—

NIOUT EE NR H SW OOSIMUILE NID WOON NDF OW OONSIMULE NN HOW OOS IMU EE WN OWL OONI OUT EE NN HO WOON DUT NN HOW COSIMUIE NINH OWONUIMUIE WPA

O00 00 00 00 60 00 00 J AFF EES ES EST IO) CHCA OVI VTS EN NI ATI OITA ANI BO So RO RO RO RO ROD DORR ASE St tt

Genetics Society of America August 31, 1967

Friends, colleagues, and disparate genotypes.

Marshall Nirenberg did me the favor of providing the very best possible
introduction to the remarks I would like to make tonight in the form of an editorial
that appears over his signature in the 11 August issue of Science, and I would like
to ask you to hear me first read that editorial. It's entitled "Will Society Be

Prepared?"

Sah fren

All of the foregoing is a quotation from Marshall W. Nirenberg.

I have quoted Dr. Nirenberg's remarks because they make a good stalking
horse for some criticisms which I would like to offer, and not in the spirit of
any kind of personal criticism of Dr. Nirenberg himself. I must say that in self -
defense, because his own accomplishments in this particular field are so vast and
so well known that I would hardly dare to stand up against him in his absence

without some sort of reminder that I may be exaggerating the import of his remarks,

 

y briefstatement—ef—them, and
that further elaboration on his part might given a different interpretation than
for the sake of discussion I choose to put upon them at the present time. Never-
theless, I think the language thet—he-hes-ueed will evoke a familiar chord with
neny~-of—yeu. %I think there is a reaction of fright about man's control of his
own destiny, in particular about the use of genetic as compared to other forms
of biological intervention, and I think it is important that we succeeda in
achieving a realistic point of view about what we can do, what we should do,

what is likely to come about, the kinds of information that we need to find for

ourselves to lead indeed to the wisest possible application of these new kinds ma

of discovery. I will take a few of exe! texts from these remarks, and comment on

them.
NOU WIR HOW OUTEE WIN OD 00ND UE WRI O00 IOUT EE WRI O00 TOUTE INFO 1D 00 SICHUT EE Ud NOP 60 IOUT FCN C> DOO MICH UTES Ui WOONIM UTE RH!

OD i Ng SN es Ts FT OT FT EG I TS TN NT NS ENS TS EAS NS Nd Vege he i fe ee hee he ge he WN NALA NN UNNI AS PODS RPO RID ROR Bt Ft et a et ft ft — pt fet

The most awesome phrase, and I have heard it at least twice tonight, and
hear it every day, and I use it myself on frequent occasions, is the reference

a n
to man!s power to shape his own biological destiny. This is an awesome statement,

and it is probably true, atl I'm not sure what
Our
it means. Tthink-—jhe central question about man's biological destiny is whether
we will have a posterity able and willing to commend us for our foresight, intel-
ligence and good wihl. Molecular genetics undoubtedly plays a role in the ultimate
answer to this question. Even more do politics, military technology, and what we
might call the religious aspects of owe eee generally. The way that we deal
with Indian famine and with Chinese nuclear power may be even more relevant to
whether there is a biological destiny of man on earth. We also know that that
destiny is finite in any absolute sense of the term, either with respect to
catastrophic accidents of our own making, or with respect to the long term future
cokes
of the solar system, and unless we, for example, peitent#e and propagandize the
universe, we do have a finite, ultimate destiny. I say these remarks in hopes
of achieving a certain re-focus about the nature of the problems that we should
be concerned about;if we look too far in the future we may overlook the <beam in
our own eye.

The phrase "the betterment of mankind" also offers many difficulties of
reference in any circumstances, and particusrly when we're talking in evolutionary
terms, which is the framework in which I choose to interpret Dr. Nirenberg's
remarks. I could ask whether it was for the betterment of apekind when pre=
hominids left the trees and moved on the ground, and had arms available for
the acquisition and inspection of objects. Will any intelligent species stop
evolution, in the conservative attitude that change is likely to destrey the
existing framework of the species? Will it insist on having a completely rational
view of the events that concern the existence of future generations many years,

la
centuries, millenia hence, again the framework ,which we must judge any issues
Fe ON en nn et eee eee eee een mt me men AE = 1 oth 4
IOUT EE UR HMOWOUIMULE WIN HO DONIMULE UNH OWONIMULE WN HOW 00 IOUT EE WINS 10 00 0 0 OE ee oo ie ie

that concern the evolution of our own kind. But if we do insist on that rational
possibly
outlook, how can we/anticipate the unknown social and technological milieu of

existence of such future generations? The one principle that we can probably
find common ground on for all of us is to avoid rash irrevocability. of the de-
cisions that we make. Unless the very exitence of scientific thinking is
included in thg/irrevocable thes we might wish teftold in order to avoid change,
no isolated experiments can be regarded as globally irrevocable steps. In
fact, they are indispensable for the wisdom needed to judge which institutions
should be set up. When Nirenberg refers-er recommends that when man becomes
capable of instructing his own cells he must refrain from doing so, I believe
we should translate that into "We should be very cautious” about instituting

of
social and political frameworks/change which constitute irrevocable steps for

W4IS-
the entire species". But these remarks could very easily be interpreted, and

point of view
some of us might be misled into adopting a fmxmuiu that suggests that we not
undertake any isolated experiments whatsoever in an area so full of mystique.
gaxutnexxunrixy the genetic programming of human cells, untki we can under-
stand all of the implications. How will we ever learn what these implications
might be if we never do any such experiments? The must distinguish the rash
irrevocability of isolated events in other spheres $s those which would apply
to experimentation with single organisms of our own species. History tells
us that a nation infected with nuclear power has no choice but to use and
develop it in the existing context of world affairs. A single nuclear detonation
was an irrevocable event for the politics of our time. It is doubtful, but not
certain, that any nation would make quite such a threatening use of genetic
weapons, and they are likely to be less immediately impactful, and to have much
longer time scales than the physical ones, which will permit some possibility of

intervention in the social misapplication in—the—paemature—coctet imposition of

the single standard of biological control.
ID NID NI NINE NINE Nd NE A a ET RT TENE TN TRE TRG BRS TRS DN IN NE De ENS Dh Bd ES Lede ee ee tee ie hes fee me fe he NUN NAL LANL A,
f PO PORO ROR ROR Pt be ht bt

