Yrery HE“ lady
OC prker, Jo CL, Ae

As Dr. Jacobs said I am a biochemist but I have the feeling and I really
should state now that a topic such as this - to really do justice to it--one
needs a guru of sorts--some wise man, and I am afraid that I can perhaps pose
some questions but there are no pat answers to these questions--at least I
have none. My only objective today will be to, at least, raise these questions
eo that they can be considered and perhaps you may have some answers.

-Now, in considering the possibilities for genetics for the future this
is really a question of evolution--biological evolution--and there are three
broad areas that fall into this tpic.. The first is that a molecular supple-
mentation, which is a very familiar area; that is, an individual, for example,
has a deficiency disease and by simple supplementation, insulin, for example,
for a diabetic, or vitamins, or what-have-you, it's possible to at least
remedy this disease. Now, obviously a great deal more remains to be determined
about the nature of the deficiencies, or the nature of the various diseases
before it will be possible to supplement in any way.

Now the second broad area really is the topic of euthenics. This is a
term coined by Joshua Letterberg in Stanford, some years ago, Euthenics means
to simplify--to modify gene expression, not the genes themselves but the
expression of the genes. It is a sort of engineering, human engineering and
to alter either the embryonic development of the individual or the develop-
ment of the adult. Included in this topic would be organ transplantations
as well. The essential thing is that the genes are not modified. It is
simply thé individual.

The third topic, or obviously for euphantics one must again learn

much more about the nature of embryonic differentiation. This is an area

that“€xtraordinarily topical and interesting to anyone who has worked in

molecular biology today because most of the people in the field have the

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very, very strong feeling that many things can be attempted--that it is
possible to do many studies now and that a great deal. of information should
be forthcoming related to embryonic development and the mechanisms involved.

The third broad area is that of eugenics and this is simply an attempt
to improve the genetic quality of the genes by selective breeding and this,
of course, has had wide application in agriculture and in certain societies
as well--human societies--a voluntary type of eugenics has been applied.
Also in this topic all the questions of population, population explosion,
and the third aspect of eugenics, I think is a genetic manipulation; that is,
to program cells with artificial genes, and it is really this last aspect
that I would like to address myself to. It really would be impossible to do
justice to the many exciting possibilities that can be envisioned for the
future, so I would really Like to focus on the possibility of using synthetic
genes to program cells; ;where we stand today, what the problems are, and
what the potential is, at least for the future, but before I can do that it
is essential really to first point ‘out the basic strategy that the cell
employs in order to store the information, how it is stored and how the
information is read. Now, may I have the first slide

FIRST SLIDE PLEASE: Now on this slide is shown very diagramatically
a very simple protein. Each circle represents an amino acid. There are 20
varieties of amino acids and they are linked together in different sequences
and essentially the protein is a linear sequence then composed of hundreds
building blocks and there are 20 varieties of building blocks. Now the
information that is passed on from generation to generation tells the cell
how to build this protein. This particular protein is an enxyme and it's
really a molecular machine--a beautifully designed machine. The funazxkx

function of this particular protein is to aid in digestion. It simply cuts

a certain type of foodstuff into very small pieces which can easily be
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‘digested and then reused. The cell will reuse the building blocks to build
new molecules. Now the secret of each amino acid is the all important thing
because although one can make some changes in sequence without drastically.
effecting the function of the molecule, other changes-~even removing a single
amino acid, or substituting a single kind of amino acid for another variety of
amino acid may completely inactivate the function of the protein,

NEXT SLIDE PLEASE--Now an essential cell will contain perhaps 3000 or
5,000 kinds of proteins and there may be many molecules of each kind of protein
and each one will perform | a different function so the information that specify
about how to build this machine is encoded in DNA, and the top line shows DNA
in a highly diagramatic fashion, Actually this particular slide came from that
great scientific journal Fortune Magazine. It illustrates the point I think
diy well, It is a backbone and there are four kinds of letters, &xtxHx@
C A and C G are the initials of each letter. Now it is a linear sequence--

a very long linear sequence. In an average mammalian cell, for ES
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single strand of DNA, a single cell may contain about three bé-kitor-vetty—, ~

