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245  Life Sciences
     Patterns of Change  1960-1980
     October 9, 1962

     I will be spending a good deal of time on the structure and 
importance of DNA (Deoxyribonucleic Acid) which plays such an important
role in contemporary biological research.  My colleagues in the
physical sciences keep assuring me that the real breakthroughs of
science and technology for the next couple of decades are going to
be in biology.  I am not sure to what extent this represents the
universal feeling that the grass is greener on the other side of
the fence and predictions of this kind, as all predictions which 
depend on new discovery for their implementation, are always dangerous.
I need only remind you of the famous prediction around 1890
or 1892 that all that was left for the development of the physical 
sciences was the more precise determination of some of the physical
constants, adding a few decimal points to some measurements, which,
of course, was the immediate signal that radioactivity was about to
be discovered.  Any statement as to what the future looks like can,
therefore, only reflect our present insight into current science and
its developments.

     I think it is true that biology is on the threshold of an
immensely important revolution both from the standpoint of natural
philosophy and from the standpoint of human affairs.  For the first 
time the people working in diverse fields of biology have a sense of
pulling together, of working on problems that are related to one
another and of being able to ask the most significant questions at
the chemical level of organization of the cell that they had hoped
to be able to do over the past thirty, forty, fifty or sixty years.
Much of this new outlook in biology, of this unifying theme of the
predictability of the research of the next five or ten years, has
come about from the sudden onrush of success in attack on the
problems of the structure of the nucleic acids in their relationship
to protein synthesis.

MAJOR TRENDS IN BIOLOGICAL RESEARCH
     My remarks are directed to major trends in biological research
as they can be discerned at the present time.  In trying to think
what the impact of such research will be on the world of the 1970's
and the 1980's, it is very difficult to isolate biology from other
aspects of our scientific culture.  The technological or scientific
advances that we can now predict would give us a very narrow view of
what the future has in store for us.  The very technique of disco-
very of immense significance for the pace with which new science is
accumulating and will continue to accumulate in the future.  It has
meant that the universities have again become the focal point for
basic scientific work.  It has also, of course, raised many problems
concerning the proper relationship of basic scientific work in the
universities and industry.  We must all be very much concerned about
the patterns of relationship that must be evolved in order to take
full advantage of scientific innovation and to see to it that they
come into the main stream of technological development for human
benefit with the least possible delay.  Such questions as the 
responsibilities of the academic and professional communities, of 
industry, and of the Federal Government in maximum assurance of the
safety of the public have not been properly worked out.  These are
all issues of the most serious consequence which, of course, are
bound to become more and more important as our capacity enlarges to
deal with biological problems from a technological standpoint.  We
will have to work out the appropriate mechanisms whereby these
interferences with the normal development of man, if I can use this
in the most general terms, can be regulated to the best benefit of
all.  Suboptimization, a perfectionist answer to a partial problem,
is a particularly vicious trap in human affairs.

     Another development which is not biology, but is bound to have
enormous influence on human biology and on the way science is done
is, of course, the automatic electronic computer.  The wonders of
the computer age take a long time before they filter down into the
research laboratory.  (Characteristically, the technology of scientific
investigation tends to be the most conservative.)  But I think it is
most unrealistic to underestimate the importance of the computer
for discovery, for invention, for technological development and
for daily life, and it ranks high among the premises of my own
thinking of the next decades.  Its impact on human biology is perhaps
mainly the redefinition of human talent, which may be even more
pointed than that of the industrial and commercial revolutions of
recent history.

     Mr. Winter mentioned space biology as an early point of contact
between our interests.  Actually I have not planned to say a great
deal about this, as it is only one element, and perhaps the least
predictable, of our outlook of biological research.  The technological
problems of supporting man in space flight is coming along with
astounding success, as we know from recent flights.  This has the
flavor of careful and sometimes inspired engineering more than
scientific discovery.  It is certain that medicine will benefit
greatly from the stimulus that these needs have given to life-support
instrumentation.  But the deeper issues of space biology refer
to the search for different kinds of life outside the confines of
the earth-which has been the limit of our investigation so far.

     Mars, at the present time, is the one foreseeably accessible
celestial target on which we can suggest, with any reasonable 
conviction that life may have evolved, where conditions are in any
sense attractive for life.  In fact, the Martian environment is most
unattractive for higher forms of earthly life as they have evolved a
specialized adaptation here.  There is very little water, there is
very little oxygen, the temperature cycle is severe.  You and I would
not be very comfortable trying to live on Mars although we could
probably make a go of it with adequate protection.  However, the
conditions that we do know of (and our information here is severely
limited) make it at least possible that kinds of life roughly similar
to those as evolved on the earth have evolved on Mars.  If so, they
must have followed a completely independent pathway of evolution
with presumably no communication with life systems on earth
until the development of the space rocket.

     This gives us our first chance at a really large experiment in
biology, one which compares a life system on one planet with
another.  We may be in for some important surprises in regard to the
way in which the fundamental bases of living matter could have developed
in ways different from the way in which they have developed on
earth.  When you stop to think about it, biology is very much a
human preoccupation and is a very limited kind of science.  So far,
our study of biology has been confined to one small speck of matter
in the solar system, itself an insignificant speck in the cosmos;
whereas physics and chemistry have had the means, to a considerable
degree, of demonstrating the generality of the basic laws throughout
the universe.  We can look at the spectra from stars, we can watch
the planets in their motion and from information of this kind deduce
that the basic laws we have developed on earth are equally well
applicable throughout the entire range of the universe.