4,

With respect to future developments, Dr. Nirenberg makes some remarks that
I must characterize as imprecise. He refers to the synthesis of messages, and
their possible use in programming twe cells. Whether the messages are synthetic
or natural, so long as they are calculatedly used, would beem to me to make
very little difference. I think when we talk about programming cells, and talk
about messages, we should inquire for some greater precision into Just what kinds
of messages we are talking about, and what impact they will have on respective
organisms. And the harm is that language of this kind read by laymen, read by
political leaders, read by religous leaders, may be misunderstood, that very
important distinctinns may be blurred, and that we may end up with significant
restrictions on our sense of freedom of action and experimentation, which in turn,
as I have already remarked, is what we must have if we are ever to achieve the
kind of wisdom that has been alluded to. Some of these distinctions are with
respect to somatic,vs. germinal effects of these messages. Are we talking about
the now conventional messages of the messenger RNA { the means by which DNA trans-
nits/information to the protein synthetic machinery) or are we talking about the
message which is implicit in the DNA structure of the cell? na are we talking
about somatic effeets or germinal effects? In general somatic effects are highly
personal, An RNA megsage that I may use for the repair of many of my own genetic
defects is something that may help me live, but will surely die with me, and it
is very difficult for me to distinguish the social relevance of the use of an
RNA message for the remedy of such a defect in my own person from that of any
other aspectz of medicine, eect in fact, many therapeutic agents are already
involved in this kind of meddling with my somatic genetic programming. If, for
example, according to most contemporary theories, I were to partake of the use
of a hormone, its purpose is to elicit the calculated production of specific

messages in certain of my cells in order to make protein synthesis occur in

cells in which it otherwise would not. If I were a diabetic and could anti-
eee eee ee eT TF RD TD RD RS TO TT DU A AS SNS Fagen chee pe he tee ee ge ee WN CANAAN
3 ANDO BIRO RO RO ROR ROD bb

5.
cipate the possibility of taking a single shot of the appropriate messenger
RNA to reprogram the synthesis of insulin in some of my liver cells after my
pancreas gave out, I think I might resent any blockage to my taking advantage
of this on the vague grounds that this is in some general way a genetic message
that we should refrain from using until we may know for sure whether it will
ultimately be for the benefit of mankind. If we are to use that criterion, we
should use the criterion with respect to every medical intervention for individual
human betterment. In fact, I think it must be stressed that the point of view
which is implied in the presentation of this editorial runs counter to the funda-
mental responsibilities of medicine‘ The-—fundamentad—rnespensivitity of-medieime
4a the care of the individual patient. It is certainly the concern of the rest
of the social milieu thatthhe sum of xm care of individual patients works to
the benefit of the entire community, but a literal following out of the pre~
scription that Dr. Nirenberg has presented would be the total stoppage of medical
practice. Show when we come to germinal effects, of course we must have some
much clearer idea of what we're doing than might be the case with the personal
intervention of somatic repair. If the ‘use of a medicament -om—me has an implica-
tion not only on my health and my survival and my longevity, and my ability to

perform, but also that of my progeny, then of course we would insist, emé-t-
think—id a es ¢ 4 per~ptetepieintoineis!

Ht
that we have a clearer idea of what we're up to. Here we are already guilty of
some sins, I think most geneticists would deplore the sometimes careless use
of anti-cancer agents, for example, that are known to cause chromosome breakage,
and are known to cause mutations, sometimes possibly in patients who may still
have progeny, and of course we have had a very necessary and very important
furor about the indiscriminate use of radiation. If the reports about the

breakage of chromosomes by LSD are correct, there might indeed be a very strong

rationale for social control of the use of this agent, or for the compulsory
eee Nt TN Nat Nat EN Natt That ON Fat ON UNA EN TN Tat UT TN UN Be oat Fagen eee Gee me fee ae en gee ae pe AA NAAN UAT RO RO RO RO RO ROR ROR ee ee en et pt rd Pt ent et poe j

6.

sterilization of individuals who insist on receiving LSD, because they may then
be laying a basis tor/very severe penalty that society as a whole must adopt
with respect to the increased incidence of congenital malformation.in the next
generation. Here again, I don't think this is what Nirenberg was driving at;
if he was concerned primarily about genetic messages with germinal effect, I
don't believe that either he or I would be that greatly exerciseal about the pos-
sibility of some transgression in enue experimental context. The occurrence of
an occasional individual whose genotype is other than it might have been xk as
& result of the use of genetic message of calculated composition Pa some point
in its formation just does not have that kind of social impact. aor yout
kuxe to be cautious about, but it is a caution already within the framework of
medicine as it is now practiced. A more precise statement of what I trust are
his concerns would be a caution against the imposed social control of those
techniques, those apparent benefits, those advances that molecular biology may
help to bring about. And in this we have a certain analogy with rational
germinal choice, as has been advocated by by Huxley and Muller, for example, au.
f Muller was constantly being misquoted with respect wkk to his advocacy of the
use of the technique of artifical insemination of chosen donors. He had in mind
individual choice of specific genotypes mf as sources of sperm for the production
of what he hoped might oscasionally be superior kinds of individuals and he was

constantly misinterpreted as advocating social imposition of such germinal choice

on families that would have preferred to make their own mistakes rather than

adopt those of the community in which they lived. New-it—te—possibie—te-—argre;
GL
S21 0e+inee—LhavreangTed my seri eee that distinction isn't as easy as it

might appear. The mere introduction of an attractive technique, of a technique
which seems to confer a dertain degree of social benefits, and which has unkrown
social hazards, may lead to its social adoption, bIf this is the problem, this

is what ought to be stated, and this is what we should attack. I think, though,
DDI ON EF NF ENF ENF PN FN INF TR BRD FOS TN TNS Os Br Ue er Ts Os Pe Ee Vee ee ee i ee he ee eee NAA LA LNAI ROR DORI RO RO DORI RID et ee ee
NIDUTE WD HM OWOOSNIOUTE NINH OW 00 SIMU EE NDI LOCOS UE WN HOW NIMUTE WN HOW CON OUT EE NID HIO LOCO SICUTEE NN IW OONIOUTE WN HOWWONIOULE WDE

