HARVARD MEDICAL SCHOOL

THE DEPARTMENT OF PHARMACOLOGY
23 SHATTUCK S8T., BOSTON 15, MASS.

December 17, 1954

Dr. Joshua Lederberg
Department of Genetics
University of Wisconsin

Dear Joshua:

I am sorry you cannot participate in the panel discussion,
and puzzled at your question what I have in mind as the connection
between this topic (transduction) and the biochemical basis of
acquired (7?) resistance. By acquired resistance I mean the development
of resistance in a cell that was not previously resistant. This is
meant to narrow the scope by excluding from primary consideration the
enormous question why some cells are more sensitive to drugs than
others, a question that is really the whole problem of drug selectivity.
That would be too much.

By biochemical I mean the molecular basis of the changed
resistance of the cell, insofar as it can be intelligently discussed
at this time. I mean also to direct attention and emphasis to the
idea that the genetic changes are controlling (very likely) the
macromoleculas systems interacting with drugs, but the genetic material
is usually not itself interacting with drug-- i.e, the fumamental
change in the cell, which makes it drug-resistant, is to be explained
in biochemical terms, although it came about through a genetic mechanism.

I did not ask you to discuss transduction. I asked for a
discussion of “directed heritable transformations". Whether the
transformations to drug-resistance are related to transduction, and
in what way, is somethin g I am ignorant about, but hope to learn about
from whomever I can persuade to discuss this topic.

I am glad to see that an aspect of pharmacology has causht
your fancy. The literature is poor and scanty beyond that the organisn
becomes able to tolerate many lethal doses of a variety of drugs after
continued exposure to theme Morphine has been best studied, but poorly,
and it is only within the last few years that we know for certain that
enormous morphine concentmtions circulate in the blood of tolerant
animals-~ i.e. that the phenomenon is a change at the cellular level.
Nicotine is a classic example. A rapidly developing tolerance called
by the fancy name tachyphylaxis can be demonstrated in isolated smooth
muscle with drugs like ephedrine. I don't know of any case in which
mechanism has been demonstrated.

At Washington last year there was a symposium organized by
Sevag that tried to put all these questions of changed resnonses to
chemicals into one basket but it turned out to be an indizestible
omelet and I want to steer clear of it. Thanks anyway.

Sincerely, we

Avram Goldstein