UNIVERSITY COLLEGE LONDON
DEPARTMENT OF ZOOLOGY

Telephone ; EUSton 7050 GOWER STREET WCI
Professor P. B. Medawar

lith July 1959

Dr Joshua Lederberg,
Department of Genetics,
School of Medicine,
Stanford University,
Stanford,

California, U.S.A.

Dear Josh,

Very many thanks for your letter. Science of 19th June arrived
between my writing and your reply, and I read your article with the
utmost pleasure and interest. Whatever else may turn out right or wrong
in it, I feel convinced of the essential truth of the elective theory.
As your propositions are proposais rather than assertions there is
nothing to quarrel with - things will sort themselves out in time.
Three points come to mind which I'd like you to comment on sometime.

1. I don't see how A}, according to which genetic variants among
antibody forming cells arise randomly, provides for the possibility that
certain individual animals may be incapable of forming antibodies against
particular determinant groups. Here see some wise and informative remarks
by Eisen, pp. 645-649 in “Cellular and humoral aspects of hypersensitive
states", ed. H.S.Lawrence, Hoeber 1959. Indeed, I don't see at the
moment how to reconcile A3 with the possibility that immunological
performance may meridelize in the manner hinted at by the data in your
ref (33). If you write some additional notes to accompany the reprint
of your paper, I hope therefore you will amplify the last para. of A4.

Incidentally, Avrion's paper at Royaumont called attention to
the extraordinary speed with which normal reactivity returns to
formerly tolerant animals after antigen has expired. This argues for a
high mutation rate among immunologically competent cells. On the other
hand one has to remember that Jim Gowans's new work on the longevity
of lymphocytes shows that the mitotic rate inlymphoid tissue has been

greatly exaggerated, under the impression that all lymphocytes entering the
blood stream are newly formed.

2. What you say about embryonic differentiation in para. 3 of A3 and
in the last para of your paper is open to misunderstanding. Burnet
explicitly states that the diversification of antibody forming cells is
due to the same kind of process as that which occurs in embryonic differen-
tiation generally. You. refer to "a specific mechanism of cellular
differentiation" in para. 3 of A}. I'm almost sure you mean that

the diversification of lymphoid cells is one among several possible kinds
of differentiation -—- not that A3 provides a specific explanation of
embryonic differentiation.

It strikes me that Burnet's belief that somatic mutation accounts
for embryonic differentiation generally is inherently paradoxical.
For, here, the mutat@ions must be orderly and not random. If they are
orderly, the zygote must contain enough information to ensure that the
right mutat@ions occur at the right time, place and order. But if the
zygote contains this wealth of information anyway, it becomes pointless to
pring in somatic mutation in order to enlarge it. I'm ali for differentiation
being an elective process but still have to be convinced that there isn't
enough information in the zygote to subsidize it.

3. <A fascinating news item occurs on p. 179 of the Abstracts of
the VIIth Int. Congress of Microbiology in Stockholm. You probably know
that the intracutaneous injection of diphtheria toxin produces a violent
inflammation unless specific antitoxin is present in the subject's blood
(Schick test). Milgrom and his colleagues claim to have produced tolerance
of diphtheria toxin in guinea pigs in the sense that theyion' t produce
antitoxin after antigenic challenge — but the interesting and paradoxical
point is that these tolerant animals are Schick-negative, i.e. they don't
produce the inflammatory response to be expected of animals with no
circulating antitoxin.

This is exactly the result one would predict if tolerance were
due to induced enzyme formation, as suggested at Royaumont: a specific
enzyme is formed which catabolizes toxin too fast for antibody formation
and too fast for it to produce dermal necrosis. However, I expect there's a
catch somewhere in this explanation!

Don't fail to send a reprint of the Science paper —and apologies
for a not very coherent letter.

All good wishes,

Det.

P.S. I la:ghed a lot at your lexicographical analysis of entailment. It's
a perfectly respectable word in old-fashioned logic — ask an old-fashioned
logician ,if there are any on the Stanford campus!