7.

that most of us would agree that while isolated modificafitons of existing genotypes
in either a random way, or in a calculated way,can increase the range of variability
and sometimes bias the range of candidates for natural selection to operate, tut
the overwhelming source of man's biological destiny in the sense of the over-
whelming basis of the changes in gene frequencies axe the changes of the genotype
of the human species come from our physical and cultural environment operating
by natural selection; that differential reproduction is overwhelmingly a more
important source of the definition of the next generation than any isolated
changes in availability of individual genotypes.

Now Nirenberg says it has not been pessible to program mammalian cells.
That remark, strictly within the context of his statement is correct. He was
talking about the use of isolated DNA operating to replace mutant genes by
other mutant genes or by normal alleles, by anabagy with the well known pneumococcus
transformation experiments I_shourid-remazk—thet (that possibility has been known
for twenty-nine years, It did not require the development of synthetic DNA, ve
actually sccomplish-she-feet. But-es~er-metteroffeety-t~ean.t..quarre), with
Niznenbere“s~stattiient in the precise Torii “in which he Mat@-rts-bet-i-vetteve-we~

a ‘tn : :

have to consides—-thie—irr-a—somewiat Ilhreer comeess. -Gan we in fact program
maithalian cells, in the sense of introducing genetic information of known
import, calculated to produce an explicit purpose related to the genetic
machinery?, As—e-matter—of-—fact we do,—im—this—lLight, already practice biological
engineering on a very large scale, and we are doing a rather sloppy job of it,
and since this particular element of applied biology may indeed be a prototype
for the way in which we may end up broadcasting favorable genes in other ways
in the future, I would like to spend a little more time on it.

I am talking about viruses used for immunization. Polio virus particles,

measles virus particles, any of a number of other agents have been developed

in forms whibh have been attenuated in order to reduce their acute pathogenicity,
TN NE RT TOF TNF NF Rat PRP INS PR OR PRS EN NS Te Oe a ee ge ee te pe te te ee WANA AA LN UN RRO RO ROR ROR RI DIR ee ee et Pe ee

so as to make convenient the job of immunizing children so that they will not
come down with frank disease. tear, I don't want to rock the boat on this ques-
tion; I still think Iinmunization is a good thing tee, and I don't deplore its
development or its application at the present time. But I think I must speak
out for a much more intense study than now exists of the human impact of these
practices. It is very sloppy, it is unconscionably sloppy, considering the
scope with which this form of biological engineering ;is carried out at the
present time. The use of live virus is as sloppy first of all because mf the
techniques of production, monitoring, specification, characterization of live
viral agents belongs to the dark ages. I-ecen-give-you-empivicalproofof—that-

~statement._hy the fact that approximately e-thindeer half a@ a billion doses of
«
{

SV-4O virus were included in the polio virus immunization of the last decade!
This was a passenger virus, originally, in fact constantly present in the
monkey kidney cells that we used for growing both the Sabin and the Salk vaccines.
It proved to be more resistant to formaldehyde than polio virus, and therefore
was particularly prevalent in Salk vaccine preparations since these were used at
a higher dose in terms of total virus particles. It was also present in the
Sabin preparations. It may have been a subject of greater concern in the SAlk
virus because this is administered parenterally and the SV-40 would not have to
face the barrier of penetrating the intestinal mucosa before it entered into the
general circulation. SU-40 is a virus which seems to be a harmless passenger
in the rhesus monkeys used as » seunees of tissue cultures for growing the

VErizx
polio xmmxine virus - in fact, it is very difficult to demonstrate the virus
in that species and very difficult to demonstrate it using human material, and
one needs the green monkey to obtain good plagques with enough cytolytic action
to demonstrate it. It's a notorious virus because it will induce cancer when

injected into newborn hamsters, but after the hamter is a few days old, it has

no known important effect on these organisms.
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&

4°

9.

It is a little late in the day to raise any alarums about this particular
subject. Nothing very catastrophic actually seems to have happened, in spite
of the fact that many millions of children and adults have received rather large
doses of this virus in past history. The Public Health Service thinks badly
enough of the procedure that it now prohibits the presence of SV-40 virus in
current batches of wzaccine, so with one hand we have expert assurance that it can
do no harm, but on the other, well,we'a better not have any more of it,

I deplore the fact that we have no way of knowing whether either e& the
SV-40 virus - bet—me—sayy-pesttenterty“the DV-so views - or even the attenuated
polio virus - have caused more subtle deleterious effects on mankind. We may
never know whether the use of these vaccines was for the betterment of mankind,
because we don't collect the kind of data that could enable us to reach this
conclusion. It seems rather likely, judging from ohher characteristics of the
present generation, that these viruses may have caused a reduction in IQ of the
contemporary generation. Mketkexr If that were a matter of 20 points on the m
usual scales, we miggt have discovered it. If it were a matter of 2 points, we
couldn't possibly have discovered it. And yet an average reduction of 2 points
of IQ, whebever-that—mesns,—but_uheberer~ie-sebinda-statement like that, would
surely be regarded as something most deleterious to mankind. Well, it could have
happened. It could also have happened that the IQ's mye went up py, B°SE* Bo,
and our current generation may be too smart to want to bother with taking such |
tests very aggressively!

