratory is increasingly caught up in irresist-
ible pressures at the periphery for social goals that are
orthogonal to scientific knowletlge: equal opportunity
in ctlucation and employment for minority groups and
women, amenities for the local community, and the
ideals of participatory democracy. (The laboratory, of
course, did ser1.c other masters in the past-vi[., the
ego-aggrantlirement of the chief Forschcr, 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
a so
1  foresee the outcome of complexly interwoven
trentls 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. TVhat is manifest is that
scientists will be less and less indulgetl 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 tlemantls a deeper un-
derstantling 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-
vironmcntal ravagemcnt. An even more tlurable com-
plaint may be the Ludtlitcs'-that new machines tlc-
prive men of a sense of worth in their work by unregu-
lated technical progress that ou~paccs human atlaptabil-
ity.

Scientists shoultl also seek a deeper understanding of
their own profession-what inspiration ant1 discovery
really consist ol' ant1 the forces that mold lhc choice of
researchworthy problems. They may then be more
likely to face up to the rationalization of their work
(even in ways that may load to their own technological
tlisplacemcnl); for example, through more efficient dis-
semination of research literature or through the rlevcl-
opment of romputers 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
effect% performance in different fields or that the dis-
ciplines themselves are most effectively and adaptively
organized?

This preamble may be summari7etl 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 tln?z
vi&d, 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 (Letlcrberg, 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 ;I mother who has
delivered a trisomic child. And we arc 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 ant1 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 ant1 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 hat1 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


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 seeds,
evidently depends on the diminution of Lein 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 tlesign
of a sect1 protein optimiLet1 for liiirr~an nutrition. With
ii more detailed analysis of gene-controlled protein
sequences, we would have ;I firm basis for the stepwisc
accumulation of point  mutations or recombinnnts
towartl that optimum. The substitution of threonine
for scrinc, or of lysine for arginine, in ;I seed Ijrotein
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 genie ex-
pression and with the traditional problems of diploitl
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
cells 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 ;I
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 x IOR) 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;
it 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

reasoning. It is difficult to see how striving countries
will be induced to limit their population growth so
long as the weight of numbc~-s is a l)olitical, and even :I
military, weapon in interstate competition. The tech-
nical IIIC;II~Y of contraception are improvable, but
scarcely lacking now. I\`c have little basis for optimism
except the hope that world ortlcr ;rntl economic niotl-
erni/ation may atlvanc-e in spite of the population drag,
and that these factors will e~icour;i~ge a demographic
reversal. The natural xntl ~n;~n-~n;~tle disasters that hnvc
afflictetl Beng;il al-e visions of the alternate paths.

Another crushing affliction of most of the \vorltl is
infeslation with animal par;isitcc, especially malaria,
blood flukes, ant1 worms. Environmental sanitation,
directed at vector control, has been the most effective
public health measure th mitigate these tlcbilitations,
but tropical countries are likely to remaitt burdened
with them for ~nany years nevertheless. The well-tlc-
fined life cycle of these par;lsites should make them
biologically fascinating, as well as humanely rewarding,
targets for more profound study with modern methods.
The attenuated Iilutant already plays ;I 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. I\`ith the flukes and
worms, well-defined niorphogenetic stages are involved
in the progress of a11 infestation, ;intl with the malaria
plasmotlia, it should be even easier to superimpose bio-
chemical analyses of the critically alteretl 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-
medium falciparum vies with that of OryLa sativa as a
further target of molecular genetics.

From the standpoint of scientific nntl technical nc-
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, oE course, conflicted
head 011 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 argutnent 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 WUI~-
kind and those 0E individual men and women. In many

14


arenas, utopian aims for the ordering of human affairs
might be ;rchicvetl at the sacrifice of intlivitlual liberties.
In the economic sphere, "from each according to his
abilities" is a plausible humanit;n%ln itleal, but it can
be enforced only with the apparatus of a police state
ant1 a11 arbitrary determination of what each has to
contribute. Apart from the alrcatly fatal obstacles of
political implementation, genetic planning fares frus-
trations analogous lo the failures of ld;~nnetl economies,
both with respect to technique ant1 to the validation of
consensual purposes. In the real world, social movc-
ments will continue to have much more incisive effects
on the human gene pool than any conceivable technical
atlvanccs that could bc labellctl as "tampering with the
genes."

Geneticists, in the main, have been so critical of largc-
scale eugenics that they may forget that the allegation ol
seeking to bred Supermen will be renewed in every
popular discussion. Some of my own efforts to outline
the difficulties ant1 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 CO deeper cx-
ploration, both technically and morally. Social atti-
tudes on questions like contraception ant1 abortion
have changed too dramatically in one or two genera-
tions to reinforce the posture of scmpiternity 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 untler-
standing; the principal target for its applications to
man is the alleviation of individual distress-which
the Idlysician 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 01 his patient.

