July 15, 1959

Dr. Peter B. Medawar
Department of Zoology
University College
Gower Street WC!
Londan, England

Dear Peter:
Promptly to yours of the IIth.

| am happy to take up the three points you refer to. Undoubtedly,
many more are golng to arise.

I would not be too alarmed at having to explain Mendelian genes
influencing Immunological performance untI! the two cautions of the
last paragraph of Al have been adequately dealt with. If we have to
go beyond this, | should say that a random configuration of nucleotides,
In a restricted segment, might sometimes fal! to encompass all possible
antibody configurations. The homogeneous cerrier segments Into which
the specific segment Is inserted might also Jimit the overall possibilities.
But | would suspect that the main effects are due to a fortultous tie-
in with autotolerance.

| had a chance to talk with Avrion about your other point on
this paragraph. | would stress that the mutations in the stem Tine
and the subsequent stepwise maturation of the progeny sells are
continuous processes. At any moment, therefore, the organism should
contain cells which have already mutated to a given ‘configuration but
not yet had time for its phenotypic expression. These mutants, already
formed, might then be avallable for the prompt revival of reactivity
when the antigen Is no longer ubiquitous.

1 am sorry for the ambiguity in paragraph 3 of A3. | am afraid
1 just do not agree with Burnet as you quote him on this particular
subject. Yes, | do mean that somatic mutation is one of several
possible kinds of differentiation and concur with you that It Is a
most farfetched possibility for morphogenetic Inductions other than
those Involved In antibody synthesis. 1! probably should have left
this out all together. That It Is In here at all, is probably a
carry over from the discusston at Gat! Inburg where | had taken such
pains to Infer that the orderliness of differentiation precluded a
process of naucleotide alteration. 1 still think it does but found
that | had to admit that nucleotide alterations might be Involved if
they occurred at random and were then elected. | don't think | take
this possibility, for the genera! problem of differentiation, any more
serlously than you do.

Thank you for bringing Milgrom's paper to my attention. It does
ralse a number of Important Issues -- so much so that | would hesitate
to build too far on such a fragmentary statement as appears In the
abstracts. Certainly It would be a most Informative experiment to
-~2-

find out whether the skin of the unreactive guinea plgs Is capable
of neutralizing added toxin and If SO, whether by an antibody-
neutralizatlon or an enzymatic-degradation mechanism. My only other
thought Is that the toxicity he Is looking at is not the typical
cytotoxicity, but some sort of hypersensitivity reaction dependent
on the presence of homologous immune cells, or a minimal level of
antibody, In the host. But why ltnger too long over so detailed

a speculation when the experiment that suggests Itself seems so
Straight forward.

AS ever,

Joshua Lederberg