ake STANFORD UNIVERSITY MEDICAL CENTER
iy STANFORD, CALIFORNIA 94305

 

August 19, 1974
STANFORD UNIVERSITY SCHOOL OF MEDICINE

Department of Genetics
(415) 497-5052

Dear Dr. Schatz,

I am not sure how many first-order examples I can recall of
paradoxical effects but the following considerations may be relevant.

1. Most mutagenic (carcinogenic) substances both bill and alter cells,
at different rates, If the mutation rate << killing rate there will

ob-iously be an optimum dose qua absolute number of surviving mutated
cells, namely that dose giving e7l survivors. (Lederberg 1948 -
Heredity 2:145-198, at p. 165).

2. I believe there are optimum rates of coding and of level of residual
moisture for survival of organisms (cryobiology; lyophil.)

3. Water, indeed most nutrients qualify formally - unless one has
ancillary knowledge that classifies the "toxicity of low doses" as a
specific deficiency effect. I do not think the distinction is logically
rigorous, ,

4. From the standpoint of behavior of the whole organism, most narcotics
and anesthetics show paradoxical effect. cf the half-drunk who tries

to drive vs the sleepy drunk who cannot. There are many other dose-
dependent reversals of narcotic effects you should investigate.

5. In immunology, there are optimum doses of antigens for immunization -
notoriously pn. polysaccharides, and of course for precipitation with
antibody.

6. Excess phage multiplicity inhibits phage growth (lysis from without
and related phenomena).

Viruses can do the same thing to animal cells via induction of
interferon. (Isaacs early observations; his papers may also have given
examples involving experiments with whole animals).

7. The most startling example in my own experience was penicillin/
E. coli for survival of L colonies. (J, Bact. 75:151 ff). Recent

findings of several receptors for penicillin may rationalize those
observations.

You may find other examples of paradoxical inhibition by anti-
biotics and of the related (?) phenomenon of therapeutic interference

LT. J. P. KENNEDY, JR. LARORATORIES FOR MOLECULAR MEDICINE, DEDICATED TO RESEARCH IN MENTAL RETARDATION

MOLECULAR BIOLOGY HEREDITY NEUROBIOLOGY DEVELOPMENTAL MEDICINE
Dr. A. Schatz -2- 8/19/74

in the books on antibiotic action, approximately 1950 by Work and Work
and Albert.

8. There are of course many examples of substrate inhibition of
enzymes that offer a kinetic model of paradoxical effects. Goldstein
made a detailed analysis some years ago which is still worth reading
and I recommend you do a citation search on this reference (Go¥stein,
A. 1944, J. Gen. Physiol. 27:529; see also his book - Principles of
drug action; and P. Wilson's chapter in Lardy H.A. ~ Respiratory
Enzymes, 1949).

Sincerely yours,

Joshua Lederberg
Professor of Genetics

JIL/rr