     We know that the same elements that characterize the earth are 
certainly present in all of the nearby stars and many of them can be
directly demonstrated by spectral analysis of the light even from 
other galaxies.  We can make no such generalizations with regard to
problems of biology.  We haven't the foggiest idea as to whether
there is or is not life elsewhere in the solar system or elsewhere
in the universe.  We can say that we have no reason to believe that
we are unique in the conditions which might have led to the possible
development of life.  Our knowledge of theoretical biology gives us
no assurance that there is only one pathway by which life could have
evolved; that there was only one set of chemical solutions to the 
problem of adaptation and evolution that has led ultimately to
living man who represents the most advanced product of the life system
on this particular planet.

     Our instrumentation on the detection of life elsewhere in the
solar system is fairly crude both from a technological and a 
philosophical standpoint.  Some laboratories are making so far a too
feeble effort.  We have so little information we hardly know where
to begin.  The best point of departure that we can think of is to try
to set up detection systems that would detect earthly life.  My furthur
remarks on terrestrial life will thus also have their application
to exobiology (the study of life outside the earth).  I intend
to discuss the most general aspects of terrestrial life and it is
certainly these that we would wish to concentrate on in our
exploration of the planets.

Fundamental Unity Of Life

     The outstanding theme of biology, and particularly the application
of chemistry to biology, over the past three or four decades
has been the growing realization of the underlying unity of life on 
earth.  We see life everywhere about us; it is hard to get away from
it (apart from getting away from ourselves).  There is life in the
air we breathe, in the microbes suspended in the atmosphere, in the
dust that falls on the ground, in the water and, of course, every-
where about us on the landscape.  We see the green plants; we see
the animals eating them; we see the microbes which are eventually
responsible for the decay of both of them.  At first sight they are
very different kinds of organisms.  We don't often identify ourselves
with the plants in our gardens, or the bugs on them; but more and
more as we look into the basic processes which underlie the activity
of each of these forms of life, we discover a single underlying
theme.  In fact, if one pulls apart the cells of which these
different forms of life are composed, and boils them down in a test
tube, one might then be very hard put to determine whether this
extract had come from a bit of flesh from an animal, or the boiled-
down residue of a bacteria culture or yeast culture, or whether it
had come from a plant.  This is to say that the fundamental constituents
from which life is built are limited to a very narrow set of
innumerable possibilities of organic compounds that might have been
tested, most of which are found wanting as possible candidates for
the evolution of a biochemical system -- or at best they failed on 
earth.

Of the materials of which life is composed, it has long been recognized
that those that have the highest degree of specificity, those that
are most particularly associated with life and into whose structure
we must look for basic answers are the proteins and the nucleic
acids.  Since the convergence of biochemical analysis, which began 
almost one hundred years ago, and genetics which had its reflowering
about sixty years ago, it has been gradually realized that the 
fundamental genetic material of all cells consisted of nucleic acids,
whereas the working materials of the cell, the ones that are 
responsible for the implementation of the instructions that are passed
on by heredity from one generation to another, are the proteins.
Thus, with increasing sharpness in recent years, it has been realized
that the fundamental problem of biology is twofold: one is the
structure of nucleic acids and the chemical means by which they
transmit information from one generation to the next--the problem of
heredity.  The second problem is one of translation.  How is this
information which consists of a linear code in the nucleic acids
transmitted to the proteins and how can we build a general world
picture which will encompass all of the varieties of microorganisms
and plants and animals around these elementary premises as we are
now beginning to do?

     The fundamental strategy that seems to have evolved in the 
development of organisms on the earth has been the determination of
three-dimensional structures by the linear code to produce the most
wonderful results.  The specification, point by point along a single
fiber, as represented in the primary structure of the proteins, the
primary sequence of one amino acid after another in a protein chain,
is translated by the specifically directed secondary folding of this 
polypeptide chain to produce highly specific structures, the ones we
know of as the proteins.  It is this strategy that gives effective
meaning to the reproductive functions of the nucleic acids.

     For evolution to have anything to work on, it was necessary for
there to have developed on earth a chemical sequence which had the
nearly unique power of self-reproduction, a chemical sequence which
in a suitable environment would result in the formation of polymer
sequences similar in structure to the one used to seed the system.  
This has been an especially wonderful attribute of the nucleic acids
which we have learned the fundamental basis of during the past ten
years.  Nucleic acids are large polymers of which the elementary
unit is a backbone sugar phosphate chain.  We have a sugar deoxyribose
which is linked through a phosphate ester link to the next
deoxyribose, to the next phosphate, to the next deoxyribose, and so
forth.  These chains are hundreds of thousands of units long in the
actual DNA that is found within the cells of the organism.  Coiled
up in each nucleus of each of these cells are polynucleotide chains
which if unravelled would be just about as long as I am tall--some 5
billions units long.  This part of the chain, the phosphodeoxyribose
sequence has no particular informational specificity.  It has
approximately the same relationship to the transfer of information
that the "Mylar"*-base of a computer tape has.  It provides the
necessary backbone of continuity of structure on which information 
put on that sequence?   The trick that nature seems to have hit upon
in terrestrial evolution is the insertion of one out of four bases--
guanine, cytosine, thymine, and adenine.

