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SOME POSSIBLE BEARINGS OF GENETICS ON PATHOLOGY

THOMAS HUNT MORGAN Professor of Experimental Zoology, Columbia University, New York.

Middleton Goldsmith Lecture delivered before the New York Pathological Society on February 3, 1922.

PRESS OF THE NEW ERA PRINTING COMPANY LANCASTER, PA. 1922

SOME POSSIBLE BEARINGS OF GENETICS ON PATHOLOGY

THOMAS HUNT MORGAN, PROFESSOR EXPERIMENTAL ZOOLOGY, COLUMBIA UNIVERSITY.

It has been pointed out in derision that modern genetics deals, for the most part, with the inheritance of abnormalities and disorders of various kinds--albinos, brachydactyls, cretins, dwarfs, freaks, giants, hermaphrodites, imbeciles, Jukes, Kallikaks, lunatics, morons, polydactyls, runts, simpletons, twins, and Zeros: in a word, with pathological phenomena in a very broad sense. This statement, intended as a reflection on genetics, carries with it an implication that a study dealing with such material cannot be of first rate importance. Such condemnation will probably be received by pathologists with the kind of smile it deserves, and I feel that I am not likely to be called upon here to answer such an indictment. Nevertheless, I am going to ask your indulgence, for a moment, since this slightly malicious statement should not be allowed to pass unchallenged, both because it is inaccurate, and because, even were it true, the result of such work might still be of more importance than its critics seem to realize. The source of this criticism is not without significance. It comes almost always from those whose interests lie in the field of evolution--in the old-fashioned use of that word. Now the articles of all evolutionary platforms include a plank about heredity. This plank is for the most part an ancient article that has been worn pretty thin. It is difficult to replace it with the new wood of Mendelian genetics. Hence, I think, originates the criticism referred to.

It is true that the student of Mendelian heredity does not often trouble himself about the nature of the character that he studies. He is concerned rather with its mode of inheritance. But the geneticist knows that opposed to each defect-producing element in the germ-plasm there is a normal partner of that element which we call its allelomorph. We can not study the inheritance of one member of such a pair of genes without at the same time studying the other. Hence whatever we learn about those hereditary elements that stand for defects, we learn just as much about the behavior of the normal partners of those elements. In a word, heredity is not confined to a study of the shuffling of those genes that produce abnormal forms, but is equally concerned with what is going on when normal genes are redistributed. This method of pitting one gene against the other furnishes the only kind of information relating to heredity about which we have precise knowledge.

In man and in domesticated animals we find that individuals appear occasionally that are defective in one or another respect. Some of the defects are inherited. Rarely a new one appears that has not been seen before. But the majority of them are reappearances of characters that have been carried under the surface as recessive genes in the germ-plasm. Today we recognize that each of these modifications, if recessive, has first arisen as a mutational change in a single gene before it appeared on the surface as a character by the coming together of two such genes. Mendelism has furnished some information as to the way in which these hidden genes may get dispersed in the race. An example will serve to make this clear, Fig. 1.

If a fly with vestigial wings, a recessive character, is crossed to a wild fly with long wings, all the offspring will have long wings. If these are bred to each other the offspring will be of two kinds, like their grandparents, in the ratio of three long winged to one vestigial fly. The extracted vestigials will breed true to vestigial. The fact that the gene for vestigial has been carried by long winged F? parents has not affected the gene in any way, for the second generation of vestigials has wings as short as those of their grandparents.

I have brought forward this case not so much to illustrate Mendel's law of segregation as to use the facts for another purpose.

When the vestigial fly was crossed to normal the mutant character disappeared in the hybrid. If such a hybrid is out-bred to normal all the offspring are again normal, but half of them carry the vestigial gene. If these are out-crossed again still only normal flies appear, Fig. 2. If such out-breeding is continued the vestigial gene will become widely distributed without ever showing itself at the surface, so to speak. If, however, at any time two hybrid flies mate, then a quarter of the offspring will have vestigial wings. It might seem then that the character had appeared for the first time in the race, if one did not know its past. In reality its gene may have been there for some time. Probably many of the recessive defects and malformations that appear in the human race--at least those due to hereditary factors--have had representative genes in the germ-plasm for several generations before they have appeared on the surface.

We do not know how widespread recessive genes are in the human germ-plasm. The fact that defective individuals appear in certain communities may be safely interpreted to mean that individuals bearing the same gene have at last come together. On the other hand, the absence of such individuals from the community, at large, may only mean that the chance of suitable combinations is small, and does not mean necessarily that the gene in question is confined to the community within which the defects have been recorded.

Let us turn for a moment to the inheritance of a Mendelian dominant character, and to simplify the situation let us first assume that the character itself is neither advantageous nor disadvantageous.

It is popularly supposed that if a trait is dominant it will be expected to spread more widely in the race than will a recessive character. This is owing largely to a verbal confusion. Colloquially we think of dominance as meaning spreading. A dominant nation, for example, is one that is spread widely over the face of the earth. But a Mendelian dominant should carry no such implications. A dominant gene, if crossed into a race, will stand the same chances of being lost as a recessive gene, Fig. 3.