Table 1 catalogs a number oE 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 shouId be called "genetic"

tlisezse ;irc also uncertain, for every pathology must
have both ;I genetic and an cnvironmcnt;tl component.
Many common diseases, as well as over;ill longevity,
h~vc ;I significant heritability.. r\bout 5 percent of ol'er-
all morbidity can be related to specific genetic defects
with ;I relatively simple b:lsil;: if ICC also take accoutlt
of the heritable component of pre\.alent diseases, like
schizophrenia, diabetes, c-artlio~ascular tliscase, ant1 so
on, at lea5t ;I fourth of total morbidit) (in mctlically atl-
vanted comrnunitics) must be attributed to genetic inl-
perfections.

Genetic Load, Mutagenesis, and Environmental Hygiene

The genetic load is, therefore, a forniitl;rblc p;irt of
the problems that must be facctl by mct1ic;lI practition-
ers ant1 tllcir patients. Plainly, preventive measures
should have ;I high priorit),, if we could, thcrcby, pre-
vent the intrusion of genetic defects in the first instance.
This may not nl~v;rys be possible-an unknown part of
the genetic load is "segreg;~tion;rl"; it derives fro111
hetcrosis; i.e., an advantage of the hclcro~ygote over
either homo~ygote. Natut-al sclec tion, then, tends to
keep both of the alternative alleles in the population,
notwithstanding the inevitable quota of impaired
homozygotes that must recur at cl'ery generation.

Heterosis is important to framing reasonable cxpectn-
tions for genetic improvement since 110 freely breeding
population can then be composed exclusively of the
healthiest (heterozygous) 1dienot)pes. 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 arc then crossed to 1"educe Yigor-
ous hybrids. The farmer who tries to use the$e, in turn,
as scctl coral courts tlisaster--n fact hardly in keeping
with racist mythology or with the naiver forms ol eugen-
icism.

Furthermore, the heritability of different diseases
gives no assurance that ;I single optimum genotype can
exist. Susceptibility to cancer JJKIY rdlect a low excitn-
bility of the immune mechanism; allerg). the converse.
Total freedom, both from cancer ant1 allergy, may be
physiologically unattainable. U'e have only provoca-
tive data about mutual exclusions in predisposition to
tliscasc, but WC 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 3 historical context of medical
ant1 olher cultural determinants that ha~c changed far
more rapidly than gene frequencies cati have respond-
ed. Furthermore, Darwinian fitness, or reproductivity,
is becoming less and less congruent with the stnntlartls
of somatic quality by which we judge ourselves and our
peers.

15


A.

B.

Table I

!iclectivc 777nliP7g:

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

a) negative - distracting, discouraging, or steriliring
tl1c "unfit"
b) positivc-

i) encouraging select pairs
ii) with artificial insemination, donor ("rational
germinal choice")

iii) with oral or ovarian transplant
iv) both ii and iii, or fertilimtion in ijill-0, followed
by implantation

x) extracorporeal gestation (test tube baby)--sPc
nlso euphenics

(i-v arc not very dilferent in tfieir ge77rtic consc-
quences)

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

3) By relationship of parents
a) inbreeding-The main impact is to expose reces-
  sive, usually deleterious, genes: increase phenotypic
  variability of F1; decrease the gcnotypic variability
  of later generations.

b) outbreeding-antithesis of (a). hlost cultures strong-
ly encourage outbreeding.

4) By age of parents-to forfend accumulation of dcle-
terious mutations and chromosome anomalies which
increase with parental age

5) By phenotype or genotype of the zygote or of the fetus
(antenatal diagnosis and voluntary abortion)-Earlier
selections would a\:oid the trauma of aflorting an cs-
tablishcd fetus.

6) By genotype of the gametes: e.g., separation of X from
Y or normal from defect-bearing sperm
7) With sperm of other species (compare [l] [b] [iv])-
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.

Innovutiof7s in Zygote Biology -Vegetative (asexual)
f>ropagation. Cloning. (Almost unit ersal among plant
W.)

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

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

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

,I)

5)

6)

7)

Somatic reduction in gamctc-forming cells in culture
(somatic inl,reeding)-should allow predictable out-
come of further matings front :I gi\,cn parent ruhith is
not now assured.

Nuclear tr;insl'l;lnt;ltioll-rcliucle;ltion of a fertilized
cnucleatetl egg. Genetically equiwleut to clauing Cram
the s0urc.e of the nu( leus.