One of the principle indictments that I would make in our contemporary
exercises in genetic engineering is that we don't realize that we're doing it,
aiid we're not following what's happening. One of the reasons for this is that
we are looking too far in the future instead of /yesterday and today for the
kind of wise outlook on what is happenzing right now in the species in the use
of contemporary applied xk} biology so that we can ask the right questions on

{
a large enough population base phat perhaps we could tell that what's going on
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NDT E WR HOW O0 IQUE ND FAO WO SIMU EE WIDOW ONT EE NNO W600 SIMU EE WN MO WD CONIMUT EE WN LOCONICUTE WIRD HOW COSI UTE WN HOW OONIO UTE WIPO

10.

is for better or for worse. Now, it's not implausible that polio virus might
get into some of the neurones of a developing child and have some specific
morphogenetic effects, in_that—eonteet,—_but—we-heve ne-ay-06-danewing= tee
In fact, it's even possible that the neurone count of children who have
received these viruses is larger than that of other individuals in the
population, by 10 or 152%, and we would have no way of knowing it from our
existing data. I can't stress this point too strongly, that we do not
watch our populations closely enough to see ewen major movements taking
place within then.

My second criticism has to do with the way that these agents are

prepared,

 

wheat we are not taking
advantage of the kind of techniques that Nirenberg and Kornberg and I and
others like to use daily in our own laboratories in a more rarified research
context. There is no excuse for virus preparation being as contaminated as
polio virus was, bere from the difficulties of detection, the only

way it could possibly happen is that we are content to use biological reagents
of enormous potency without taking any real care to see that they are pure,
homogeneous and That they are intended to be bx, physical chemical

criteria. It was enough that the polio virus preparations produced the

right kind of plaques on a selective group of tissue culture media for them

to be authenticated as being pure polio virus.

  

baboratories.
Bue Che virus agents used for this kind of genetic engineering applied on a
large scale to our population are crude culture filtrates. They are subjected
to no biological or chemical purification whatsoever before they are

packaged in sugar cubes and passed out to the kids in school. And I don't

see any excuse for it except the fact there is a moth that virus
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ll.

immunizaj$ion programs are mass medicine, thet—they*re—net—te—be—done_under_any
Che cumst.2n668ib th thank ind GF seem tert Trine G edited LL
exerciseordinssy-medtetnes and of course they're not at all to be labelled

as biological engineering having anything whatsoever to do with the new
a

molecular biology. However, before we become to exercised about biological

engineering and its hazards and a lack of decision in our understanding of

the mechanisms that we're using on such a large scale, I think we ought

also to remember that we practice psychological engineering also on a very,
very large scale. horzible_cxample—_of
it, is_peyehoiogicai-engineering 15 tertainty—onder—very—vrehonent-~ssetat

Conta?’ It's compulsory. It's mostly pretty-well programmed from reasonably
central authorities, It's equally unscientific,and we call it education.
Ct I think we should consider very literally that education shapes the child,
shapes the character of the next generation in just as explicit a sense as any
of the biological innovations that we have in mind and possibly if you believe
some theories of the nature of learning, even from a morphological point of
view, that is if you believe learning has something to do with the morpho-
genesis of the central nervous system as many people do. If we try to
look beyond the specifications of what Dr. Nirenberg has laid out so con-
veniently for me to use as a point of exposure, aight ask what else would I
quarrel with him about. I've already quarrelled with him on the time scale.
He says something twenty-five years in the future and I've tried to point out

that we're talking about events that were well launched dive years ago or

ten years ago. The future events that he's talking about happened yeaterday.

. even

within-the—-frame~work- vf -vwirat’ te-wae-talLking.abouty-the-twenty~five-years..
tang
ie-muveh~-too~-torge-2t ine ...diewamem, permit me ,to indulge in some of my own

a
hypotheses of sources of evolutionary innovation. Let me begin with the

Te Bon
most explicitly germinal | i ne
re

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12.

Here I would like to go back to viruses. Some of you may have been puzzled
exactly why I called the virus immunization an example of genetic engineering.
Well, let me illustrate what I meant by a hypothetical proposal that was put
forward most explicitly recently by R . He found that in tissue
culture the Thy virus will, ss-manyviruses—to;~te-feet as all
viruses do, induce the formation of certain special enzymes, many of which
have a perceptible relationship to specific virus growth in the cells in
question. Many viruses for example induce a unique Caegperidert Rinses
Most of the bacteri@ phages induce unique DNA polgmerases that have properties
somewhat different from the typical DNA polg¢merase of the bacteria that
they previously infect, and so on. So, in fact, it is nog” regarded as
commonplace to think that one of the special functions of the information
in a virus particle is to impose a few special enzymes that are related
to the unique replicability of the viral nucleic acid as compared to that |
of the host. In addition, the virus generates a capsgbrotein to protect
itself outside of the infected cell, and that's what viruses are all about.
Induced enzyme synthesis by viruses in a rather non-human context are very
familiar now. Dr. Rodgers at Oak Ridge noted, and I believe others have as
well, that the Shope virus in tissue culture would also in induce another
enzyme, arginase, which has no obvious adaptive urna fe Pre virus,
but we take it for granted chat “due to our own myppia that we areunable
to see why it's there. That waa a stepping=stone to another finding of his,
namely, this waa reported in Nature last December, that a considerable number
of people who have used the Shojee virus in the laboratory had very low serum

any laws, on . pretty convincing
fase that they are statistically different from the

K

x SEP by-theedy ~<a ree Ae 5 oe et
ay

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13.

rest of us, and-though I do not believe he has definately demonstrated that

ww
this is the same phenomenon as has been demonstrated tissue culture, it's

indeed very plausible that virus workers in the laboratory have acquired

infections with the Shoke virus which is known to have no effect in
. D> a Lf. °
Man, but that they have indeed been cay cad 1 infected that some of those
been to .
tiddue cells have/induced/a form a particularly active argenase -and—ehts

’

 

This has had no

\
perceptual effect on the performance of these individuals unless their pre-
fr

Qa. '
occupation with the Shoke visus is somehow wetet@i to their low serum argenase !