The situation is similar in many ways to the inheritance of surnames in any human population. A new surname introduced is likely to disappear after a few generations. There is a bare chance, however, that it may spread.

An excellent illustration of dominance is that recently published by Mohr. He has traced, through five generations of a Norwegian family, the inheritance of a shortened first digit. In the history of this case there is one record that is extraordinarily interesting. A child was born that was so completely crippled that it died in infancy. One parent was short fingered; the other, a cousin, was probably also short fingered. It is possible that the child had a double inheritance of this character; it was a pure dominant. If this is true, then it appears that this character can survive to maturity only in the hybrid condition. As a matter of fact, in other animals there are some well-recognized cases of this sort. That of the yellow mouse is the best known. Yellow is a dominant and in double dose it kills; therefore when yellow is bred to yellow all the pure yellows die. The hybrid yellows and the pure blacks survive. Here yellow is discriminated against in the embryo; but, being dominant, it still appears twice as frequently in each generation as does the alternate character . In the fly, Drosophila, we have at least 25 dominant lethal characters, but as yet we have no knowledge as to why such a high percentage of dominant characters should be lethal when homozygous.

In man there are no certain cases known of lethal dominants unless some of the short-fingered types come under this heading.

Dominant and recessive characters have been so much discussed in modern Mendelian literature that it is popularly supposed that all Mendelian characters must be either dominant or recessive when bred to the type. This is not the case. The hybrid is frequently intermediate. In fact, it might be said, almost without exaggeration, that the heterozygote nearly always shows some traces of its double origin. Sometimes the hybrid character is nearly midway between the parent types, sometimes more like one, or like the other. The important fact, however, is that in the germ cell of such intermediate hybrids, there is the same clean separation of the parental genes. In consequence, we find in the second generation the two grandparental types in pure form and an array of intermediates connecting them.

It is probable that in most of our domesticated animals, including man, much of the variability is due to multiple factors, which makes a study of inheritance in these groups extremely difficult, especially when, as in the case of man, the number of offspring from a pair is small, and critical combinations for study can not be made.

If then it is highly improbable that any particular defective trait could ever become widely spread in the human germ-plasm, how does it come about that such defects as feeblemindedness and insanity are so widespread in the racial inheritance? There are several possibilities here to keep in mind, but I think we ought not to pretend that we can give a completely satisfactory account of the situation.

First. While the chance is heavily against any one defect establishing itself, there is always the possibility that some one defect may establish itself. It must be remembered that while many defective strains may be lost, one would notice only those that had taken root. It is the presence of these that may give us an exaggerated idea of the generality of such occurrences.

Second. If the human germ-plasm is continually mutating to produce one or another kind of specific defect, this will increase the chance for any recurrent defect to finally establish itself. That particular mutations do recur in other animals is now abundantly established by evidence that comes from several sources.

Third. There is a growing impression that a good deal of feeblemindedness and insanity are environmental rather than hereditary traits; poverty, malnutrition, and especially syphilis are said to play a considerable r?le in their production. It is unsafe therefore to conclude that the human germ-plasm is as badly contaminated as some pessimists seem to think.

If we turn now more directly to special kinds of human inheritance we shall find a great deal of evidence showing that the same laws of inheritance that hold for animals and for plants apply to man. It would be surprising if this were not the case.

On the other hand, when we scrutinize the pedigrees that have been published to illustrate heredity in man, we shall find many of them very unsatisfactory in two main respects. The number of offspring in a family is usually too small to serve as a sample of the germ-plasm of the parents. Therefore, since recourse must be had to many families for sufficient data, it is essential that the diagnosis of the defects of the parents and of the children is correct. A single mistake may throw the result into confusion. In cases where the defect is structural, a correct classification may be possible, but in other cases, especially where psychological defects are involved, the diagnosis is difficult and the results, in consequence, less certain. Often the best that we can do in the case of man is to try to find the simplest Mendelian formula to which the evidence will fit. If one factor-difference will not suffice, then two must be tried; if two will not do, then three must be tried, etc. Now I need hardly point out that we can explain almost anything if we are allowed enough factors. It is, at best, a dangerous practice, one to be used only with great caution and the conclusion stated as provisional and checked in every possible way.

I propose now to pass in review some characters in man known to be inherited, choosing preferably those that come nearest to the field of pathology, or belonging to it. I shall begin with comparatively simple cases, about which there can be little doubt, and pass to more and more difficult situations. I am taking the risk of reaching an anticlimax, but nevertheless such a procedure will, I hope, serve our purpose this evening if I can point out where the evidence is satisfactory and where it is deficient.

My first illustration of inheritance in man may be said to be a physiological one, mainly because we do not know at present any structural or chemical basis for the reaction.

Color-blindness in man is clearly a case of sex-linked inheritance. It conforms to the general scheme of inheritance in other animals; in Drosophila, for example, we have about sixty mutant characters which show this form of inheritance.

A color-blind man married to a normal woman has only normal daughters and sons; all of the daughters, however, transmit color-blindness to half of their sons, Fig. 6.