Eull,r);o-splittiaF; to produce tlvins or multiplets. Not
to be confused with multiple owlation (occasionally
induced by fertility-promoting drugs). About one-third
of sf)ontancous twins arc monozygotic, i.c., arise from
the splitting of one cmlqo. Note also the of~f~osite
p11en0men011.

f~mbryo fusion (tliimcrism) -so tllat one indi~idu:~l
comprises t\vo or more genotypes. `l-his grades into
tissue tranapl;int;ition at later stages. It slloultl allow
diffcrcnt genotypes a new latitude for mutual comple-
mcntntion, e.g., n1cns s0?2(2 in co~~~~orc snflo. Somelvflnt
less than l/ 1000 lir-e births arc spontaneous cflimcrns,
but some of thcsc arise by other mechanisms.

C. Adj77nct.s f)-on7 sonrrrfif roll bioloF)`-For eugenic applic;i-
tions, these would I)c co~~pletl u'ltfl f~rocedures like B(5).
For cuphenic effects, alter4 cells can be grafted back to
a host or sonic manipulations done directly on his tissues.

2)




3)



4)

.Ugeny-directed alterations of genes
a) contro\.ersial claims of efferts of 1)X.-\ uptake in
mammalian cells following a long tradition of ,ge-
  netic lvork lvith KIN.1 in bnctcria
I,) incorporation of liruscs

i) experimental tumor viruses
ii) use of specially modified 1 irusrs
1) xiccination to induce immunity to viruses
2) \ irogcnic tflcrapy to replace missing genes
3) virogenic enhancement for superior pcr-
  formnncc-if we but knew the biochemistry
   thereof

c) incorporation of chromosome fragments transmit-

ted by cell fusion

d) specifically induced mutations - No plausible ap-

proaches arc now apparent.

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

Cell fusion to form somatic hybrids-Tflcse cells may
then lost various chromosomes to gi1.c many new
forms. Extends scope of (2). Can be readily applied to
fuse cells from "distant" species, c.g., fisfi and human.
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 tflc help of acfapta-
tions to thwart immunological rejection. In principle,
they might be domesticated. So also migfxt 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, 197lb; see also Davis, 19TO.

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 eliminatctl 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
         c
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 etlu-
catetl 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 useful to assert that a compound is mutagenic with-
out proceeding to it 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 ant1 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 woulcl 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:

Antcnatal Diagnosis

An increasing number of diseases will be reliably
diagnosed by cytological and biochemical studies on cell
cultures derived by amniocentesis (Dorfman, 1972). TYe
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. M'e can visualize more direct
assays for specific information content of DNA with
techniques for the isolation oC specific messenger RNA
and, then, the homologous genes. The DNA segments
can then, in principle, bc tcstctl in cell-free systems for
protein synthesis or, perhaps, even subjected to direct
analysis of their nucleotitlc 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 ;I 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 SC): of offspring
might encourage a limitation of family size (e.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.

Transplantntim

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

17


( I
,   ;
  t
/ ;

1 \

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 immunogenetic 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 last 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

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 clue
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-

18


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, ant1 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 bc a fortunate tocsin.

Viruses used for prophylaxis in man have been de-
veloped and monitored with scarcely more sophistica-
tion than that available to Jenncr. 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 WC 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 hat1 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-
F-Y.

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 bc 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
;I 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 tliscoveretl
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 stateenforced reproduction of
any kind. Conversely, to what extent sho~lltl individual
patients be deprived of the possibility oE using techni-
cal devices they, ant1 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 separ:~tely. They do resemble one another
more closely than other relatives, to be sure, ant1 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: ant1 students of humAn na-
ture will not want to waste SLICK opportunities. So man)-
clevelopmental ha7artls may bc associated with renuclea-
tion that very extensive animal studies ~voultl 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 mctlicd ex-
periment require that it serve a reasonable humani-
tarian purpose ant1 that it have the informetl consent
of the individuals concerned. The problem of renuclea-
tion sets into relief the general problem of pal-enthood.
Who else can speak for the welfare of the individual
not yet in being? Shoultl parents bc held in contempt
if they procreate despite the knowledge that they arc
risking a significant deformity in their offspring?
Should they be encouraged to undertake :lrtificial mea-
sures that will give their young an easier start? -Ant1
where is the boundary line between the responsibility

19


." ---- "-_-- . . . I    "". "._ ^" __- " __.