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on the strand. That is enough information to specify something like for 3

million kinds of proteins. New-the sequence of the otter EER apnea
thing that specifies the ‘sequence of amino acid in protein. ‘First the DNA
message is transcribed. It is rewritten in a different form--in the form of
RNA, messenger RNA which is indicated diagramatically in the bottom and the
important fact here is that there is a complementarity, that a C, the first
letter in DNA correspond to G in-RNA; A in DNA corresponds to U, etc., as
shown here, and it is the RNA that really is the message that is translated,
Nor how is the RNA message read? We will show this on the NEXT SLIDE

NEXT SLIDE PLEASE: The cell is filled with gray particles as illustrated

here. The message--the long RNA message attaches to one of the particles as
shown and the amino acid which is indicated in the upper, right-hand portion
of the diagram are linked enzymatically to specific adaptors. The letters
in the RNA message are not read directly by the amino acids but there is an’.
RNA adaptor--that coil, hair-pin like structure with the red amino acid
fastened to it at the top and three letters in RNA corresponding to one amino
acid in protein as shown. You will see in the upper left hand corner of the
slide is a growing peptide chain and amino acids are added on one by one
starting from the left and proceeding toward the right, reading three bases
at a time, three letters in RNA at a time.

The next slide shows this in a little more detail. The messenger
RNA is starting there and the ribosome, the particles attach to it at one
e@ and start reading down. One space will hold many translating units or
many particles and as the particles proceed down the message the protein
synthesis comes along and is finally released. Now the translating particle
is in effect a robot. It can read any message if it is written in the
correct form—~in the correct molecular Language and this is really how the
code, which is really of the translation between the letters in a nucleic
acid sequence and the sequence of amino acids in protein, It would prove
to Be relatively simple to décipher this language by simply adding to the
robot particles of synthetic messages composed of one or two kinds of bases
and then determining what kinds of proteins, what kinds of amino acids that
were incorporated into proteins. One could even determine more by simply
using three letters alone and just looking to see which adaptors carrying
the particular amino acid associated with the ribosomes.

Now the next slide shows--this is the last slide»- and it simply
summarizes the language. My intention is not to go into detail here, other

than to make one or two points. That is, that the language is a very, very

Simple language--and a logical language. There are many synonyms and the ~
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words in nucleic acid are listed on the upper left hand; for example, one UUG
is equal to phenylalanine, so is UUC. Now both are synonyms and synonyms
differ only in the letter occupying the third position of the triplet and
there are only certain kinds of letters of permissible combinations of letters
so it is a very simple, logical kind of language and it has been translated,
and there are also some words for start and other words for stop because it
is a continuous message.

LIGHTS PLEASE: Now, it is not only a logical kind of language. All
the available information now indicates that it is a universal language.
That is, that all, or virtually all living forms on this planet at least
uses essentially the same genetic language. There may be slight dialects
or slight differences, but a considerable amount of evidence has been accumulated
fl, very recent evidence, which does indicate that the same language is used
by all living things. There are a few general principals, <ngieeries—tirat~ ore
‘cam-state, First, changes in the way the logic that the cell apparently uses
the simple principal the cell uses. Use ,the principal of standardization.
There are few kinds of parts and they are standardized. But great variety
is achieved and great diversity also. By combining the part in different
sequences and making many different kinds of sequences. Secondly, well, I
mantioned the universality; but the important thing that I want to stress
is that the particles will read any massage that is given to them. Now this
raises the possibility that synthetic messages could be inserted into the
cells and the particles will follow the instructions. This is essentially
what happened in viral infection, Virus by and large is simply a strand of
information of genetic information with a code around it to protect it. The

