The words "Read by Peyton Rous, 1946, who had nothing to say", are written in Pauling's hand in the top left corner
of the draft.
Item is handwritten.
Number of Image Pages:
10 (499,205 Bytes)
1946-10-05 (October 5, 1946)
Original Repository: Oregon State University. Library. Ava Helen and Linus Pauling Papers
Reproduced with permission of the Ava Helen and Linus Pauling Papers. Oregon State University Library.
Medical Subject Headings (MeSH):
How Antibodies and Enzymes Work
Memorandum from Linus Pauling to Emile Zuckerkandl, Ewan Cameron, and Robert Paradowski (July 31, 1981)
The Nature and Causes of Cancer
By Linus Pauling
During the life of an organism there occurs continuously the process of synthesis of molecules, simple, and complex. The
nature of the molecules that are synthesized is determined by the nature of the environment in which the synthesis takes place
-- by the genes, enzymes, cystoplasmic substances, cellular constituents in general. A striking illustration of the effect
of change in environment (pressure of molecules of antigen) is the production of specific antibodies, which are presumably
formed with the power of combining with the antigen as the result of the tendency of a system to assume the configuration
of minimum energy, which in this case is a configuration of the globulin molecule
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that has the greatest degree of complementariness to the surface structure of the antigen molecule.
Let us consider the normal life history of an organism. The fertilized egg carries out the process of early development and
the first cell division in the way determined by the molecular structure -- the genes, cytoplasmic constituents, molecular
framework -- of the fertilized egg. These cells continue to divide, to differentiate; and the organism develops, reaches
maturity, and ultimately dies -- all in the way determined by the molecular structure of the fertilized egg, with whatever
variations are produced by interaction with a varying environment.
One way to change the nature of an organism is to change the configuration of one of the important molecules in the fertilized
egg; in particular, of one of
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the genes; that is to produce a mutant. A change of this sort, a mutation, can be made to occur by irradiation with x-rays
of ultraviolet light or neutrons by treatment with antibodies, by change in temperature, or by treatment with chemical substances.
Mutations also occur spontaneously, perhaps usually in response to cosmic radiation.
A striking aspect of normal growth is the control of the growth of differentiated calls of different sorts. The different
parts of an organism normally develop to a certain extent, which is essentially the same in different individuals of the same
strain. Biologists have not found it easy to prepare a simple mechanism by which this control of growth could be achieved;
and it is hard to imagine how this is done.
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In general, indeed, we might expect that during the sequence of changes representing the development of an organism conditions
would at some stage be such as greatly to favor the growth of cells of one sort at the expense of those of other sorts, and
that in consequence these cells would proliferate wildly -- and presumably lead to the death of the individual. I believe
that a very great part of the process of the origin and evolution of plants and animals has been the selection of just those
molecular complexes (for the fertilized egg) that lead to what we may call normal differentiation and growth, and that
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manage to avoid the uncontrolled preferential cataclysmic growth of one class of differentiated cells. We are now ready to
discuss the nature and causes of cancer.
Our postulates are:
1. Cancer is the uncontrolled proliferation of differentiated cells of one type at the expense of those of other types.
2. The molecular constitution of an organism which leads to controlled ("normal") development and function is not
a likely one, but an unlikely one; and random changes are expected to destroy the control.
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3. In the development of species of organisms natural selection has operated to dominate molecular constitutions with lethal
factors, and in particular those that lead to cancerous growths before reproduction occurs.
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From these postulates we make the following deductions:
1. Cancer might occur as a part of the normal course of life of an individual with a certain genetic constitution. A pure
strain produced under natural conditions of competition would not, however, be expected to have a normal history of cancer
which would place it at a competitive disadvantage. On the other hand, if conditions are changed artificially in such a way
as to increase the normal span of life, the regular development of cancer during the added life period might occur as the
consequence of the genetic constitution of the pure strain.
A hybrid of two native pure strains would have a considerable chance of having a genetic
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constitution which would permit the regular development of cancer at some stage in the development of the organism.
2. The introduction of a virus molecule (a vagrant gene) in a cell might so change the molecular constitution of the organism
as to lead to the development of a cancer/ (Rous sarcoma, shope rabbit papilloma).
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3. A determinative molecule in a cell (a gene on plasmagene) might be so changed in configuration by thermal agitation, by
irradiation with x-rays, ultraviolet light, neutrons, or other waves or particles, or by some chemical substance as to cause
a changed course of development, leading to cancer, which can be described as due to spontaneous or induced somatic mutation.
Native strains would presumably be selected so that the probability of cancer from somatic mutation under normal conditions
would be small. Our postulates lead to the deduction that this probably would be greater for hybrids.
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4. A foreign substance present in sufficient amount in the cells during a period of time which would permit a cancer to develop,
or a normal cell constituent present in an abnormal quantity, might so influence the process of growth as to lead to cancer.
This effect might occur, for example, by the inhibition by the substance of the normal mechanism of control.
Substances with this effect might be due to parasitic infection, or to long-continued inflammation.