October 28, 1952

Dear Norton:

I hope all of the cultures will have arrived safely—— let me know
if any replacements are needed.

Some sort of ploture of variation is emerging from experinents
with abony ~x typhimurium. (-x signifies transduction to, x transinduction
by]. SW-§35 is not entirely satisfactory: ite motility ani phase—variation
are somewhat erratic.I have been using LT-2.

In general, FA from phase 2 8 no trace of the phase 1 factors. This

was_spparent in your ty me~ —~% typhi, and sver: more strikingly in
tym x S¥~543 and ab x SW-543. To dhe extent of a limited nunber of

teste this also holds up in abony -x tym. In wany cases, the second phase
evidently cannot be maintained in a ponophasic type sush as SW-543 or typhi.
[the 1,2 phase in 3W-534 and ~588 muy be exceptional, see beluw], The following
results have been obtained with ubony -x LT-2+,

abony?2 -x + NEDO 80 enx <4 1

abony 7 -x : b — 1,2

Tf thie result man be generalized, we have the following conclusions:

1) The alternative phase is not inherent in’ the transdpoed allele

2) The alternative phase is not represented in any aotive fora in the FA

3) ce a ternative phase ig retained in an inactive state in the recipient
cell.

&) The specific and non-specific are, in ganeral, homologues at two distinct
joci, but are not allelic to each other

[5] Monophasicity may be accounted for in som cages by the unsuitability
of the residual genotype for the expression of the alternative phase.
fn ather cases, it my have to do with the frequency of the shift itself.

The consideration of 2} with 3) leads to a paradox. In previous thinking,
I had specuhAted about a phase-shifting locus whose autation determined the

of either phase; one could imagine a "cytoplasaic state" mechanism
in s terms. But whatever type of suppression of one locus 1s involved
is pot separable from it by tranaduction. If we accept shat transduction Le
makxx confined to nuclear factors, usually single, we have to infer more or
lass permanent gene states, autually exclusive as between the two looi. This
sounds rather like McClintock. One can also imagine that one locus is replicated
many fold, elther into the cytoplasa (gene-initiated plasmggenes) or at the
locus itself, like Huskins’ lamellae. I don{t want to go to far in speculative
analogies mukkk with somatic differentiation until the facts are more thoroughly
established. I am fairly convinced, however, that phase variation is not a
mitation in the ordinary sense, bat a semi-permanent inactivation, of some sort,
of one of a pair of loci— the inactivation being so closely associated with

the locus that it is not separated by transduction.

I had thought that the monophasic behavior of SW-543 H” could be understood
by its inability to sustain the 1,2 phases. Stocker showed, however, that
SR-~534 -x 543 gave 1,2, and I have confirmed this, also ruling oub the possibility
of contamination. 43% SW-534 itself reverts occasionally to give the 1,2 phase
(9.g. SW-588). More recently, I have gone back to what I regarded as SW~-703
(i.e. Edwards #3) which should be equivalent to SW-533, the source of SW-534.
However, FA (SW-703) either Il or I gave only b, and no 1,2 from SW-543.

It is rather important, therefore, to trace the history of these cultures accurately.
Unfortunately, at the time these experiments were done, not too great care was
taken to identify the serotypes. In the lyophii collection, there is an anvelope
labelled S. paratyphi B, with no other designation. I have assumed that this
represents Edwards #3, on the one hand, and the parent of 534, SW-533 on the other.
Is there any possibility that this is incorrect? To add to the confusion, there
was a contaminating Salmonella, so far untypable, in the stock culture of
S$Bx'"Paratyphi B #3", but I don't think this is related to the present question.

At any rate, it would help to clear this up if you could send back to me any
cultures that you may have under the des{friation SW-533, or Edwards 3, or any
others that might be confused with these. Please alsp record how they have been
jabelled in your hands, and perhaps the situation can be clarified.

Sinceraly,

Joshua Lederberg

P.S. Thanks for the check, which has been forwarded. It will help.