September 13, 1946.
Dear Dr. Edwards:

First let me thank you for a very constructive reply to what was per-
baps a prejudicially one-sided presentation of the case that I had sent in
my last letter. I do, however, disagree with your concluding paragraph, that
we are talking at cross-purposes and do not understand each other. Bacteria
are only since very recently under genetic study, and it is not at all unlikely
that new conce;ts of inheritance will have to be erected. ‘Ve must, however,
start on the basis of what is already knowp, and interpret new findings in
the light of thie when they appear, rather than abandon existing concepts
in favor of a vague formation of th ca;acity of bacteria to be coaxed.
Spiegelman (at ‘Jashinton University) 4s doing a classical piece of resesrch
on adaptive enzymes, primarily in yeasts, which is tying together the older
genetic ideas with these most interesting phenomena,

I am particularly interested in your observation that induced variation
by a serum may not necessarily be exactly associated with its agglutinin
content. It would be of the very greatest importance to elucicate the mechanisms
of this process, both from an acadeiic genetical, and a practical point of
view.

Phage adaptations have, I think, been shom fairly clearly to be instances
of random variation (Luria, Genetics, 1945.)
Please do not get the impression that I have a cause that I am trying
to impress on you, sir. With your cordial cooperation (as s0 far evidenced)
I am trying to apply certain processea and principles that were developed
with nutritional mubants in =, coli, to the inheritance of antirenic characters

in Salmonella. To tht part of it, I doubt that a priori argument is any

it ba ae :
longer fruitful.

So far, I have had the opportunity to study about 120 strains from the
Hartford Laboratories for their nutritional requiremmts. Host Salmonella
strains are apparently prototrophic, i.e. have very simple requirenents, growlLng
well on a basil synthetic medium. Salmonella pullorum strains evidently require
leucine and cystine fairly consistently, with some variations, and some other
Salmonellas seem to require only a source of reduced sulfur. There may, however,
be a few naturally occurring strains wth well marked requirements that can be
used as discussed previously. One of these is a pagatyphi strains which requires
tryptophme end methionine. Attempts to get prototrophs by crossing this with
pullorum have not, however, been successful.

I am enclosing a reprint of som of our Neurospora wopk which may be of
interest as the basis of some the ddeas which I expressed about ‘induced variation.'
It would be very desirable to visit you at Le-ington, and I shall if thet seems
possible,

Very sincerely yours,
Joshua Lederberg.