     Nucleic acids, therefore, all have this common structure.  They
have this clear plastic backbone on which we find the insertion of
the specific bases in a very particular order, so that if I wanted
to specify the structure of a particular nucleic acid, I could take
for granted the presence of the backbone and I could write a formula
for as many thousands of times as I needed to write the full genetic
message.  Each of these letters, G, C, T, A, would refer to which
one of the four alternative bases--guanine, cytosine, thymine, or
adenine--was present in the DNA sequence at any particular point in
the chain.

     The full picture of the structure of DNA was completed by the
theoretical "bihelical" model of Dr. James D. Watson and Dr. F. H. C.
Crick.  The DNA as it occurs in living organisms is not a simple single
nucleotide chain but consists of a pair of complementary chains
twisted around one another: the important bihelix around which all
life is built.  A good deal of evidence has accumulated that when
one isolates the DNA from the nuclei of cells, the DNA consists of
two chains intertwined around one another, and that at every position
where we have adenine on one chain, we have thymine on the 
alternative chain.  When one proceeds to build three-dimensional space
models of these structures, one discovers a very plausible basis for
this specific complementarity, around which most of the rest of
molecular biological theory has been built.  That plausibility is
that in the three-dimensional models there is a specific fit between
the molecular structure of guanine and cytosine--that there are
three places where there are opposed hydrogens that can be used for 
hydrogen bonds between oxygen and nitrogen or nitrogen and nitrogen,
respectively, in these two molecules.

     Conversely, adenine has a corresponding fit to thymine.  In the
three-dimensional structure the positions of these atoms, either the
ring or the substituted oxygens and nitrogens on the structures, are
located just so that they are locked in, in this case by two hydrogen
bonds between adenine and thymine.  This then led to the speculation
(for which again there has been very substantial confirmatory
evidence) of how DNA replicates; how one chain of DNA can be copied
in order to produce another chain with the same information.  There
is strong evidence in support of the idea that the double-stranded
material of DNA as it is customarily found in its static form in the
cell is pulled apart, perhaps just unit by unit, rather than completely
unzipped, and that from a pool of activated forms of the four
nucleotides which go to make up the polymer, one is selected to fill
a particular slot which is complementary to the base that was
already there in the parent chain from which we are attempting to
derive the progeny.  The climax of these considerations was the
accomplishment of the same process in the test tube starting around
1955 by Kornberg who, in setting out to look for just such an
enzyme, succeeded in finding a enzyme system which would accomplish
precisely what I have described here.  Given a primer amount of a
specific DNA put into the test tube together with the enzyme and
with a supply of the activated forms of the nucleotides, they are
polymerized into polynucleotides whose sequences match the primer's.
The nucleotides are activated by being triphosphates; they have two
additional phosphate groups attached to them in the monomer form.
The condensation is a transfer process whereby a link between the
monomer phosphate and the pyro-phos-phate group is transferred to
the hydroxyl on the deoxyribose of the next molecule.  One could now
accomplish this act of copying of the sequence of a polymer chain in
the test tube--and there can be little doubt that this represents 
what is going on in the cell as the basic mechanism of heredity.

These accomplishments were something of a surprise to the philosopher
of biology of the 1950's.  We had, let us say in 1950, much
less information about the detailed structure of genetic material 
than we did about proteins and I think it would have been anyone's 
guess at that time that the problem of protein synthesis would have
been cracked long before we would even begin to get around to the
problem of how nucleic acid is duplicated.  In fact, just the 
converse has been true and it indeed was necessary to get a great deal
of basic information in regard to the structure and the mechanism of
duplication of the nucleic acid before we had the necessary equipment
to begin to look at the problem of protein synthesis within the
cell.  It was far from there being a vague connection between
the "information in nucleic acid and the information in the protein"
as if these somehow were linked together by a telephone cable en-
abling them to talk to one another; there is a material connection.
For protein synthesis to take place in a cell extract, one must furnish
definite information as to the amino acid sequence that must be
put together in forming the protein; and that information is indeed
provided by the kind of nucleic acid that one puts into the system.
However, the cell has created an intermediary between the protein and
the primary tape, the DNA, in which its instructions are durably
stored and passed on from one generation to another.  It also has
furnished a kind of scratch tape (in computer jargon) on which
those instructions can be copied many times and then thrown away when
no longer needed.  This in turn has provided the basic mechanism for
the regulation of protein synthetic processes in the cell.  We have
the information for 10,000 or 10,000,000 alternative proteins in
every one of the cells in our body, but we only use a very small
fraction of this information at any particular point in our own
development.  The regulation of these synthetic processes appears to
be determined at this point of copying the information from the DNA
into ribonucleic acid (RNA), structures differing only in some
details from the DNA, but serving as the "messengers" carrying the
DNA information.

Now, what then happens next?  The picture is perhaps murkiest at
just this point.  We know that there is a rather intricate mechanism
for the activation of the individual amino acids so that they
in turn can be used in synthetic processes for the formation of the
higher polymers.  The free amino acids themselves would not have a
very substantial free energy of reaction for the formation of the
larger polymers and they go through a cycle of reaction where they
are first of all reacted with ATP, and second, they form complexes
with little chunks of another kind of RNA, the so-called soluble RNA
of the cell.  Its main functions seem to be twofold: to activate the
amino acid for condensation to form longer chains; and second, to
provide the specificity, the recognition mechanisms, which responds to
the messenger tape in order to locate a given amino acid at its
precise place on the chain.