 

J
hou ‘ i ee
types.ofman.that...can-beaday- make ° for-phenemene®--
aeetiebi. But you could not have told them apart by looking at them or by

“ang
watching them, you had to measure their serum argeny to know that they'd had

any previous experience of this kind. ted? this may have been the first
understood example in Man of the appaxamk appearance of a virus~ induced
enzyme as an augmentation of the genotype of these individuals, at least
with respect to the sematic behavior, these individuals are mat stigmatized
by the fact that they have some additional genetic information than what
they were born with, the information coded by the Shojfe virus for the pro-
duction of this specific protein. M dnd_thatde-cugquosednuiywe don't know
of any use for argenase in Man, Tdon't—helieve._there..ase—ady-engenrase”

humans..known—os—-eny~genetie—diseasestiat Nipir be iicorperate d
iirwiearay so we can't cure any known metabolic defect, Tf we could just
find one it might make a very nice case for using Shqke viruses in a
constructive sense. The-virus—dees—net—teseti————~-———_i 2 these-peopie
py-the-way, aid tiat tt appeere—te—grewn—itr-2-erypete—Sarm_to_leave at

whether or

   
ee eee ENN EN NN NNN at Eat Nal OMe Fat Pat EN EN Ee FNS Eat VN ae Ue Be Ee Te Ne Be ae Ce ee ge pe ee pee ee A NL UA RR RO RRS RRO RRR et ee et et ee
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14.

 

Rodgers proposed {lees look for viruses that make more useful enzymes, for

example, tet's—took—for-visuses-that maka will induce the formation of
phenylalanine hydroxylase, and. you all know that we could then cure

PKU at a fundamental level, we might even want to get into the fetus and not
wait for the birth of the recessive homozygote who might be impaired in his
mental development because of his accumulation of phenylalanine

on an ordinary diet. And if we can't find such viruses we really are just
in the brink of being able to make them, that is a possibility of splicing
a messenger RNA that codes for ordinary human phenylalanine hydroxalase to

the viral RNA of one or another infectious virus seems like a very plausible

: ’ ‘7
qa mame ce con

possibtie, both in the point of view of the chemical steps needed to fabricate
such hybrids and from the point of view of the likely persistance of such
xkxaua viruses themselves in much the same fashion as the original passenger
viruses would have done. So this would have seento me the nearest thing on
the horizon by way of the calculated yeast of viruses for genetic engineering -
Tui >

and soit occured to-me—it's exactly what we are already doing for immunization
purposes. The only difference is that the induced enzyme which Rodgers is
calling fory is, in fact, an induced antigenic protein which _may—indeed—ex be

eee encoded by the
viral nucleic acid, yhe we would like to see aaa prodeced in the human

being who receives this information whe-woutd—tike—to—be-—produced—on a life-
long basis (s0 we don't have to reimmunize}4e-gad the purpose of introducing
that protein is to evoke an antibody that responds against it so that you will

have immunity covering against infection by other virus mxm particles. But
bs

ee ee eee ee a eee nn NT NE Ne EN TN EN EN TN ae EN END Nad EN Ne TN Ee Nr ON ON le Vee ee ee ee ee AAA AAA AA RRO RO RO RO RO RO RO RIA et ee I

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15.

it%s fundamental biological operation is exactly the same as that of the
late addition of the gene to the organism so the calculated production of
the specific protein encoded by that genetic information.

ck

This has come to the top of my list as candidate phenomenon for human

intervention because it's already here. It's hard to think of explicit ways

in which soneunt-the germinal changes, -but—many—ef—us—are—concermed—on-—hepe
by heart

might be brought about under calculated control. One wonders exactly how

we are going to introduce nucledtgpe changes into germ cells so that they

get into the zygote, otherwitse-you-are-tatking about spmeatic—sex. ~~ Thugs
14¢¢1e—pussled—how-we-widi—ever—be—abie—to-do” tira without doing something

else first, namely enabling the vegatative propagation of an existing
Organism. My argument is that we will somehow, if we are ever to get to

the stage of the kind of genetic surgery that I think was in the back of

Dr. Wirenberg's mind, have to be able to manipulate nuclei of specified
origin to do something to aia hie then put them into an egg so that they

can operate in the normal developnent? nfetkncio. -And-—-woutt “ttke~to—rerind
-yor=mmet if we can do that, even if we don't alter the genetic composition

of that nuclefs, we have already accomplished a major deviation in the
reproductive habits of our species from an evolutionary standpoint, because

=
we will have introduced vegatative copying of existing genotypes ( sed—that

implye—e-necessity—for—secenbtrartun at every pernereation. We—sdiwese_do
have—to—face—up-to-the—ttketthoot” that re technology ror tits witt-be-

.

dieeovered. As a matter of fact_it‘ts already been done long sinee, but—se

nany—of—these-things hevetr-seme-centem, but so far only in amphibia.
4
t
I'm talking about Briggs and } <j uy $ experiment on nuclei 1
transplant ationgwhichlye. usuatty thought-of—in tits tight beeause—cheis
~ ti tidtiy examples they coulttake-nvetet-fvem-differentiateade
NOU E ND HOW OMIOUIE NIN HOW OSI ENDOW OO NIOIUT EE NDF OW 00 SIO UT EE WD HO LO CONIUT EE WN DOH O WOO NIMUT EE ND IO LW COSI UTE NID HOO OoSIO UTE WIDE
—

DDD i FN tg Nr ET TB ID NTS PR PS Spee ee tee de ee ee UN UAN UNLALANA RORRO DO ROR ROR ROIIRI  ePe e  e  e

   
 

16.
po
tissues, put them into eggs and get normal development. ually
found very considerable restrictions on development, ut they always do

