MERCK INSTITUTE
FOR
THERAPEUTIC RESEARCH

RAHWAY, N. J.

March 4, 1954

Dr. J. Lederberg
Department of Genetics
University of Wisconsin
Madison 6, Wis.

Dear Doctor Lederberg:

Some weeks ago you sent me a set of reprints
which I shall always cherish as an example of the con-
fidence scientists place in the assumption that their
publications are read. On page 128 of a paper called
"Genetics of Resistance to Bacterial Inhibitors," you
have a question written in the margin. The chences that
I would ever read a paper with this title are so remote
that I can only conclude that the Umbreit luck is still

holding, inasmuch as out of the group I actually did read
this.

The question has to do with the properties of
the Sr mutants. The ones reported on were mutants that
had been brought to resistance of 2 mg./cc. and held in
culture for several months before study. A further study
of this same problem $s in about twelve different strains
and following their metabolic properties from the time
they were selected until they had been cultured for
several months showed that the nature of the physiological
deviation in the Sr mutants was purely a matter of chance.
some strains were unable to utilize oxygen for increased
growth. Others were perfectly capable of this. The
ability to use oxygen could be lost in one step or a cell
could become resistant and still retain the ability to use
oxygen and either retain it throughout the period of
Study or else lose it at some subsequent date. Throughout
all of the strains, however, the one characteristic was that

the oxalacetate-pyruvate reaction as we were able to measure
it was apparently lost.
Dr. J. Lederberg -2- March 4, 1954

With the information that the product of the
oxalacetate-pyruvate reaction seems to be a seven-carbon
phosphorylated intermediate it was possible to distinguish
between two alternatives which had previously arisen. If
the resistant and dependent strains had lost the oxalacetate-
pyruvate reaction, then they had either acquired the ability
to dispense with this compound entirely or acquired the
ability to synthesize 1t by some route which was not
sensitive to streptomycin, said route not influencing the
same kind of pathway as that from oxalacetate and pyruvate.
We, therefore, grew both resistant and dependent strains
in considerable quantity in the presence of streptomycin,
and found that we were able to isolate the 7-carbon
substance from both types and that it was present in
apparently one-third the concentration that it occurred
in the sensitive strain. To my mind, this means that
the substance cannot be dispensed with, but that the
resistant strain has "learned" how to make it by a route
not inhibited by streptomycin.

With best wishes,

Sincerely yours,

WWU: VMF hee Vee it