TRANSCRIZED FROM RECORD FROM J, LEDEREERG RECEIVED 6/16/58

May 2%, 1958
Madison, Wisconsin

Dr. Joseph Lein
Bristol Laboratories Ine,
Syracuse, New York

Dear Joe:

From time to time I try to reflect over ‘the broader ains of the screening
programs to see whether I can think of any objectives that night be overs
looked from day to day,

It has been quite some time now since substitution chemotherapy came up and

I must confess that I have still bean unable to think of a sounder basic
approach that has not yet been well worked over, Expensive as the sersening
for antinioroblal agents is, it is, of course, a basieally simpler proposition
than the search for other pharmacological agonts, and I see no help for it but
to contemplate the expenditure of larger anounts of money to make further
Progress in other fields where the assay systems are more complex,

A propros antimicrobial chemotherapy, I wonder if you still have rreat
difficulty in translating the production of a promising compound fron your

flask seale cultures to larger seals, If this is still a significant proble:,

as of course it haa been in the past, I wonder whether the sound approach is

to continues to try to use optim conditions in the prelininary screening or
whether it would not be better to set up a prelininary screening regine that
from the start would more nearly reflect the technical procedures that Ou

would have to use later on, This supposes that you know something of the
variables which are responsible for the difficulty in translating fron Laboratory
to pllot scale operations, Since you are often unable to ceive fill attention
except to those compounds that can be handled on a 2zarger scale, it would he
better to limit your screening to those compounds which were, in a sonse,
preadapted for it. If, as one Suspects, oxygen Limitation is the chief factor
liniting production in larger scale cultures, then one might try to find

methods of laboratory handling which would more nearly simlate the pilot plant
and production plant situation, I am sure your engineers have gone as far as
they are likely to in the near future in tho dirsetion of optinizing the production
facility itself, So at this point, it would sean to me to ake food gense to
try to match your production conditions in your small scale screening orpertivents
insofar as possible, It 1s just conceivable that the very vigorous aeration that
one customarily uses may help to defeat this purpose,

I know that you must be mainly preccoupled with setting up the tumor screening
program that you have been telling me about during the past several tonths,

It is very difficult for ma to comment on such a program in the abstract with
out knowing the general organization and limitations of this operation, Onee
you have shakenedown its initial organization, along what must be fairly self
evident lines, I would very much like to have an abstract of your procedure and
will see if I can offer any useful covent at that tive, Also, if there have
been any inovations in the antinicrobial sereening procran or if there are any
J. Lein fron J, Lederberg 2 6/15/58

aspects of it that might be worthwhile poing over once again, I would be happy
to hear from you about it,

It is hard to think of any fundanental approach to the tumor problem that haa

not already been worked over quite a few tines before. Obviously the empirical
search while it has no particular rational basis is something that must go on
and must be pushed with great vigor, I myself believe that transplantable tunors
in the host strain of origin, provided they had not been selected too far for
further anaplasia by repeated transplantation, a= the most suitable material. A
trouble with something like Hela cells in tissue culture is that they are so far
removed from their oells of origin, and there is no possibility of retesting them
ag such jy ylyo under suitable conditions that they represent only one step more
than a miorocorganiam in screening programs, That does not, of course, mean that
they are without value, However your substitution chemotherapy progran for coli
works out I hope you will also give it a try in the tumor program, It is
Teasonably obvious that compounds like fluorouracil should have been picked up
by such a regine,

There is one problem in medicine that is going to be of huge dimensions once

the appropriate technical tools have been devised, This 1s the capacity to
comiuct homotransplantation in the replacement of diseased or damiged organs
from one individual to ancther, At the present time, there is no practical way
to get around the homograft destruction response that follows transplantation
of tissues from any individual to any other, Eventuslly, 1t may be possible to
stimilate the conditions of prenatally-acquired tolerance in adult life, but at
the present time this is somewhat visio e X~radiation has been used but this
has such a non discriminate effect on a variety of cell types that it represents
a cure hardly better than the disease in most instances, ‘what we are obviously
looking for would be an agent which could selectively inhibit the homograft
response without too badly imparing other vital functions, While one can argue
that this might mean interrupting the entire defense mechanisms of the host, this
is not necessarily so, There is good evidence that humoral antibodias play a
very small role, if any, in homograft destruction, It looks as if it requires
the specific activity of a certain type of cell, predumably the lynohoeyte, to
destroy homograft cells, It might be possible, therefore, to find an agent which
would selectively destroy this aspect of the hosts imume mechanisms without
preventing the formation of soluble antibodies and without imparing the overall
blood forming ability, It 1s in this raspect that a specific agent would be far
superior to Xerays,

How then would you go about sereening for such effects? Historically, the easiest
technique for testing histocompatability has been the use of tumar cells derived
from genetically different strains, When transplanted into incompatable mice

such tunora will ordinarily regress after a short period required for the develop~
ment of the immune raaction, Anomalously then, you would be looking for a reagent
that would modify this reaction in such a way that the graft implant would then
grow progressively and kill the hoet,
J, Lein fron J, Lederberg 3 6/16/58

The most promising agent that one should screen in such a progran, are those
Which appear to have some effect against cells of the lymphocytic series, and
there are bound to be some clues in the course of routine tumor soreening.
Since it is conceivable, however, that the desired agent would have a blocking
effect without necessarily destroying the lymphooytic cells 1t would probably
be worthwhile considering an extended program of blind screening as wall. And,
of course, the possibility of developing a reagent through the principles of
substitutional chemotherapy, that is, by chemical modification of products fron
lymphocytes, should not be neglected. Since a screening program along these
lines could be integrated without great difficulty into your program already in
progress for screening antitumor agents, it may deserve particular consideration.

Sometine ago we touched on the question of antiblotic sereening for contraceptive
purposes, Iam told that such an agent has in fact been found having been
developed by Warner Chilaott, which has the effect of causing the lysis of
spermatosoa, If the rumor is correct, the lysis will take place whether the
material is injected by either the mile or the female.

Well, that's about all for now.

Yours,

Joshua Lederberg