Yeport a few cases of seemingly normal deyst6pment from such transplanta~-

. 1 nee
cme ft. Mt 4%,

ao here re ,
tions, and Gurden working! aigeetent species has had considerabl
OO g
different luck in this respéct ,and what's outstanding about Gurden's
a

experiments to my mind, is the frequency with which

    
  
   

repetitions of th
essentially normal development can be obtained from the nuclear transplan-
tatéon of tissues of much later and sometimes even adult origin into enucleated
eggs. So that vegetatively reproduced | frogs” are almost a commonplace, but
——

how long will it be before they are commonplace in many who can telly But

I don't think any of you can give me any fundamental biological reason why

man should differ from amphibia in this particular respect, Why nucl&a~—

transplantation should work any differently in man than it does in ampbhibia.
Gimmie would be a prototype of the base-line experiment that would have to have

been realized in order to exercise genetic surgery by any route I'm able to

think of at the present time, and I think it'll be there first. Hopefully

conmected/am this is a paxkwaxyx topic that has fascinated a few people

in every biological generation. I'm reminded that ximksagx Holdang referred

to it and Mrs. Holdang; Helen Spurway, actually attempted a demographic

survey to look for the possiblity of partheno_genesis in man. She found

that there was a certain confusion about what _. weg bry A actually

ee

~ment. You may recall she advertised fg@r examples of this over the BBC

Pe tenn
about 12 or 13 or so years ago. She did so not because of-the-possiblity..
etparthenogenesis was a new idea, but Naame because a diagnosis of itg
aetvettytraving -tappered—appeased-—durilig tirte—timev—-Li. became possible by
the development of our udderstanding of the genetic transplantation, te-be~
abie~t0 devetup—ebjectivecriterte of the yenetie-seretionship-of-effspring”
to parent, one step-better -even-then—bieod-greup-compartsours would trave

wAS
ome; Her idea was that if any example of proported parthenogenesis
ht

TT TP TT TOD OG OG TNS TNS TN TNS NS ET NS ES te ee te te de te ee ee UN NNN UN ALAIN ROR PO ROR ORO RID DIRE bot et et
NSIDULE NHS WOO NIOUT EE NINH SO WONIMUI EE WIN HOW OOSIMUTEE WIN OW 00 SIOUIE WN HI OW OONIMIUTEE WNHO WO0SIMUIE NN HOW OSI UTIE WN HOWOONIM ULE UND

17.
passed the oter searchers, then she ought to try reciprocal skin transplan-

tations, and if they worked in one direction at least hich is the expecta-

ote
tion for parthenogenetic set )ymost any mechanism o&-perthenegenesis than

corroborative
it would be pretty good sakeamhakkxx evidence that it actually happened.

Her failure to find an un equivocal example, says nothing about the future,
either on a random or a contrived basis. And I was really quite excited to
see an article in last months ‘cenetice by Olson and-l—forget—the_name—of
hie~cotieague-at-Perdue, on parthenogenesis in turkeys, where he remarks

that the kkgkxfxx highest frequencyof parthenogenesis in these birds is

a fundtion of the simultaneous presence of an appropriate genotype and of

the Rees “ virus infecting these birda! hice substantiel yields of several.
turkey eggs parthenogenetically produced, are capable in quite a few cases

of developing into normal male adults, s0—you-know-wiret—thehetegenstic—son——
is,.ase—ebvrendy~known. Well, again, if it can happen in turkeys, its gping

to happen in man i'm quite sure. tails tay evolutionist looking at what

has happened particularly at plant species is likely to remark that experiments
in vegetative propogation are likely to have a much more profound evolutionary
impact on the further development of the species than is the occurrenceof any
other sort of variability of genotypes present at any given time. These of
course can work together, but the point about” oe of course

is that it is such a ca answer to the woes prayers. It the way

of expanding an immediately adaptive genotype to the circumstances thén
existing, which is of course what the (ugenesis Yare crying for, and well, you
worry later about what happens when the emmironment changes or gour ideals
change. I¢hinie-ebro 2 very reasonable predicate for future development
besides the viruses that we may introduce forxaymakkeak somata eps

(we may have to generalize our concept of the virus in a couple of directions)

one_for which there is alseady—ample-precedances, is that it takes very little
a

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NOU E NS HO WOONIOUT ENNIO WOO SUIMUT ENDIF OW O0SIMIVIEE NII OW OO NIUE INI HOW OONICIUT EE WIR PO WOO SIMULE WIN HMOWOONIM UTE WN HI OLOOOSIGUTE WARD

ee ee ee ee enn Ne ee ORF ear Rae Fhe 2

18.

to turn dm a virus into a p> a It’s only necessary that the virus be
very adherent to the embryo on its way through or be passed through the milk,
or be actually present within the cell of the egg as well as other cells of
the body. There are any number of viruses which defacto are inherited as if
they were( ip} asmogens) even though I believe in mammals there is no archer Ce ©
example of actual trim oval 24757 low“ pangmission of a virus
particle. I may be wrong about that and I'm not sure that pragmatically it
matters very much from the point of view of the potential human impact. If

it is in fact true{ that mothers who are infected with a virus eee Ce he eG
introduced are going to pass that infection onto their offspring, it's hair—
splitting to g#@ the question whether that was done through some external

to incorporate dSmmunizing viruses in this way, axxagx but as a matter of facg
the odds are shat we would prefer to avoid it. The reason we will want to
; avoid it axz is that by all odds we want to keep the next generation of
infants from being builtin paseat to polio virus origin, ‘which they are

likely to be if that antigen is present wn oof Ltn . Wat that
also suggests the kinds of antigens that we wookd indeed want to be sure are.
pretty regularly transmitted, ond_1 Gnagine, for example, wanting to produce
viruses that have a seet-of.pasené-=-geneedc capability of coding the more
common histocompatibity antigens eesmected So wae to give these kids
fresh kidneys when they are adults and their old kidneys have been worn out.
But gkeyxilexxapxaxamk this kind of engineering does represent a very plausible
way of getting around some of the other engineering problems of building
genetic information into existing chromosomes. Faother way to

do that is to avoid using/existing chromosome and put in another one. And

what I envisage @s seummg the next step along this line is building some

very small chromosomes with just a few genes on them and transmitting these

from cell to cell, for example by se&$—fusion which is already a very well
NOU WN HOW SIMU WN HODONIOUTLE UN HOW00NIOULE UN HOW 00 IO UTE WR HOW OoNIONUTE WN (L000 UTE WINO0D 60 UTE Win ea DWeoNIUTE LINE