Now this is important enough that I should perhaps summarize.
We have first of all the genetic mechanism, or double-stranded DNA,
and this should be taken to indicate the interwining of two 
complementary strands.  The information is, in fact, represented in 
duplicate at every position; where we have A on one side, we have T on
the other, so we can accurately deduce one chain if we know the
other.  The replication of the DNA involves the pulling apart of the
strands and laying down of another one, also complementary to the
one which is being copied.  For protein synthesis, a segment of the
total DNA is copied to RNA, a messenger RNA to be used as the template.
A given amino acid is reacted first with ATP, and then becomes
transferred onto a transfer RNA (also called soluble RNA or 
sRNA) which performs a very different function: the activation of
the amino acid, and the recognition of a segment of the messenger
RNA.  The messenger RNA has groups of nucleotides, words of the
message that came from the DNA.  We now know from the recent
exciting experiments of Dr. Marshall Nirenberg and Dr. Severo Ochoa
many of the details of the coding, the correspondence of a sequence
of bases in messenger RNA to a particular amino acid.  This UUU in
RNA corresponds to phenylalanine.  Hypothetically a complementary
sequence, AAA, in the sRNA just matches the UUU in the messenger
RNA.  So, at that place a phenylalanine residue will be placed in
linking up to a sequence of previous, and then later on additional,
amino acids in forming a given polypeptide in forming a given
protein.

Now this translation mechanism has in fact been pulled apart; to a
large extent it can be made to go in a number of systems in living 
cells.  To a very large extent, though perhaps not completely,
pieces of the system each extracted from very different kinds of
cells will work together in the test tube.  One other kind of RNA,
complexed with protein in the ribosomal apparatus of the cell is
needed for this to work.  On the ribosome as a kind of machine jig,
it is the conjunction of the messenger and the activated sRNA-amino
acids which results in the polymerization of amino acids to form
these specific chains.

     By itself, a sequence of amino acids might appear to be no more
interesting, basically, than a sequence of nucleotides from the
point of view of doing any chemical work.  It is one of the beauties
of the system that the DNA, when it is in its double-stranded form,
is, from a chemical standpoint, relatively unreactive.  You wonder
how in the world it, of itself, could ever have learned to do anything.
In fact, it does nothing except reproduce itself and furnish the
information from which messenger RNA is made.  This in turn becomes
a working material.  There are, however, not just four but twenty
different amino acids and when an amino-acid polymer chain is
formed, it does not form a highly stereotyped structure.

POLYPEPTIDE CHAIN

     By virtue of forces that we do not understand very well but
which must include charge neutralization, hydrogen bond formation,
and hydrophobic attractions among the non-covalent forces, a poly-
peptide chain folds into a very specific and definite three-dimensional
shape.  What would have been a long string with no particular
unique quality to it becomes ravelled into a rather definite three-
dimensional shape.  This then permits that protein to act as a 
specific catalyst if it is going to be functioning as an enzyme; or 
react with other like molecules in forming larger polymeric aggregates
if it is going to function as a structural element in the cell
and form parts of cell wall or a fiber.  Likewise, its three-dimensional
shape that it assumes after this folding process is going to 
determine how it can function--if it is going to be an antibody which
the cell can learn to produce as a means of reacting with a deleterious
substance that may be introduced in the animal.  This aspect
of the strategy of development is the one that we understand the
least at the present time in explicit chemical terms, but we do know
that purified proteins can be prepared, and their primary structure
can be thoroughly worked out as has been done in perhaps half a
dozen cases at the present time.  They can be placed in media at
high temperatures at low salt concentration, or presence of high
concentrations of urea, for example, where we have physical 
evidence that they become completely unravelled.  Then if they are
treated carefully and these external influences removed, we find
that the extended chains of naturally occurring proteins will very
often fold back again into exactly the same configuration that they
had before and one in which their biological activity is restored.
So, we infer that it is indeed the actual linear sequence of amino
acids in the proteins that determines the shape into which it folds
up, and the distribution of specific reactive residues like the 
imidazole groups of histidine, and the distribution of charges, as
well as the shape, then determines how that protein is going to be
able to function in the cell.

     I want to stress that in evolution the cell had no way of knowing
beforehand what would be a good protein to do a particular job.
The strategy of evolution seems to have been unable to avoid random
errors that take place in the primary message in the original storage
tape.  These are the mutations.  These random errors will give 
rise to new experiments in substituting one amino acid for another
in the formation of a polypeptide chain.  Very often those experiments
are disastrous.  The protein that is formed may no longer be
able to perform-even to fold up at all.  This is one of the most
common consequences in actual experimental work on mutations under
genetic control of a specific protein.  Sometimes a new configuration
is accidentally discovered: polypeptide is formed that can fold
up into a new three-dimensional configuration; then the cell that
produces the protein is put to a test.  Does this new three-dimensional
shape do anything for the cell in its present environment any
better than what it had to go with before? If it does any better for
the cell, if the cell has discovered a better enzyme or a better
component with which to build a contractile protein for muscle or a
better component for cell wall that insulates it better from its
environment, then that protein and, consequently in turn, the nucleic
acid in the cell producing that protein have stood the test of
selection.  That mutation will then be preserved.  It will have 
conferred some advantage and we will then have a new starting point for
further evolution.  This may be an arrogant assertion, but the 
biochemists do believe that is precisely how life evolves.  The poly-
nucleotides were formed by some more or less spontaneous processes
(many of which surprisingly are being worked out or duplicated,
although we don't have the complete chain from one end to the other
at the present time).  These experiments in structure are going on
all the time by this process of extensive trial and error and 
implementation of these trials through production of different protein.
From an elementary polynucleotide we thus have had the full progress
of evolution from the primordial slime, from the precellular organism
which was just a lump of DNA, to the exquisite product of evolution
that we are today.

