MAR 2 5 ww

OAK RIDGE NATIONAL LABORATORY

OPERATED BY

UNION CARBIDE CORPORATION
NUCLEAR DIVISION G bye
N
CARBIDE

POST OFFICE BOX X
OAK RIDGE, TENNESSEE 37830

March 22, 1971

Dr. Joshua Lederberg

Department of Human Genetics
Stanford University Medical School
Palo Alto, California

Dear Josh:

Between work on zonal centrifuges and clinical analyzers for the
SKYLAB, we have been working on the problem of the origin of the
variable sequence in antibodies, mostly via theoretical models.
One has to strain very hard indeed to make any model based on
somatic mutations credible, and my conclusion is that it can't
and doesn't work. The same is true of the simple germ line
theory which states that we have evolved a gene for each distinct
antibody which has only an antibody producing function. The con-
clusion that no present theory was tenable has therefore been my
starting point. It seemed to me that there must be a dead simple
basis for the entire process of recognition of foreignness and I
set out to find it. The results are described in the enclosed
paper. I would appreciate your reaction to it. So far, biochemists
and structural chemists understand the idea and a few are busy
exploring it. My immunologist friends mostly don't catch on, and
some also appear to dislike the idea of not having a number of
theories to choose between (i.e., of solving the problem).

The most important result of the idea of cellular perfect sets has
been the realization that a special type of sequencing of cell
protein groups would be required during differentiation as mutually
forbidden surfaces were expressed in different cell types. This
suggested that many early proteins would be antigens in the adult,
which turns out to be true even in isogenic strains. This in turn
led to the realization that tumor specific transplantation antigens
may all be early fetal proteins. From there to immunizing against
tumor challenge with fetal antigens was a direct and logical step.
It works with all the tumors we have tried, and we now have an ex-
panding program to evolve both methods of early cancer detection
and therapy based on it.
Dr. Joseph Lederberg 2 March 22, 1971

All aspects of this work is being reviewed in a small symposium
here on May 23-25. If you are interested, we would like to have
you attend.

It's rather odd to have gotten a firm experimental hold on a
tough problem using a theoretical approach that seems to have so
little appeal.
Let us know if you can come.

As ever,

Morante

NGA: jdr Norman G. Anderson, Director
Molecular Anatomy (MAN) Program