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19.

authenticated technique, and is able to produce ) Peshould—tihe—te—semind To)
of—webey somatic cell hybrids between forms ad distantly related as fish and
man in tissue culture. These hybrid | Range types do undergo very striking
>

| eneusete?iBerechanges: once they are produced they eventually shake down to a
number of Seruhe ep lineg-and we're just/very beginning of understanding
how to control this and what it takes to produce a balanced Ateitdtype that
is able to be well adapted to the circumstances of tissue culture like of
any one kind. I think you can see what can lie behind that, by way of very

detailed manipulations not of the molecular biological level, but at the level

of chromosomeg introduction for producing new genotypes. Combine that again

Put re AtCh/ me ,
with ausimax transplantation and we really do have 7<"''"*© genetic
engineering on a very large scale. 7

Up to a few years ago I think gametic selection would have been

f

near the top of the list of anyone who wanted to look past the usual ap opera-
4

tion of contrived somatic selection that is the ordinaly forms of selection

of somatic phenotypes. This is, in fact, turned out to %e almost the

least promising of all. It does look as if the gamete are expeesssing

 

a very small peeportion of all of their genes and 4f you manipulate a gameton
being in such a way that it tells you what its’existing genotype is, at the

moment at least, you've removed the possibility of using that same gamete

 
 

for any other purpose, for fertilization or whatever. But I think wa before
we reach too rapidly at the very Aneffective methods that are now being proposed,
that would have been proposed“in the last 40 years for gam waéeeeie manipula-
tion in man we could wd some consideration to the possibility of inducing

or the proces ‘s and using somesort of somatic selection on

    
 

those cells in order to find those genotypes which are appropriate for use
This sounds so weak these days by comparison with the other

kinds of engineering eperations that are starting right before us that Io 2@-->7—

hesipate to mention it,
re

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20.

OK And I'm sure that any of you to this kind of joint psychedelic exercise
would be able to add some of your own experiences many other ways in which
we could contrive to do a considerable amount of genetic engineering in man

if we just remember that man is an organism and not very different from your
in
own typical subject of experimental investigation, except kkhak/his resistance

wi phy
to being experimented with. Cell and tissue culture smethat resistance
work
seems to dissapear and you can do a lot of your anticigatpry/without running

gore F social interdiction. However I so far stress what I called eugenic

ae

effects, Chet~i-hed—hr~ekedwere: gerainal modifications and I wonder about.

the long-term relexwnnse of that distinction. Now it's a little hard for
geneticist to play it down; our image, our unique distinctions from all the
rest of the biclogists is our ability to foist that sim distinction on all
the rest of us. What is genetic and germinal is something YQxy, very
different from what is somatic developmental. There is something permanent
about the geen ets of an organism, But I'm not sure whether this

will /becone obsolete in the framework of 4% yo, te-e-degree of

whe reasoning I would put forward is along the same lineSthat you would now
regard certain genetic differences as already substantially irrelevant in man.

I hope, for example, that the amount of hair on my head, which I do believe

is under some genetic control, really is not very important because I can

wear kk a cap,and-we—can-make—snucir-woTe sophistteeted-cinds..of contrixaness
Veli—

te-takeplace.of what_ourbiologieab-eadeamantnwas . tiar~cinrete—ehelsodees

example~e6wheb~eusSaneA lL BSCS SABA LL NEL Md AANA DEES W dbo

—2.@,,

anNded-WOns§n0108805860=8Oe—The—-expent to-wittir culture replaces biological
endowment in the conduct of our own afairs. The more we learn about

development the ma deeper that's going to be. The medical example of this

re well known and are sometimes d¢ - It's also less unfertvuaste——
pa dayton
now if I'm a diabetic because we know about dnsulin and better ensulins have
21/

come along, other kinds of drugs have come along, we sort of on the edge of
thinking about using cell transplants to take the place of a failed

lung and so on. And while this will entail a certain amount of
extra cost it's just part of the cost of keeping civilization going that
we become dependent on it in so many vays Nek tbis is seest—-ef the lowest
level of genotypic irrelevance, the technicological substitution of other
kinds of artifices to the things we uskally depend on. It isn’t tertibly
important that we have great strength anymore, we have machines to take
their place. We have automobiles to take the place of/iees, and so on and

Gaon ¥
so forth. (There are some, aspects to good legs.) Fheo-petat-t-woatd ttre

 

to stress, : tt

~te—that

 

this kind of developmental intervention end im vrder-te-serese how firnly
opposed it is to eugenics ye try to coin a sufficiently opposite name, so
I thought ‘euphenics, but euphenics is really the same thing as medicine.

qe Euphenics is beginning to acquire the kind of resources that make it
relevant to the most fundamental aspects of human personality. Now here,
or all things I've talked about so far, Lot ato insignificance by
comparison with the one thing that distinguishes man from the other species 7
and that is his brain. We are just beginning to get the faintest glance nye
of what it is that controls the development of the brain. And the things
we do as soon as we do understand that control, as soon as we know which
hormones involved in programing the development of the brain, what relevance
will Bhere be to the existing assortment of genes that control the count of
neurons that we might have or the other much more complicated ways to
determine what our performance on an IQ test is going to be. We so far

just do not intervene at all, we don't even provide reasonable support for

the most important of our developmental processes. Mostly because we don't

* Me, Leaume wend wef Gee faa frase aves J
ra

i Fg a TT TS BF OS EI NS TS TS Ts Ts Th TS Ss lepe e e ge he ee Ge ha he WIN INI NANA AI RI RO ROR RRO RRR ee re

