Part 3

The next illustration carries its into a more debatable field. Many human defects are connected with the nervous system, and it is interesting to find that many of them are believed to be inherited; even when no corresponding structural basis in the brain can be made responsible for the defect.

Feeblemindedness, insanity, and even some types of criminality have been said to be inherited according to a simple one-factor Mendelian difference. Owing to the difficulty of diagnosis it is obvious that the student of genetics would be expected to approach these problems with the utmost caution. The data, on which some rather sweeping conclusions have been based, sometimes show, on closer scrutiny, obvious contradictions. Take, for example, the case of feeblemindedness which has been represented as though it differed from the normal (whatever that may be) by a single Mendelian factor difference. The evidence for this is far from convincing, and all that can be safely said, I think, is that there are types of imbecility that may possibly be due to multiple factors, but until the relation of imbecility to various disorders of the glands and to syphilis has been thoroughly studied, even my cautious statement may seem to go too far. Curiously enough no one has as yet had the temerity to suggest that some of the high-grade imbecile types—the moron, for example—might represent an ancestral stage of the human race. If this were true, intelligence would then be looked upon as an innovation in the race, that has not yet spread to all of its members. I am aware that a similar suggestion has been made with respect to the criminal. Lombroso’s “criminal type” is notorious. The criminal has been painted as the ancestral brute from which the more docile human animal has arisen through loss of “wild-type” genes. I need not state, perhaps, that no one takes such speculations seriously today from a genetic standpoint.

Immunity and resistance to disease are subjects of great interest to geneticists as well as to pathologists.

Setting aside, of course, cases where the immunity is due to some temporary physiological state (little understood at present, I believe), and also setting aside immunity acquired by recovery from attack or inoculation, there still remain races that have, as we say, a constitutional resistance.

The best ascertained cases in this field are those worked out by Tyzzer and Tyzzer and Little. A carcinoma that originated in Japanese waltzing mice grew in practically every individual of the race when implanted. It failed to grow in “common” mice. The hybrid mice from these two races were also susceptible in nearly every case.

When the F₁’s were back-crossed to “common mice” the offspring were not susceptible. When the F₁’s were back-crossed to the Japanese waltzer all were susceptible. When the F₁’s were inbred only about 2.5 per cent. of the offspring were susceptible, Fig. 13.

These results show at least that there must be more than one, two or three factor differences between the two races that are concerned with tumor susceptibility.

Tyzzer and Little suggest in fact that 12 to 14 independently inherited factors are involved. Larger numbers of tests will be necessary before it is possible to state how many factors are needed. A curious feature of the case should not pass unnoticed. Many or all of the factors for susceptibility must be assumed to be dominant. It is not generally known, but there is some evidence that the so-called Japanese waltzer originated from Asiatic house mice, which according to some writers belong to a distinct species or at least a distinct variety. The results suggest that we may be dealing here with species or varietal differences, hence the large number of factor differences involved. It may be necessary to work with a simpler situation where fewer factors are involved; possibly such a case as that of the Jensen tumor will furnish proper material, but it will be necessary to work with pedigreed material rather than with “Danish,” “French,” “German,” or even English breeds of mice.

In plants also the inheritance of immunity of wheat to rust has been studied. Biffen’s results with wheat are those best known. An immune race crossed to a susceptible race gave first generation plants that were attacked. This means that immunity is a recessive character. In the next generation there were 64 immune and 194 affected plants (a 1:3 ratio). If the immune plants are self-fertilized, they yield only immune plants in later generations.

Nilsson-Ehle and Vavilov think that such simple relations are rather the exception than the rule. Vavilov found that Persian wheat, immune to mildew, crossed to different susceptible species produced offspring that were immune in 13 combinations. In these cases immunity is dominant.

In the next generation several degrees of resistance were noted—and a few plants were even more susceptible than their grandparents.

It is interesting again to note that susceptibility and immunity are species and variety characters in these cases, but this does not mean that the differences are not Mendelian. It suggests however the possibility that several or many factor differences are often involved.

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.

All males that get their single X with this tumor-gene will die; therefore, since no adult males carry it, normal males must be used for mating in each generation. They are mated to females that are heterozygous for the chromosome carrying the tumor genes. Such matings as I have said always give two daughters to one son. But since half the daughters are normal and half carry the gene for tumor it is desirable to be able to pick out the latter from the stock. Therefore we have made use of a trick we call “marking the chromosome,” which means that we use a male whose sex chromosome carries a known gene near the tumor locus. By using this type of male in successive generations we get two types of daughters: one type like their surviving brothers in eye color that do not carry the tumor-gene and the other daughter with normal eyes that carries it. We use only the latter to continue the stock, but we could eliminate the tumor from the stock at once by using the other kind of daughters.

Curiously enough the tumor no longer appears in the inbred stock but reappears again on out-breeding. Nevertheless the sex-ratio in the inbred stock continues as before, and since the missing males are those with red eyes we know that the tumor-gene is still present and doing its deadly work—only now the young male larvæ die even before they reach the age at which the tumor is due to appear.

So far I have spoken of heredity as though that term had become synonymous with Mendelian heredity. Those of as who are at work on Mendelian inheritance are often criticized as too narrow. It is said that we do not recognize that any other kind of inheritance takes place. I do not think the criticism is quite fair, because, in the first place, the very great number of variations studied has been shown to conform to the Mendelian principles or at least to be capable of such interpretation. There are, however, a few exceptional cases. In certain albino plants it has been shown that the inheritance of albinism can be traced to the behavior of the chlorophyll bodies in the cytoplasm. The chlorophyll bodies are known to divide and to be distributed to the two daughter cells at each division independently of the nuclear division and of the maturation process in the egg.

Why, then, it is asked, may not there be present in the cytoplasm of the cell other self-perpetuating bodies that are responsible for certain kinds of inheritance? Why not go further and ask, why, since the cytoplasm appears to be handed down from cell to cell, may it not furnish also a different medium for inheritance of characters? Theoretically such an argument is logical. No student of Mendelism would I think deny such a possibility. But, as a matter of fact, it is not going too far to say that, at present, there is little evidence that such inheritance takes place, except in a few special cases, like that of the chlorophyll bodies. It is safe, I think, to say that if cytoplasmic inheritance played any important rôle in heredity in the higher animals and plants, we should expect, by now, to have found many cases of it. None are known to us.

Whether Mendel’s laws of heredity apply to unicellular animals, to bacteria and to similar types, in which the mechanism for this type of inheritance has not been shown to exist, can not be affirmed or denied from the evidence at hand.

There are at present three outstanding cases in the higher animals, in which an induced variation is said to be inherited afterwards. These cases are of great interest to pathology. We can not afford to pass them over. First, there is Brown-Sequard’s claim that injuries to the nerve cord or to the cervical or sciatic nerves of guinea pigs produce effects that are transmitted.

Second, there are the cases of the inherited effects caused by alcohol in guinea pigs discovered by Stockard.