Columbia Guitbersity
inthe City of Netw Pork

[New YorK 27, N. ¥.]

DEPARTMENT OF ZOOLOGY

January 24, 1950

Dr. Joshua Lederberg
Department of Genetics
University of Wisconsin
Madison 6, Wisconsin

Dear Josh:

Peg Lieb is interested in a post-doctor-
ate fellowship for next year, and one of the
people we naturally thought of her associating with
was youe She has recently heard from Max Delbruck
that she would be most welcome in his laboratories,
and she would like to work there. I think you
could do for her every bit what Max can, but since
it seems an uncertain thing at Wisconsin, I believe
she should aim at Cal. Teche Max knows Peg--a fact
which, combined with his willingness to have her,
should convey the notion that she's not bad. In
fact, she's quite bright. A little quick and a
little demanding, but industrious enough to turn
out ok.

Max thought she might like to work on the
rate of formation of recombinants, a problem into
which I think you will agree Tom Nelsdén has at
least gotten his incisors.e When Max hears of Tom's
results he may feel somewhat more kindly towards
your work. What the hell was bothering Harriett?
Such reactionaries! Ah well, I suppose devil's
advocates have a real place.

My own problems have been dissolving a
bit more rapidly recently. I do not have the ans-
wer to the one on the discontinuous distribution of
ht+ mutants. I have never been able to convince
myself that the distribution is multi-modal and
still want to test it against the theoretical one.
Dr. Joshua Lederberg -2- January 24, 1950

For this reason, I have written Coulson regarding
his solution to the L.D. equation but have not had
a response.

In somewhat better shape are several
other jobs- Population equilibrium is pretty cer-
tainly accounted for by mutation rates and a chang-
ing selection pressuree We have been able to do
more than calculate selection pressure at equili-
brium by introducing a marked ht at this frequency
and measuring its rate of disappearance (tracer
technique). The measurement confirms the calcula-
tion (a 0.02% change in frequency of ht's per gen-
eration) and we are now using the same technique for
other ht frequenciese In the meanwhile, I have been
able to calculate that s = 1/nt+ frequency by a con-
sideration of the rate of increase of h+ through
serial transfer to equilibrium.

At very low frequencies s turns out to be
about 0.6. Such a selection allows an increase of
h+ bacteria (including those arising by mutation)
which is operationally indistinguishable from that
observed by the fractionation of liquid cultures
and the use of the Posson formulation. So much for
the logarithmic increase of ht's in an h- culture--
we had already ruled out by other experiments the
effect of one mutation on others.

We used the fractionation technique to
avoid any influence of agar on the frequency of ht
colonies. But it turned out our agar was not at
fault. Adapted colonies do continue to appear on
agar even when they cannot be accounted for by an
increase in h- number. Indeed, stationary phase
adaptations occur in liquid cultures, aven after 7
days, with no increase in h-. By the use of vari-
ance analysis we have been able to show that these
Dr. Joshua Lederberg -3- January 24, 1950

adaptations are not due to the eventual growth of
slow ht mutants which appeared during growth of the
culture before it passed into the stationary phase.
Now we are attempting to measure cell turnover dur-
ing that phase by the use of marked bacteria. But
our biggest problem is to decide whether we are
simply observing release from phenotypic lag of

the sort Evelyn Witkin thinks she is dealing with
in her ribonucleate experiments. If mutations do
occur in the stationary phase, it would be very
worthwhile knowing, for the system would be ideal
for the study of induced mutation.

Enough babble--

Sincerely yours,

Francis Je Ryan

FUR: LF