    
   

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22.

understand it at all. We are just beginning to investigate it, we have such
fiadings as one nerve growth factor finally being gotten out in reasonahbjy pure
form, some understanding of its nature as a protein hormone. We are obliged

to believe that a similar kind of programming is going to apply to the central
nervous system generally. Not only will existing genotypes for the develop-
ment of intelligence te irrelevent, it's to be expected that there will be

peux 2 “Stfects. We now dntireti our estimate of genotypic performance
in terms éf-what happens in the relatively uncontrolled situation of a normal
gestation with no external hormone control of brain development, aww Fe fact,
until reasonably recently it was rather important that the child not be born
with too large a brain, because if he did he'd run into obstetrical dfficulties.
Well these are all points that we of course can get around to in considerable
extent by medical and surgical intervention and there will be no relationship
between the response of the endgigenous development of the organism, which

is what is now measured and what will happen when we are putting in an

explicit program. We can use variations of genotype as a control brain
development to learn a great deal about the development of the brain, "mre

oo cine choXienylaianine Mette Mental development is one of the kind of

things we can't afford to ignore. But I can see very little place for s

development/or the autotoni

   

/é /
hen we are pitting in an \

\
\
\

i
control /brain \

   
     
   
 

e\, We can us variations of g otype as
t to leatn a great deal about the dev ‘Igpment of the\brain. I

 

‘
' v
treasuring too much the existing genotypes for a-month's intellectual

performance in terms of their probable relevance to the control, workd of
>

A

)

  
 
 
  
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23.

brain development.

Now there are going to be some paradoxes and délemmas in this field
as there are anywhere else. There's a price to be paid for almost any kind
of advance and here we're talking about something that sort of happened
yesterday also. There are some fascinating reports from Dr. Money's labora-
| tory, John Hopkins, about the impact of hommonal virilization on intellectuaal
development. Though his data really are not very good, I'11 pretent) that
they are, Ehey are just hints; you really can't rely on them as being
affirmative truths.For intellectual development the situtation is must too
complicated for that to happen easily. But these are pointed at series of
cases for which there has been either a natural accident, for example the
idiopathic virilization syndrome in which girls with an excessive output of
Cote where in fact there has been a contrived euphenic intervention
where little girls were exposed to j t theiz-own while in utero in order
to have them be born at all. This is thexpxax Oiect>~~L indicated as a

meana of sustaining a pregnancy in the face of a threatened abortion on the

part of the gother. It has been known for some time that the administration

of this hormone could lead to anatomical unscuslua pele or development

. surgically
of excessively large cLcteidee which could be x»2umgenbosby diminished

wt int

and—theugh—denete important evidence that this resulted in any deleterious
Money has

changes in leter development. Well, manyxxmaxa found two things about some
of these girld as they grew up to be young women. First of all, by the
kinds of tests that as a psychologist he as able to administer, they were
tomboys. They had adopted a masculine point-of-view about the world and
if this mexplicit influence of a hormone and the parts of the brain that
are concerned with gender identification, it will of course be of extra-
ordinary interest in that light alone. Now, life is too complicated to

draw auch a simple conclusion. Of course the parents of these girld knew

something about their history, and they've learned something about it them-

selves, and we don't know to what extent the social milieu was the vehicle
eae eee eee IT TNT TNE ONE FNS PND PND BND UND BRD EN UN BN TNE Ee EN NE TN TN UNE ete ete ee ee ee te INNA ANN DRO RI RI DROID ROR ROR Pee Pe ee
NOTE ND FHOWOONIOAUIE NINH OWONI OUTED © WONT NID OL 00 SIMUL EE NINH O LO CONIOIUT EE WFO WO CONIMUTE WN HOW ONOUTIEWNHOWONIOUTLE Whe

24.

psychological
for this/mass immunization) Together with that I think none of you might be

H
too surprised to find that they also had an exaltation of their IQ's. The

reason one shouldn't be surprbsed is thatwith the biological endowment of a
complete set of X chromosomes and with some of the pagnacity of the male, how

H
can you beat that kind of fenale! Well, there's already enough of a hint that

this workd that i-Han'tknow if there are any pregnant women here tonight, -but
chat some of ua

I'\dbe-—suspeieed/you te template trying to masculinize fetéses at
/y ose on emplate trying culinize your fe a

the present time, particularly if you knew that they were girls / Theat +s—why

Ht we have a culture that recognizes male values very much more than it does
female, and most of/eugenic efforts are dedicated to producing super man and
the hell with the women. (Are you going to go along with that or not?)

H until we can resdlve that very simple issue of human values as to whether
we have a bisexual society or a unisexual society in fact, I think we have
to be very restrained about the other interventions that we want to amke in
human performance. And I should perhaps also remind you that everytiing by
which we now calibrate human genotypes is in the framework of our existing
culture, our existing educational system, and all of the rest of it, and
ne of these days we are going to find out something about education, and
I wonder then if any of the ground rules of that calibration are going to
be relevant at all, along the same lines of argument that I had with respect
to euphenics.

I would like to revert to the main thrust of Dr. Nirenberg's concerns,
and that is, should we wait to use genetic messages for the programming
of human cells until we can understand all of the condequences and be able
to make a final judgement about human betterment: I would reiterate my

concern about rash irrevocabidity of any of the steps we take, and I would

like to ask for the most sympathetic consideration and for the most savage
ra

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25.

intellectural criticism of individual experiments that go to the roots of
human nature. Unless, in fact, we do use genetic messages in an intelligent
way to do these kinds of experiments, you will never learn anything about
man himself and we will have no future other chan /endownent that we received
at the time that intelligence first appeared in the species. I do not think

we want to characterize ourselves as man, the uniquely conservative animal,

Thank you.