TRANSCRIEBL FROM ReCORD RuChIVeD 4/23/58 FROM DR. LebeRPERG

Madison, wisconsin
April 21, 1953

Lr. J. Lein
Bristol Laboratories Inc.
Syracuse, New York

Dear Joe:

I am enclosing a program for a symposium on somatic cell variation that I
thought might be of some passing interest to you. The topic, of course,
impinges directly on the nature of cancer, but I have to say that nothing
very startling came out of this particular meeting. It may be of some
ultimate significance in the chemotherapy of cancer that so many tumors do
have abnormal chromosome constitutions especially after they have shown
some degree of neoplastic progression. This is brought about especially
in the contributions by Hauschka and Ford.

The only other item that I wanted to bring up at this time has to do with
the microbiological evaluation of potential tumor a,ents. Certainly the
inhibition of growth in an appropriate system would be the simplest basis
for an assay, but one might find that this failed for some possible
materials. I would like to remind you of an alternative approach which 1
think may have been brought up before but is more pertinent at the present
time. You may have become familiar with Atwood's studies on the effects of
jodizing radiatione on hetrocariotic conidia of Neurospora, Without going
into all of the aspects, one of his useful findings was the efficiency with
which segregation of hetrocarions is induced by radiation. In fact, rather
smal] doses are capable of giving measurable increases in the proportion of
no longer hetrocariotic spores. I had proposed this some time ago as a
method of screening for nucleotoxic agents and, in fact, Charlotte Auerbach
has been spending some months with Atwood at Oak Aidge applying similar
technics to the screening of various Weutagenic chemicals. The procedure
is not too complicated to be managed by anyone familiar with the culture of
Reurospora. It involves the maintenance of a balanced hetrocarion,
preferably with additional colonial or color markers for the hetrocariotic
genotype, and then plating treated conidia to examine the fraction which
has been made homocariotic by the treatment. In this way the technic ise
not so much a more sensitive index of inhibition as it is a specific index
of nucleotoxic effect as compared to other modes of inhibition, and I would
rank a procedure of this kind quite high among possibilities for preliminary
screening of agents that might be expected to have antitumor activity. The
procedure might also be valuable for the biological assay of a potentially
active component.

As a matter of fact, there is a bacterial system which is perhaps theoretically
a little bit more obscure but which in practice I am certain will give exactly
the same results and which might be rather more easy to handle, especially

for weaker agents which ought to be applied over a considerable period of

time. This is the induced haploidization of hetrozygous diploids of be coli
and it is described at some length in my 1951 Cold Sprin, Harbor review,

The chief problem here would be the effective maintenance of suitable diploid
stocks, but this is not really terribly difficult either, and the wiole
Record from Dr. Lederberg Uf21/3s

technic can rather easily be put on a routine basis. The effect that would
be looked for would be the increased proportion of laduinus, haploid,
segregates out of treated oultures of a balanced hetrozygote. One advantage
of the bacterial system is ite extreme sensitivity and we were able to
diagnose genetic effects of doses of radiations and chemicals that had quite
small bactericidal effects in total. Again, I would recommend this type

of procedure for the biological assay only if a simpler zrowth inhibition
were not readily available for a particularly promising compound. On the
other hand, I would think that this sesay approach should be quite valuable
in the primary screening of nucleotaxic compounds such ag might arise in the
attempts at substitutional chemotherapy, and in fact it might be applied
quite independently of growth inhibitory effects if the latter happened to
be not too powerful. If your reading of the Cold Spring Harbor account,
between pages 1,20 and 430 and referring to figures 7A and 72, sugyest that
we ought to go further into this, I will give you a more detailed prescription
on how you might go after it.

It is quite unlikely now that I will be going down to the meetings, but if
you can find time for a side trip to Madison from Chicago, we'll ve very
glad to see you here. Esther may show up on the 29th.

With all best regards.

Your sincerely,

Joshua Lederberg

JLiac
Typed 5/6/58

copy sent to Dr. Lederberg 5/968