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 (or at least it
is supposed to be 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 (F₁’s) 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 F₁ 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.

[Illustration: FIG. 1. Cross between long-winged (wild type) _Drosophila
melanogaster_ and vestigial-winged fly, producing long-winged offspring
(F₁), which if bred to each other give in the next generation 3 long to 1
vestigial. In the middle of the diagram, the pair of chromosomes that are
involved in this cross are represented. The chromosome with the factor
(gene) for long wings is here black; that for vestigial is open (v).]

[Illustration: FIG. 2. Cross between long and vestigial wings, giving
long in F₁. The long-winged hybrid F₁ female is then represented as
out-bred to a wild-type male, giving long-winged offspring again—half
pure-long and half hybrid-long. The last are represented as again
out-bred to wild type, giving long-winged offspring again and of the same
two genetic kinds as above.]

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.

My illustration may give, however, an entirely erroneous idea as to
the chance of a recessive character contaminating the race. If one can
control the matings, so that out-breeding takes place each time, the
result would undoubtedly be like that in our diagram; but what chance
is there for a recessive character, that is neither beneficial nor
injurious, if left to itself, to contaminate widely the race with its
gene? The answer is that for any one defect there is hardly any chance
at all. On the other hand, there is always a possibility that a defect
_may_ become widespread despite the chances against each in turn. If a
recessive _character_ is selected against each time it appears on the
surface, the chance is extraordinarily small that the gene for such
a character could ever become widespread in a race. If the recessive
character is advantageous, its chance is somewhat better, but still the
chance that it may be lost is very great.

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.

[Illustration: FIG. 3. Mating of short-fingered and normal individual
(the short-fingered character is dominant), giving in F₁ normal
and short-fingered individuals in equal numbers. If the latter is
out-bred to normal again, half the next generation is normal and half
short-fingered.]

Of course if a dominant _character_ is advantageous in itself, it
will have a better chance of spreading through the race, than will an
advantageous recessive character, because every hybrid that carries
one dominant gene shows also the character, which increases the chance
that it will propagate and spread the genes. But, on the other hand,
if a dominant character is injurious it will have a smaller chance of
spreading than will an injurious recessive character; for, the recessive
may be carried by the hybrid without showing itself, and therefore will
not place the hybrid individual at a disadvantage.

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 (in Fig. 4)
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 (here black). 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 (or heterozygote) 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.

[Illustration: FIG. 4. Yellow mouse (YB) crossed to yellow mouse (YB)
produces here black and yellow offspring, in the ratio of 2:1. These
yellow are again hybrid, and if bred to each other give the same result
again. Pure yellow (YY) offspring die at early stage. They constitute one
quarter of all the offspring.]

In connection with the question of spreading of mutant genes in the race
there is another consideration, seldom referred to, that may occasionally
have some weight in accounting for the dispersal of genes. In _some_
combinations the hybrid may be more vigorous and more fertile than either
parental race. Hence it may have a better chance of survival than an
individual of either parent stock. It is a difficult question, that we
cannot answer at present, whether a mixed strain has a better chance
of survival than one or another of the strains of which it is made up.
The possibility that some hybrid strains may be better than either pure
strain is enough to put one on his guard against the popular doctrine of
racial purity so-called. Whatever advantages some kinds of pure races of
mankind may have, from a political, religious or militaristic viewpoint,
this should not blind us to the possibility of the biological advantages
that certain mixtures may bring about. I emphasize the statement
that _certain_ mixtures of races _may_ have a biological advantage.
It is equally possible that other combinations may have a biological
disadvantage. We are far from being able to state at present what
combinations are beneficial and what are biologically injurious. It is an
interesting problem, one of deep significance I think for the future of
the human race, but mixed up as it is at present with difficult social
and political questions it is a problem that only a light-hearted amateur
or a politician is likely to be dogmatic about.

