October 5, 1946. Indianapolis. Read by Peyton Rous, 1946, who had nothing to say.

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, cytoplasmic substances, cellular constituents in general. A striking illustration of the effect of change in environment (presence 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 globin molecule 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 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 or 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 cells 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 propose a simple mechanism by which this control of growth could be achieved; and it is hard to imagine how this is done.

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 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. [Side annotation by LP: Cancer cells have not gained some power - rather lost control.]

3. In the development of organisms, natural selection has operated to eliminate molecular constitutions with lethal factors, and in particular those that lead to cancerous growths before reproduction occurs.

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 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).

3. A determinative molecule in a cell (a gene or plasma gene) 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 probability would be greater for hybrids.

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.