cocmation goes--a simplified vérsion obviously but in essence is correct--

the information goes inside itself and is copied or translated, by the cell's

machinery. Now, genetic surgery is a very sophisticated reality. In the
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jate 20's it was discovered - and a truly spectacular discovery, that one
colud prepare DNA from one strain of microorganism and simply add it in
volume to another related strain of microorganism and under ideal conditions
10-15% of the individual's bacteria would take up the DNA and their enzymes
inside the cell's other machines that will insert this DNA into the chromosome,
genetic material of the host so that this organism is changed and it is
changed genetically, the progeny then would have the inherited change. So
this raises the question then that synthetic information could be used to
program cells in much the same way as natural information has already been —
used to alter bacteria, Now I should say right now that this has not been
done really with mammalian cells. That there are great technical diffi-
culties in doing this. Although there have been some recent experiments that

-ggest that there are ways really of doing this. For example, it is possible
and this already has been done, to prepare DNA from a virus added to mammalian
cells and tissue culture. The DNA will get inside the cell and a virus is
formed. Recently there have been technjques in which one can take chromasomes
from one organism and two cells even from widely different species, fuse the
cells together, the nuclei fuse and one has a mixture of chromasomes from two
different organisms or 2 different species. The techniques are available for
doing this kind of thing so I think it is really a matter of technical difficulty
to find ways in which one could take a nucleic acid message and insert it into cells.
Now the major difficulty really is in the synthesis of the information.. The
chemistry is quite difficult and complicated. Thus far techniques are
available for synthesizing very simple messages, By synthesizing them, I
don't mean simply copying preexisting messages. because this can be done and
has been done for 10 or 12 years and there are enzymes--molecular machines

available that one can obtain from the cell that will copy a pre-existing strand

of DNA with great stability. It is not a matter of copying but really a matter
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of composing synthetic messages. The chemistry, as I said, is still rather
primitive, but it has been possible to synthesize long strands of DNA or RNA
containing simple repeating known sequences and technology is bound to improve
vastly in the near future. Now, it wouldn't surprise me, for example, if the
synthetic messages that are available today even quite simple used to transform
or to program bacteria and I think that this is potentially a reasonable experi-
ment even to do today and surely it will be tried and as I said technology will
almost surely “improve greatly along these lines. So the main purpose of the talk
this afternoon is to point out these possibilities and the current status of
work along these lines, the probable future development of the experiments
and ask questions because I think that when it becomes possible to do these
things then man may be in a position to in some way control, alter or shape his
bwn biologic evolution; i.e., to add information and to compose genes. Now
this power I think could be used for great good. I think that eventually man
stands to benefit greatly by techniques such as these. But I think it obvious
that a great deal - an emense amount of.basic information must be learned first
before such information could be applied. I should emphasize again that it is
not possible to do this today with synthetic information but I think that it will
be possible. My rather conservative estimate is in bacteria it is virtually
possible to at least try it today and it may be successful in 5-10 years. In
mammalian cells a conservative estimate would be 25 years. I think if you were
to ask a dozen knowledgeable molecular biologists their estimate of time you
would get varying answers but my estimate would be in 10-25 years. I could
be off very easily. Now it's necessary I think to formulate the possibilities,

state these questions because of the a ethical considerations, moral
considerations as well as the technical problems that are involved in this

because if and when man becomes able to shape his own evolution by programming
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cells with synthetic information the question will arise "which way to go?
What are the desirable goals. I think everybody will agree on certain goals
but there are many others of which a great diversity of opinion obviously
will arise, I think it very important to state this problem now, well in
advance of the need to state the problem because it requires time to think the
thing through to get reasonable answers to it and to begin to perhaps shape the
institutional framework in which this kind of approach would be used, This
essentially is the reasons that I've come here and tried to describe some
of these developments and I can only say in closing that I think that this
potential has great possibilities for good. I think that eventually
man will benefit greatly by it but there are a great many facts and a gread
deal of information that must be obtained first before it is applied.

Thank you very much,