This then is the background against which we must view the further
development of biology during the next few decades.  These discoveries
have been the framework against which every major question of
biology can now be restated and put again in very concrete and
explicit terms as I propose to illustrate in my remaining time. For 
example, in embryology, we see the wonderful phenomenon whereby a
single relatively undifferentiated cell, the egg, after having been
fertilized, undergoes a very large number of cell divisions and
gives rise to the fully developed animal.  This animal consists of
many widely diverse parts in which there has been a tremendous
amount of division of labor.  We don't find that the brain is trying
to store glycogen or secrete bile as its major metabolic function.
This in turn reflects a differentiation in the enzymatic capacities
of these tissues and even more deeply in the regulatory  decisions
as to what parts of the DNA of each cell are going to be used.
We have pretty direct evidence, although we would like to have
it verified in somewhat more chemical terms, that the DNA is
basically the same in all the cells of the body, that there has been
no inherent alteration in the actual content of the message in the
course of these cell divisions that give rise on the one hand to the
primordium for the brain and on the other hand for the primordium of
the liver; instead there has been some mechanism which tells which
of the total parts of the DNA are in fact going to be used to 
specify the protein synthesis in those cells.

THE STRATEGY OF STUDY OF EMBRYOLOGY
     
     It is now clear that we must ask these questions not in the
traditional terms that embryologists have developed in looking at
slices of these tissues under the microscope and deciding that this
is going to be a brain because we see some fibers growing out and
this is going to be a liver because we see the cells starting to
pack around in little lobules around central ducts.  We must ask the
question, "Is the DNA equally competent in extracts from these two
kinds of cells if we put them in a test system for protein synthesis?"
"Can we get the same messengers reproduced from them?" "Shall
we isolate the regulators, the repressors and the inducers which
will turn on and off the DNA isolated, let us say from eggs or sperm
which will have all these capabilities?" These questions are only
beginning to be asked and we don't have the answers yet, but they do
tell us what the strategy of study of embryology is going to be.
There is every reason for confidence that we are now asking the
right questions.

SIGNIFICANCE OF TISSUE TRANSPLANTATION

     I would like to turn now to a somewhat wider discussion of some
other currently visible topics of tremendous human significance over
the next years.  One of these is the field of tissue transplantation.
For some time many surgeons have had optimism about learning to
perform the most intricate technical feat of transplanting not
only small bits of tissue but even intact organs from one animal to
another. Having watched such a procedure, one must applaud the 
immense technical skill which is involved in transplanting a limb or
even transplanting a heart from one animal to another, retaining 
intact the normal pattern of circulation, patching up all the leaks
between the tubes that have to be put together, and seeing that
everything is indeed put back together in excellent mechanical
order.

     It does not take much imagination to realize what the impact on
human affairs would be if we could replace our detective, aging, and
sometimes inherently imperfect organs with spare parts.  From the
standpoint of the surgical technique of transplantation, of taking
out one organ and putting another in its place, this problem has
already been substantially solved.  Well then, why hasn't this
worked? Why has not transplantation been a major tool in medicine?
Why do we not make strenuous efforts to prolong the lives of the 
people whom we value the most in our community (the ones who are
able to command the technical resources which are needed to perform
these feats of skill)? Unfortunately, nature has established more
subtle barriers.  It doesn't work because we are all individuals; we
differ from one another; we have a different heredity and therefore
chemical makeup in the fine details of our structure.  Thus when an
effort is made to introduce the tissue from one organism into
another (unless these organisms are genetically identical with one
another, and this can only be achieved in inbred colonies of mice or
identical twins) a reaction takes place.  Within a period of some-
thing like two weeks, perhaps a little longer (sometimes several
months when the host organism is ill, as has happened in some
attempted kidney transplantations) the immune mechanisms of the host
go to work on the implant and eventually destroy it.  Regardless of
this, however, the self-destructive objective of this mechanism is
often our guardian against attack from deleterious implants of other
attacking microorganisms.

The problem of transplantation and all it can mean in terms of a
revolution in medicine and in human affairs is therefore inherently
one of understanding individual differences whereby the organism
distinguishes its own parts and leaves them alone but rapidly goes
to work on foreign material.  How does it know it is foreign? Even
my brother would be foreign to me if his tissue were put into my
body.  My cells would rapidly go to work on such foreign tissue and
destroy it.  This ultimately is a problem in protein specificity.
Without going into the details, the mechanism of this immunity is
eventually the formation of a specific protein (an antibody) which
reacts with the substances introduced in the foreign material.

