May 8, 1952

Dear Jacques (and Mel):

I am sorry not to have taken time before to tell you how very much I
enjoyed reading the papers you so kindly sent me in ms. The review is
very stimulating indeed-- it seems to me for the first time to discard
speculative superstititions about enzaymatic "adaptation", and to dis-
cuss the experiments in factual terms. The kinetic analysis in cellular
terms was especially valuable. I remember that during the few experiments
that Roger and I did on the UV effects on Pseudomonas, it seemed as if
it were the total yield rather than the rate of formation of adaptive
enzyme that was primarily affected. Perhaps this cai be most readily ex-
plained in terms 4f an all-or-none responsemof individual cekis. Perhaps
the terminology of neurophysiology would be as appropriate for enzyme
misiu studies as that of embryology!

I must confess that we have been essentially inert for the time being
on lactase questions. This year has been rather difficult, with space
problems, new people, and distractions from other interesting lines of
work. Perhaps we should be discouraged by your findings on the identity
of the lactases from diverse species, but I am still hoping to attack the
possibility of specific differences among the variety of new fertile strains.
Dr. Skaar has been working them up immunogenetically from a general viewpoint,
and should soon be ready for a specific consideration of this particular
antigen. I have also a great ‘amxntx deal to do with the pestiferous details
of the genetics of the Lac types. There is no question as to the correctness
of the conclusions that you, for example, cited in your review, but it is a
long way from an assurances of a diversity of genotypes to a detailed study
of the loci from a genetic viewpoint. And I don't want to get too deeply into
detailed physiological comparisons until the genetics is well worked out. I
hope that we will soon be getting well into it again; meanwhile, Bonner and
his students have been doing something on it, with no results discrepant with
your own thinking.

On p. 49 there is a slight typographical error: lac,- should read lac,~

in this case; I have taken the libertg of writing directly to the publisher
myself in hopes it can be caught before the printing.

I cannot think of any important topic thatyour review did not discuss.
Your treatment of accessibility of the enzyme foreshadows a very treacherous
but unavoidable area for the future. You are probably already aware of the
contradictions in the experiments on glycolysis by Lac,-. I have been very
much concerned over the meaning of in vitro kinetic experiments with E. coli
lactase, and have wondered whether the results do not reflect another enzyme
system concerned with "transport". To change the subject only slightly, can
one rephrase the problem of the relationship of enzyme-specificity to enzyme-
forming~system-specificity in a slightly different way. Is any inductor incapable
of reacting with (i.e. complexing) the enzyme, and vice versa. It is all very
well to introduce the "organizer" concept (and I am in full sympathy with it,
reserving, as you do, the greater qualitative control to the genotype), but
still the inductor can only influence the cell metabolism by reacting with some-
thing, almost certainly not the enzyme itself. In terms of the ability to form
any

weet

complexes, inducers and enzymes might be expected to share some specificity.
Like yourself, however, 1 see no reason whybthis should be obligatory, except
as it would be adapbive in an evolutionary sense. Because of a preoccupation
with autocatalysts, too manyvwriters have forgotten that enzymatic adaptation
is a mechanism, andevolved solution to a biological problem. It is this that
we see for the most part, rather than the physiological necessities of the
mngx unique mechanism of protein synuathe synthesis.

I thank you also for the reprints recently received. <A few of ours are
in the mail, but we are waiting for the printing of the ones you will be most
coneerned about. May I ask whether you still have a copy of your descriptions
of the bactogen? I have not yet seen this.

Esther asks to send her reggrds. She also sends (more tangibly) the ehclosed
ms. which is perhaps a little away from the focus of our joint interest, but
more than a little relevant. It is the condideration of such complexities

“‘Weexki among the genes themselves that have made me despair of easy mx solutions
. and hypothesis of enzyme synthesis and gene action. It would be better if

this inhibition did not operate: it tends to discourage the beginning experiments.

Have you been able to find any experimental substaatiation of a built-in
inductor, especially in the constitutive stocks? I would be incline to guess
against it, mmukak mostly on philosophical grounds, and partly on experimental
failure (not xmxy pushed very far). There is Also the lack of fadaptation to
galactose that one would expect, under certain conditions. Have you any infor-
mation on adaptive specificity of galactozymase that would be useful as a
"eontrol" on this thought?

to in Paris

Accordingathird- or fourth-hand correspondence, skepticism is arising anew,
as to the likelihood of a sexual basis of K-12 recombination. If or until the
morphological or chemical bases of recombination are directly verified, we are
likely to run in semantic circles, of which the issuenwill be dizziness, not
clarity. If there is any impression that lambda is directly involved, I hope
you may refer to my discussion of this with you some years ago in which I
pointed out that lambda-free parents remained fully fertile, and this still
holds more firmly than ever. There im are indeed some very interesting new
developments on genetic control of "sexual" compatibility which are opening
new avenues of insight, but I hope that judgment can be reserved until all the
facts are established. There are t®o stipulated findings that I cannot ign
ignorek the inseparability of the agent of recombination in E, coli from the
cell, and the occurrence of diploid hybrids heterozygous for each m&x of the
dozen differential markers of the parents. My 1949 paper on aberrant hetero-
aygotes already pointed out some complexities, for example that Mal and S are
usually def: deficient. It is possible that this deficiency is already present.
in the "gamete", and one can argue that this defect carried to its logical
conclusion resembles an agent of transduction or transformation. “here is a
little evidence, however, that the elimination is post~meiotic (discussed in oy
CSH paper). We Have fortunateky imam had ample opportunity to compare K-12 with
a transductive system in Salmohella, and the two systems are experimentally
very different in every respect that would be associated with the difference
in the recombination mechanism. Disregarding the details, the conceptual
differences will be similar to those surrounding the interpretation of a spermatozoon
Is it a parcel of biologically active, chemically isolable DNA, or is it a gamete
with genetic properties defined so and so? The questions are not mutually exclusive,
and we should be interested to answer both of them, according to the suitability

of the experimental material.
Sinterely,
Np lita

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