DK.JOSIWA LEDERBERC,~ native of
Montclair, ,Vew Jersey, anal a product oj
lyezu York City publicschools, Columbia
University, and Yale, won a 1958Nobel
Prize "for stztdies on organization of the
genetic material in bacteria." Dr.
Lederberg is Joseph D. Grant pi-ojessor of
genefics and biology and chairman of the
Department of Gencfics of the Stanford
University School of nledicine. He is also
director of the Lt. Joseph P. Kennedy, Jr.
Laboratories for Molecular Nedicine,
dedicated to basic research in genetics,
devclopmcntal biology, and neurobiology
for a broad attack on the problem of
mental retardation. He has related
wsponsibilifies for research programs in
instrumentation, computers for laboratory
use and in the study of mechanized
intelligence,and the defection of planetary
life. Both he and Dr. Elliott Levinthal,
director of the Instrumentation Reseawh
Laboratory in thegenetics department,
are parficipating in the design of science
packages to carq out exploration of Mars
on lriking'75 Project missions planned by
the ,Vaiional Aeronauticsflnd Space
Administration.

of the parent and of the community for manipulating   dictions about the long-range future of the species
a child's development-the socialization or education   might be substantiated as a side effect of medical care
that predestines him to function as a particular kind of   and other welfare measures that avert the pain of
human being?                     natural selection. However, the pace of discovery in
These questions are properly applied to the destinies   genetics is so rapid, compared to that of biological evo-
of particular individuals born day by clay. Gloomy pre-   lution, that we-can afford to wait another 50 or 100

20


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 freeing individual families of the anxiety
and the burden of known defects. The general ques-
tions of human improvement (Lederberg, 197 1 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-
plication 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 ther-spy. 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, qzrn physician, is to the welfare of his individ-
ual patients.

REFERENCFS

I coultl not pretend to lrnve mastered all of the works that
would have to be cited in a comprelrcnsive bibliography of
tlrc subjects of this paPer. Indeed, tlie central issues might
be obscured more than clarified by too detailed an claborn-
tion.

A comprehensive bibliography on bioetlzics is maintained
by tire Kennedy Center for Bioethics, Georgetown University,
W'aslrington, D.C.

Further references may be found in tire 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. Tire most secure
prediction that can be made about the near future is the
early obsolescence of this bibliograpl~y.
ARON, R. 1968. Progress nntl Disillusion-the Dinlcctics of
Modern Society. Signet (N.A.L.), New York.
AUERBACH, C. and J. M. ROBSON. 1944. Production of muta-
tions by ally1 isothiocyanate. Nntzc7-e, 154: 81-82.
BRIGGS, R. and T. J. KING. 1952. Transplantation of living
nuclei from blastula cells into enucleatecl frogs eggs. Pro-
cecding5 of the A'ntional Acndenzy of Sciences, lVnshi77g-
ton, 38: 455-63.

DAVIS, B. D. 1970. Prospects for genetic intervention in man.
Science, 170: 1279-83.

Dr BERARDINO, hI. A. and N. HOFF~EK. 1970. Origin of chro-
mosomal abnormalities in nuclear transplants-a re-evalu-
ation of nuclear differentiation and nuclear equivalence in
amphibians. Deuelopnentnl Z?iology, 23: 185-209.
DORFMAN, A. (ed.). 1972. Antenntnl Dingnosis. Uni\.ersity of
Chicago Press, Chicago.

FEICENBAUM, E. A., B. G. BUCHANAN, and J. LEDERBFRG. 1971.
On generality and problem solving: A case study using the
DENDRAL program. Machine Intelligence, G: 165-90.
GURDO~, J. B. 1968. Transplanted nuclei and cell clifferen-
tiation. Science, 219: 24-36.

HARRIS, H. 1970. Cell Fusion. Harvard University Press, Cam-
bridge, Mass.

IAEA Panel. 1969. New approaches to breeding for improved
plant protein. International Atomic Energy Xgency, Vi-
enna.

LEDERBERG, J. 1966. Experimental genetics and human el-o-
lution. American h'ature, 100: 519-31.

-. 1971a. Orthobiosis: the perfection of man. In: A.
TISELIUS and S. NILSSON (eds.). The Plnce of Vnlue in n
World of Facts. Nobel Symposium XIV. Wiley Intersci-
ence, New York, pp. 29-58.
   . 1971b. Biomedical frontiers: genetics. In: The Chal-
lenge of Life. Roche Jubilee Symposium, Basel, Switzer-
land.

  1972. The freedoms and the control of science: notes
from the ivory tower. Southern Califow7in Lnru Rezlieru, 45:
569-614.

RAMSEY, P. 1970. Fahicated Alan-the Ethics of Genetic
Control. Yale University Press, h'ew Hayen, Corm.
ROGERS, S. 1970. Skills for genetic engineers. xezti Scientist,
45: 194-96.

   and P. PFUDERER. 1968. Use of viruses as carriers of
added genetic information. Notwe, 219: 749.

21