     Beyond that we have to look at the way in which the genetic
system of the cell, of the antibody-forming cell, is provoked in
order to produce the antibody. Without detaining you on a detailed
exposition of the theory of antibody formation, I think you can
recognize that our understanding of the control mechanism, whereby
cells are turned on and off with regard to the kinds of proteins
that they can make, will in turn have its impact on our capacity to 
regulate the immune response which, in turn, is something we must
learn to regulate if we are to achieve the goal of effective tissue
and organ transplantation.

     There have been some imperfect advances in this direction.  We
know, for example, that the administration of analogs of the 
components of nucleic acids, of 6-mercaptopurine, for example, will 
interfere with the normal process of protein formation in antibody-
forming cells and this, in turn, can suppress the immune response
and some palliation of the graft reaction can be effected in that
way, but it doesn't last very long.  This is a very crude approach.
There's no selectivity at all in throwing just one base analog when
thereby you would be interfering with the total process of new protein
synthesis in all the cells of the body, but it does represent a
first step in the direction that I am speaking of here. Plainly,
what we must learn are the details of the specific kinds of messenger
RNA that are made for the production of very specific kinds of
antibodies, just the ones that are involved in the immune response
so that we can attack that process and leave intact the normal 
properties of protein synthesis needed elsewhere in the body.

The Biology Of Cancer

     We have in a way an analogous problem in the biologically and 
medically important problem of cancer.  The more we look into the
biology of cancer and the more we think we have reduced it to its
fundamental levels, the more puzzling that problem seems to be and
the more elusive a comprehensive solution to the problem from a
medical standpoint appears to be.  We must get down to the fundamental
origin of the cancer process.  Cancer is a sudden release from the
normal regulation of a group of cells of the body.  These cells just
suddenly take off and stop paying attention to the normal order of
things.  They proliferate wildly, they crowd out other cells in
their vicinity and their overgrowth eventually results in the loss
of the organism.  Now from one standpoint this is not a surprising
evolutionary process--the same process of trial and error that I
spoke of earlier, whereby alterations may take place in the DNA,
must be taking place in all the cells of the body at the present
time.  Some of the consequences of mutation in body cells are going
to be alterations in the regulatory mechanism which coordinates the
cells and tissues of the body.  When they result in a cell strain 
which is now free from the orderly restraint necessary for the proper
integration of the organism, from the standpoint of that cell line, 
its further evolution is a very happy one.  Those cells proliferate 
unrestrainedly, exactly like the weeds that can come through in our 
gardens.  Now something has been done about it in the evolution of
the organism or we would all be subject to cancer at a very early
age.  We do not know basically what the traditional restraints have
been.  We do not know what other discoveries the evolving animal has
made during the course of its evolution that permits the suppression
of the unhappy experiments on the part of our cells during the more
vigorous part of our life time.

It has been pointed out that from the standpoint of the evolution of
the species the age distribution of cancer will have relatively
little impact on the reproductive potential of the species since its
greatest incidence tends to fall at a period after the reproductive
period of the individual; crudely speaking, processes of natural
selection will have very little impact on the incidence of cancer
beyond that age.  Natural selection would have had a great impact on
the development of early cancer because the biological propensity to
develop early cancer would have been reproductively disadvantageous.
A genetic system which allowed this would be at a disadvantage 
compared to a genetic system that evolved in which the incidence of
cancer is altered.  So there is some hope.  The very fact that there
is an age distribution of cancer does imply that there are regulatory
mechanisms whereby these unhappy experiments can be suppressed
but we don't know what they are as yet.  The strategy I outlined for
embryology applies directly to the cancer problem, as an aspect of
abnormal development.

     It must be said this picture of cancer biology ignores some of
the most exciting developments of recent years; namely, the implication
of viruses in the induction of cancer.  But this difference may
be more apparent than real if we also keep in mind the equally
exciting developments in our understanding of what the viruses are.
We realize that they are also bits of genetic material.  The virus
is an evolutionary experiment in which fragments of nucleic acid
have managed to break away from the organism in which they originated.
It is just another bit of genetic material, but one which has
developed its own adaptations for aggressive growth within the cell
and for getting out of cells into new ones; a kind of trial and
error result which is of best advantage to that particular clump of
nucleic acids.  Well, the same approach of asking specific questions
about the intervention of the genetic material in the mechanism of
protein synthesis is, in my view and that of almost all of my   
contemporaries, the way in which we are going to answer this and 
comparable series of exciting questions in biology which are the utmost
importance in the foundation of medicine.

CHEMICAL STRUCTURE OF LIVING ORGANISMS

     I have perhaps spent too long already at a rather elementary
level of exposition when I could certainly have gone into much more
technical detail about how one does these experiments on nucleic
acid synthesis and their role in the genetic affairs of an organism,
but I rather prefer to get over the spirit with which work of this
kind is being done now.  One can find the technical details in the 
scientific literature.  The main element of this spirit that I would
like to stress is the new aggressiveness and new sense of confidence,
sometimes arrogance, not often enough humility, of our approach to
the problem of the makeup of living organisms.  It veers away from
the gloomy predictions many of us made (and I might say I was among
those at one time) that you really would not be able to pull a cell
apart without destroying its integrative capacity, and when you did
pull it apart, it would no longer tick.  The cell can be pulled
apart; we can learn how they work; we can isolate the protein synthetic
mechanism; we can write down chemical structures for the parts; we
can hope to substitute alternative structures when we learn what to
do; and this is a very different atmosphere of biological research
than the one that pervaded biology until the middle decades of this
century.
     
