Some possible bearings of genetics on pathology

by Thomas Hunt Morgan

There is no more interesting field in which genetics and pathology meet than that of cancer. I realize how careful we on our side must be in discussing this question with you who are experts, nevertheless there are certain aspects of the problems of cancer from the genetic side that I may be allowed briefly to mention—not, however, without some misgivings.

Suppose all men over seventy-five died of arteriosclerosis. Could one say that hardening of the arteries is inherited? I think that it would be proper to use the word heredity to include such a case, but we would not know how it was inherited unless there existed another race of men who never died of the malady, and suitable matings were made between the two races.

Suppose again that all old men died of pneumonia. Could we say that susceptibility to pneumonia, after eighty, is inherited? Again, yes! But again we could get no information as to the way in which this susceptibility is inherited without crossing to an immune race.

Now suppose there are strains of mice all of which die of cancer after their first year. Could we say that in them cancer is inherited? The answer would depend in part on what connotations the word inherit carries with it, for, either susceptibility might be meant, or the “spontaneous” development of cancer might be meant. The latter interpretation is, I think, generally implied, which carries with it two further implications. First implication, viz., that when a certain age is reached, a certain inherited complex leads to the development of cancer in one or more regions of the body. Here some such process as that of the hardening of the arteries seems to be vaguely implied. Second implication, viz., that a change in method of growth (a release from the ordinary restraining influences) suddenly occurs, beginning in a single cell of some particular tissue. Stated in this second way, the appearance of spontaneous cancer suggests at once a comparison with the mutation process that is known to occur in somatic cells as well as in germ cells.

Now if the first interpretation is to be placed on the word heredity, when applied to cancer, there is nothing more to be said, except that the only way such a situation can be studied as a genetic problem is to out-cross the strain of cancer mice in question to another that never develops spontaneous cancer. But if the second interpretation is implied, then the whole situation is put in a very different light. Let us examine this a little more closely.

Suppose, as a theoretical possibility, that spontaneous cancer is due to a recurrent somatic mutation of a specific gene to a dominant one that leads to cancer. Then the proportion of individuals that develop spontaneous cancer in such a strain will depend on the frequency of mutation of this specific gene. Consequently, if such a strain is out-crossed to another race (that introduces the allelomorph of the postulated gene), the number of F₁ offspring that develop the specific cancer would be half as numerous as in the original cancer strain (since the gene in question occurs only half as many times as in the original complex). In the F₂ generation the frequency for the extracted double dominant will be that of the original strain, that of the F₂ heterozygotes will be the same as that of the F₁, and the extracted double recessive class will not develop cancer at all. Now, if it is not possible to distinguish between these different F₂ classes by inspection, the difficulty of finding out how cancer is “inherited” would be very great. In such an imaginary situation, the ratio of cancer-developing mice may not appear to correspond to any of the known Mendelian ratios, because superimposed on the genetic situation there would be added results depending on the frequency of mutation when a specific gene is present.

Other complicating conditions will also suggest themselves to any one familiar with genetic and mutation processes; for, the possibility that the mutation itself is more or less likely to occur in one or another genetic complex must be reckoned with, as well as the likelihood of the mutation showing itself or developing in any tissue or only in cells of specific tissues, etc.

I am far from wishing to suggest that spontaneous cancer is a mutational process, despite certain rather obvious resemblances to mutational effects in plants and animals, but I should like to insist that the appearance of spontaneous cancer is in its nature so peculiar that one can not afford to ignore such a possibility in any discussion as to whether spontaneous cancer is or is not “inherited.”

There are several cases of inheritance of tumors in our Drosophila material. Here I am on safer ground. One of them, discovered by Dr. Bridges, worked out by Dr. Stark, I should like to speak about, because it shows how linkage of characters can be used in the study of heredity of a character and conversely in its elimination. In a certain culture one fourth of the maggots develop one or more black masses of pigment in the body; such maggots always die. They are always males. Consequently there are twice as many daughters as sons in such a strain. The gene is carried by the X-chromosome and its inheritance is like that of all sex-linked characters as shown in [Fig. 14].