eokor im January 24, 1975

(~
Dr. Edward A. Martell
National Center for Atmospheric Research

P.O. Box 1470
Boulder, Colorado 80302

Dear Dr. Martell,

This is to respond to your letter of January 2nd concerning the
role of radiation in “spontaneous” mutagenesis. I do not know of any
analyses that are directed to the specific question that you raise.
They could only be answered satisfactorily with the help of experimental
information on the dose-response figures forpphéntémm and Pb210. It should
not be too difficult to obtain such information experimentally along the
lines of the scenario that you present. As you point out, Muller and other
people who have quoted him since used a more diffuse and easentiallyliseaesr
model for environmental radiation. The best source for critical discussion
of the points you raised would probably be Dr. Howard Newcombe,d&dology
and Health Physics Division, Atomic Energy of Canada Limited, Chalk River,
Ontario, Canada.

My own experimental work has much more to do with bacteria and
viruses and I would be rather skeptical about the role of particular
sources for the single base~substitution mutants that are frequently found
in these simple forms. It would be rather difficult to account for the
very high degree of locus, even site~specificity on the basis of an external
radiation model and there is already a more than sufficient explanation in
terma of errors in DNA replication. In fact, one can obtain mutations
effecting the integrity of the DNA polymerase that are expressed in terms of
varying rates of mutation and it is therefore difficult to believe that the
initial "wild type" does not simply represent a lower rate of the same process
which is exaggerated in some of the mutants.

However, I am not sure to what extent we can always extrapolate from
these kinds of observations to the process of mutation in eukaryotes and
your question should certainly be addressed at an empirical level.

As to your second question, this is of course a completely controversial
subject, even to the question wiewherher malignant change is based on somatic
cell mutation as we customarily view it. Only very recently are we in a
position to make any experimental analysis of this point, principally by the
techniques of somatic. cell hybridization that Henry Harris has pioneered.

And I would simply suggest that you look up his numerous publications or
write to him at the Department of Pathology, Oxford. Professor George Klein
at the Karolinska Institute, Stockholm, has made a strong case for a
progressive model of malignant change in which the initial event - which may

over
 

 

Dr. Edward A. Martell -~2- 1/24/75

be a somatic cell mutation or a virus infection ~ is followed by progressive
selection of more deepseated changes resulting finally in a wide variaty

of structural changes which are commonly seen in a variety of forms of
malignancy. Some types of leukemia, for example, are commonly associated
with rather specific chromosomal-structural changes but this does not mean
that the latter reflects the initial event. And of course you are aware that
there may be a very large scale reconstruction of the entire karyotype
leading to unbalanced chromosome configurations.

I believe the poseibility of polonium as an element of the role of
tobacco emoke in lung cancer has been discussed for many years, and in my
view entirely credible. I would be inclindd to give still higher weight to
the role of chemical carcinogens in most circumstances of environmental
cancer although I would hardly wish to minimize the possibility of significant
interactions among them, or a primary role of radioactive sources in certain
special circumstances (even possibly lung cancer) and perhaps viruses as well
in particular circumstances. One point to keep in mind about the effects of
tobacco is the rather clear evidence that smoking is also associated with
a substantial rise in bladder cancer - which is notoriouslyespepstivéve to
chemical carcinogens although even in this case I suppose one could not
immediately rule out a radioactive emitter as an ideological agent also.

My own acientific work is really not in this immediate area although
I do have a few incidental comments which I will enclose.

Sincerely yours,

Joshua Lederberg
Professor of Genetics

JL/rr
Enclosure