     One of the places that I would want to expound on is certainly
the central place of the involvement in human affairs of the 
understanding of the genetic protein synthetic mechanism, the 
understanding of development of the human brain.

     I think it is becoming apparent that our technical capacity, in
fact, renders most of the physical apparatus that we are endowed
with relatively superfluous.  I'm not arguing against exercise as a
necessary basis for healthy life and this indeed might turn out to
be a very serious limitation on some of the rest of what I'm going
to say.  But people nowadays can get along very well hardly lifting 
a muscle.  This is in some respects unfortunate.  I am not necessarily
advocating some of the things I'm predicting here but there is 
little doubt that the further progress of mankind depends not on his
personal brawn but on his brain.  His brain permits him to design
the machines that are going to do the work for him.  He can put  
together the steam shovel, and put together the computer that will
design the steam shovel, by using his brain and amplifying his working
capacity many hundreds of millions of times.  Well, I think we must
take this into account in considering what the further directions
of evolution are going to be and what we may endeavor to do
about the actual nature of man himself.  This is just to point out
the obvious, that the place we are certainly going to focus on is 
intellectual capacity.

THE PROBLEM OF EUGENICS

     Now as a geneticist, the problem of eugenics is often put to me 
and one can hardly avoid it--what is the impact of our knowledge of
genetics, of the extent to which the qualities of mankind are controlled
by an inner makeup that he has received by heredity, on the
direction of human affairs? Should we make a specific effort to
breed better men in the future? Should we take drastic means to 
prevent the accumulation of harmful genes which are now allowed to 
accumulate under the conditions of relaxation of natural selection;
for example, medical care?

     There are many diseases that were once relatively incapacitating,
that reduced the reproductive potential of people, which have
a genetical basis but which we can now alleviate.  By alleviating
them and permitting the reproduction at a normal rate of individuals
carrying these genes, these genes are no longer held in check.  They
are bound to accumulate and rise in frequency.  The very means that
we have for permitting the normal development, for example, of 
children with a block in phenylalanine metabolism which in past time
gave them very severe retardation in mental development now permits
them--through the diets we now have--to mature reasonably normally
and to reproduce and pass on their genes, and we have no specific
social measures to really discourage such people from reproducing.
I am not suggesting that we should discourage their reproduction:
I am just pointing out that this does pose a further penalty on
future generations of mankind--the necessity of maintaining these
medical measures to continue to support the "defects" which in past
times minimized through the much more drastic measures of natural
selection.  The general answer that I have come to in viewing the
problem is that it would be, in fact, premature to invest very much
effort in consideration of selective breeding of the human population
for several reasons: the first and most important, and one that
most of my genetic colleagues have certainly agreed with, is that we
do not know enough about the details of the genetic control of 
specific traits; that even if we knew what the most desirable traits
were, we would be rather puzzled how to pursue any effective program
of improvement by selective breeding.
  
The heredity of intelligence is a very controversial affair.  We
could propose selecting consistently for it, at least reversing the
apparent trend of selection against intelligence in terms of repro-
ductive rate in present-day Western society.  We just do not know
what the consequences of such selection would be.  We don't have the
information that would permit us to write the engineering specifications
of the program.  Before embarking on such program, we would
want to know what the costs would be, what the expectations of   
improvement would be generation by generation.  We would want to have
some confidence that any measures that would be adopted would be
likely to have an impact within a reasonable period of time.  What
the answer is at the present time, we do not know.  We have a vague 
idea that there is an important hereditary component in intelligence
as we measure it now.  We don't really know how to measure the
intelligence very well in the existing generation in such a way that
makes it very applicable to human affairs at the present time, much
less to try to predict what aptitudes of intelligence are going to
be important in future times, and still less to try to project from
this the details of what the improvement expected from selective
breeding might be.  We would not embark on programs of intensive
selection in any cultivated animal or plant with the level of 
information that we now have for the human species.

     So, whatever one thinks about the ultimate desirability of
eugenics, there is no question but that our first requirement is the
accumulation of much more sophisticated and detailed information
about human heredity--detailed, quantitative, hard nuts and bolts
kind of information--so that one could write the blueprint and not
just very general schemes for it.  Then we could worry about how one
achieves the social implementation of any program of this kind.  How-
ever, there are perhaps even more deep-seated reasons for my own
preference for deferring this particular problem of human heredity.
There are much more timely short-run measures that we haven't begun
to explore by way of the modification of human development.  We have
just barely begun to scratch the surface.