Color-blind women are rare, because they can never arise unless a color-blind man marries a woman who is color-blind, or else marries a normal woman who had a color-blind father, or had a mother heterozygous for color-blindness, Fig. 7.

The pedigrees of color-blind families--and they are many--leave little doubt as to the mode of inheritance of this character.

While in the great majority of cases, the scheme of color-blindness is that shown by the diagram, we know that occasionally the machinery may be changed to give a somewhat different result. It is possible, for example, that a color-blind man married to a perfectly normal woman may rarely produce a color-blind son. A few years ago such a result would have appeared to upset the entire scheme of sex-linked inheritance, today we understand how such cases may arise through a process that is called non-disjunction, which is best illustrated by numerous cases well worked out in Drosophila.

My second illustration has a more obvious chemical basis. Hemophilia is also sex-linked in inheritance. It is known to be much more common in men than in women, the explanation for this is the same as in the other case. In affected individuals the blood fails to coagulate quickly and the difference in chemical composition of the blood is, in contrast to normal, the inherited character.

One of the most remarkable cases of heredity in man is found in the so-called blood groups. As first definitely shown by Von Dungern and Hirschfeld in 1910, the inheritance of the four blood groups conforms to Mendel's laws. So consistent is this relation that, as Ottenberg pointed out in 1921, the evidence might be used in certain cases to determine the parentage of the child. Since this statement has recently been disputed by Buchanan, from an entirely wrong interpretation of Mendel's principles, I should like to point out that on the Mendelian assumption of two pairs of factors, all the known results are fully accounted for. If we represent one pair of genes by A and a and the other pair by B and b, and if we represent an individual with the genetic constitution AaBb mating with another individual of like constitution , then each will contain four kinds of germ cells, viz., AB, Ab, Ba, and ab. The sixteen possible combinations formed if any sperm may fertilize any egg are shown in Fig. 8.

It is very simple to tell what the kinds of genetic offspring will be where any one of these sixteen individuals marries any other one. These possibilities are summarized in the following statement taken from Ottenberg:

Unions of I and I give I I II } } I, II II II }

Two actual pedigrees, one of them carried through three generations, will serve to illustrate particular cases, Fig. 9.

From a knowledge of the blood group to which the child belongs it is possible to predict to what groups its parents may have belonged, and in certain cases it is possible to state that an individual of a certain group could not have been the parent of a particular child.

My fourth illustration has probably in some cases a glandular basis, and in this sense has probably also a quantitative chemical background. Height or stature in man is, in part, an hereditary trait. It is sometimes said that short is dominant to tall, because short parents may have both tall and short children, but tall parents produce only tall children. This is probably an overstatement, or at least a rather loose generalization. Height may be due to long legs, or to a long body, or to a long neck or to time of reaching maturity or to any combination of these; and these differences may themselves be due to independent factors in inheritance. The best that we can do with height at present is to refer it to a multiple factor basis, the actual factors being little understood.

In addition to these differences in stature, all of which we call normal differences, there are certain extreme conditions superimposed on these as a background, in which the endocrine glands probably play an important r?le. While it may well be that many of these cases are caused by tumors of one of the glands, more especially of the pituitary, thyroid, or testis, it is quite possible that there may be actual inherited differences in the size and activity of these glands.

So far as I know there are no thoroughly worked out cases of the inheritance of such differences in man or in mammals, but in the case of certain races of birds I have been able to show both by breeding tests and by castration experiments that glandular differences are inherited according to the Mendelian scheme.

There is a race of fowls known as Campines in which there are two kinds of males, hen-feathered males and cock-feathered males. If the hen-feathered male is castrated, the new feathers that develop are the long feathers of the cock-feathered male, Fig. 10. In another race of fowls, Sebright bantams, only the hen-feathered males are known. If these are castrated, the new feathers that develop are the long feathers characteristic of all other races of poultry, Fig. 11.

If the Sebright male is out-crossed to a hen of another breed in which only cock-feathered males occur, it will be found that all the first generation males are hen-feathered. If these are now bred to their sisters there are produced, in the second generation, three hen-feathered males to one cock-feathered male, showing that the difference between the two races is inherited, Fig. 12.

Now in this case we can perhaps go further. An examination of sections of the testes has shown that in the hen-feathered Sebright male there are certain kinds of cells, called luteal cells, while these are absent in the sections of the testes of normal cocks. These same luteal cells are like those present in the stroma of the ovary of all female birds. If we assume that they make an internal secretion that prevents the development of cock-feathering, both in the normal hen and in hen-feathered cocks, we have a complete explanation of all the facts. This explanation is made more probable by the results of removing the ovary of the hen, when, as Goodale has shown, the spayed hen develops the full male plumage of her breed. Since the luteal cells are present in the hen and in the hen-feathered cock, and are absent in the adult cock-feathered male, it seems not a far-fetched hypothesis to assume that these cells are those involved.

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.

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

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 F?'s were back-crossed to "common mice" the offspring were not susceptible. When the F?'s were back-crossed to the Japanese waltzer all were susceptible. When the F?'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.

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.

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