Read Ebook: Some possible bearings of genetics on pathology by Morgan Thomas Hunt

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Ebook has 75 lines and 11415 words, and 2 pages

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 . 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 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 , the number of F? offspring that develop the specific cancer would be half as numerous as in the original cancer strain . In the F? generation the frequency for the extracted double dominant will be that of the original strain, that of the F? heterozygotes will be the same as that of the F?, and the extracted double recessive class will not develop cancer at all. Now, if it is not possible to distinguish between these different F? 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.

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 larvae 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 r?le 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.

Third, there is Guyer's evidence that an effect on the eye, caused by foreign serum, is transmitted.

Brown-Sequard's experiments have been repeated several times; almost always with negative results. Today his claims are practically forgotten.

Stockard's results with guinea pigs, unlike those of Brown-Sequard, have been done under carefully controlled conditions. He has guarded against abnormalities in his stock by using pedigreed material. The malformations that reappear in successive generations are general rather than specific. Such organs as the eye are those hardest hit, but this is supposed to be rather a by-product of the general debility of the individual. Stockard points out that the alcohol has affected the germ cells, and it is through these that the effects are transmitted. Now if one or more genes had been permanently changed we should expect to have evidence of Mendelian inheritance. The results do not show convincingly that the inheritance is not Mendelian, but it does not appear to be so. There is another possibility. Recent results have shown that rarely entire blocks of genes--pieces of the chromosomes--may be duplicated or pieces may be lost. Here the effects on the organism are more far-reaching than when a single gene is changed. It remains to be discovered whether, in some such way as this, Stockard's remarkable results may be brought into line.

Guyer injected the crushed lens of rabbits into fowls. From the blood of the fowl he obtained serum that was injected into pregnant rabbits. The offspring of these rabbits whether male or female often had defective eyes and lenses. The defect was even transmitted to later generations. Here also the germ cells of the embryo may be changed by serum that at the same time affects the development of the eyes of the embryo in utero.

If this is the case we should expect, as Guyer pointed out, that the germ cells of the pregnant mother would also show effects. It should have been a simple matter to show this by a proper test. The test that Guyer made, namely by out-breeding the mother and finding no defective F? young, was quite inadequate if, as appears to be the case, the character is a recessive.

It is important to keep clearly in mind that there are two distinct questions involved in these three cases. Genetics has to deal with only one of them. There is first the question of the action of environment on the germ cells. Genetics has nothing to do with this question. There is then to be determined whether, if variations may be induced in these ways, they fall into one or another of the Mendelian moulds. This is for the geneticist to determine, but he finds himself in a curious predicament, for it can not be claimed that any of these three cases have been shown to give a direct Mendelian result--but neither can it be denied that they may possibly come under the scheme, or some modification of it. There we must leave the matter at present.

If I have appeared at times overcritical concerning the application of genetics to pathology, it is not because I do not sympathize with the attempts that have been made to apply genetics to pathology. I realize, of course, that from the nature of the case much of this work is pioneer work, where rough and ready methods have often to be resorted to. So long as this is kept in view, no harm can be done in attempting to find how far Mendel's principles can apply to heredity in man. But I want to enter a protest against the danger of premature conclusions drawn from insufficient evidence. In our enthusiasm in applying Mendel's laws, we should be careful not to compromise them.

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