MODIFICATION OF THE BRAIN

     I would like to put particular emphasis on an area that will
deserve much greater investigation than it has had.  Perhaps the
main thing you may learn from what I have to say (what has surprised
me) is just how little work has been done in this direction.  This
is the modification of the development of the brain.  In human 
evolution the size (perhaps in the most general sense we may think of
the complexity and functional capacity) of the brain has been limited
by factors which may be extraneous to the present situation.
The most compelling of these is probably the size of the pelvis.
The head of the infant could not be very much larger than it is
without a very considerable anatomical reconstruction of the female
skeleton or there would be even more frequent accidents of delivery
than there are now.  Birth injuries to the brain are frequent enough
at the present time that you may say we have already passed the
threshold of safety with regard to the extent of cerebral development
in the developing fetus.  We could not tolerate a very much larger
incidence of birth injury during delivery without a serious social
and reproductive penalty and this, therefore, would necessarily
have discouraged any bold experiments that the genetic system 
might have undertaken that could lead to substantially increased
brain volume.  Now over a long period of time this would have 
adjusted itself.

Over a long period of time, the experiment of the "larger" brain
might have evolved along with the change in the pelvis and could
respond to natural selection.  Instead, man has evolved in a little
different direction.  Instead of the pelvic aperture getting larger,
man's evolutionary adaptation to this situation has been the development
of the kind of brain that can learn surgery.  We have the technique
of Caesarean section as a conceivable means of bypassing what
would otherwise be a very long step in reconstruction of the human
organism.  This is very simply and crudely put as there are many
other things we would have to learn to do before we could get around
that particular bypass, but I want to stress that there are some
reasons in the natural evolution of man why he is the limited miser-
able creature that he now is.

     I think we have to keep in mind (we shouldn't minimize the
success man has made) the demands that have been put on human 
capability in past years.  I should say, as a matter of fact, that I
think it is remarkable that he has the kind of brain he does have.
Consider that he evolved the brain that was able to learn Greek
before Greek was invented.  This is one of the main puzzles of human
evolution: how man got that far without more stress, without more
testing, without more compulsion for the development of the intellectual
capabilities which really could only be taken advantage of
after the event; when that kind of brain had been around for enough
generations that we had developed the society and we had developed
the social inheritance; when we developed education and schools; 
when we developed the library of information with which to fill the
brain.  This is a major puzzle.  I just have to leave it at that, but
it seems likely that even the Neanderthal man had a cerebral 
capacity not very different from ours and yet had nowhere near the kinds 
demands we now make on our own brain.  Or is our social maladaptation
the evidence that we have used up all the margin of safety in
our intellectual endowment?

     Now how can we take advantage of our hopeful insight into
past limitations on cerebral development?  Well, first of all,
we ought to take advantage of some very happy lessons that nature
provides us--the accidents on mental retardation, the natural
experiments which are often the basis of clinical advances.  From
these we know of a number of genetic and environmental influences
that are capable of interfering with the normal development of the
brain.  But much more sophisticated biochemical and developmental
studies on normal development are needed to exploit the hints
from these diseases.  Some of the most obvious kinds of experimental
effort to try to get "larger" brains in experimental animals 
have  never been attempted.  But I will predict that within ten
ten years we will know the basic facts necessary for very substantial
changes in cerebral capacity and if we knew how to translate
those facts in terms of human affairs, we really would have passed
the threshold into another biological revolution, where we had
begun a process of active modification of man himself.  Plainly
we have not given much thought to what this means in terms of
human affairs any more than we had given very much forethought
about what the impact of atomic energy would have in the kind of
of world we are in now.  I hope it doesn't leave us in the same
kind of mess!

This suggests what we might think of in terms of a long-range strategy
as a substitute for eugenics.  Basically we try to understand 
what we are about.  We are on the threshold of learning how to
achieve very far-reaching modifications of normal development by 
experimental means.  When we get the cellular repressors, when we get
at the nucleic messengers which are responsible for the formation of
particular products, we will unquestionably know how to modulate the
development of the organism in very far-reaching ways.  I mentioned 
the brain as a crucial example of these prospects.  That understanding
can let us isolate the very specific biochemical and architectual
features of the developing organism which would have to be 
manipulated in order to achieve substantial changes.  Then on the
basis of this understanding on the kind of short-term experimentation
that experimental embryology permits in modifying the organism,
we could lay out a program for genetic improvement.  Because instead
of having the vague objective of saying let us produce better men,
we might have the very specific objective of saying let us increase
the output of pituitary growth hormone during the seventh through
the ninth week of gestation--not sooner and not later because that
is the critical period for the development of the brain and if we
turn it on during that interval we will get cerebral enlargement and
we will not get some of the other possible consequences of overactivity
of the pituitary.  Now I have given you an example which is
crude and is almost certainly wrong because we don't have the 
specific facts in which to make that model right.  We substitute the
right terms and the right times and the right modes of action of the
regulatory substances, and I think a proposition of that kind is
going to turn out to be correct.  It is only the substitution of
specific chemical structural developmental information for vague
functional goals that is in fact going to let us think about 
manipulating these ends.

     There are some of us, and I am not sure I don't belong to that
group, who look with some alarm on prospects of this kind as we have
no idea what is going to come out of Pandora's box.  I think there
is no use saying that it is not a good thing to do, although I think
some vague fears of this kind probably are responsible for the
remarkable paucity of work in this area.  But it is going to be done
whether we like it or not.  We could say the same for atomic energy
for the same reasons on a much larger scale.  It is incumbent on us
to understand these developments and to be giving the widest 
possible forethought to the impact that they are going to have on the
very constitution of the human being.  I think this might be an
appropriate point to close the formal discussion of the program.  I
will be very happy to continue on the basis of explicit questions.
  
              Q and A have not been transcribed.
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