Before we take up the main questions before us this evening, I must speak
of one other form of heredity. In many instances we have evidence that
a character is the product of more than a single _mutant_ gene. I say
“mutant gene” because in fact every character is no doubt the product
of the combined action of many genes, but in addition to this general
relation there are many cases now known where there are several specific
genes whose _chief_ effect is on one character. Size differences furnish
abundant data of this sort. One of the clearest cases is that of the size
of the ear of corn. Some races of corn have short ears (and cobs), some
long. If two such races are crossed, the hybrid is intermediate with a
considerable range of variation. If the hybrid is self-fertilized, the
progeny in the next generation shows a still wider range of variation,
extending from that of the shorter grandparent to that of the longer.
Both grandparental cobs have reappeared, but also many intermediate
grades, Fig. 5.

[Illustration: FIG. 5. Cross between long- and short-eared corn. Samples
of two original types shown in upper part of figure, hybrid offspring in
the middle of figure, and samples of 2d generation in the lower part.
(After East and Hays.)]

Such cases were formerly spoken of as blended inheritance. It was
supposed that the materials of the two parents have, as it were, fused
in the offspring and have remained fused. Today we have a better
explanation. It is this. Besides two major factors that here determine
cob length, there are other _minor_ factors, some of which make the
short cob longer, others that make the long cob shorter. These go over
into the first generation hybrids, and are sorted out in the germ cells
of the hybrid. Consequently, when the F₁’s are inbred, there are all
sorts of recombinations of the minor factors. This explains the greater
variability of the second generation.

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
rôle 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. (1) The number of offspring in a
family is usually too small to serve as a sample of the germ-plasm of the
parents. (2) 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.

[Illustration: FIG. 6. Inheritance of color blindness of man which
is sex-linked (i.e., the factor for color blindness is carried in
the X-chromosome). This X-chromosome is stippled in the figure while
the X-chromosomes for normal eyes are represented by black X’s. The
color-blind eye is also stippled, and the normal eye (which distinguishes
between red and green) is here represented by an eye half black and half
cross-lined. The 1st generation offspring (F₁) are normal eyed. In the 2d
generation offspring, half the sons are color blind.]

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.

[Illustration: FIG. 7. Reciprocal of the cross shown in Fig. 6. Here a
normal-eyed male marries a color-blind female, giving all color-blind
sons and normal daughters. When two individuals like these marry, the
expectation is for half of the daughters and half of the sons to be color
blind, and half of the daughters and half of the sons to be normal eyed.]

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

Accepting this evidence as on the whole satisfactory, there is still
something more to be said. As is well-known there are many grades
of color-blindness. We do not know whether these grades are due to
fluctuating (individual) variations—assuming it to be due to one gene:
or whether there are several genes that differ in the degree to which
they produce the defect. In fact we know now of a good many cases in
other animals where there are several mutations of the same gene.
For instance, in Drosophila there is a series of ten such multiple
allelomorphs for eye colors that range from pure white to deep wine-red.
There is still another possible interpretation of the different kinds
of color-blindness—one which _a priori_ would seem to be the most
probable—namely, that the differences are due to other modifying genes
that affect the extent to which the character develops.

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.

[Illustration: FIG. 8. Representing the kinds of individuals expected
when an individual of the blood group type AaBb marries individual of the
same blood type, namely AaBb. Sixteen kinds of individuals are possible
in the ratio of 9:3:3:1. These belong to four blood types, namely, class
IV that contains at least one A and one B; class II that contains at
least one A but no B; class III that contains at least one B but no A;
and class I that contains neither A nor B.]

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 (AaBb), 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.

These sixteen individuals fall into four groups according to whether they
have both A and B, or only A, or only B, or neither A nor B (_i.e._, ab)
in the proportion of 9AB:3A:3B:1ab. These four genetic classes correspond
to the four recognized blood types IV, II, III, I, as indicated in
the diagram. Now these sixteen kinds of individuals are found in all
populations, so far studied, although in somewhat different proportions
in different “races.”

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 }

                    I     III }
                              }      I, III
                  III     III }

    Unions of II  and III give I, II, III, IV.
              IV      I        I, II, III, IV.
              IV      II       I, II, III, IV.
              IV      III      I, II, III, IV.
              IV      IV       I, II, III, IV.

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.

[Illustration: FIG. 9. The upper pedigree gives the children from the
family in which types I and IV were the parents. The offspring belong to
types II and III (two of the four possible kinds of offspring).

The lower pedigree represents three generations. The grandparents are I
and II and I and III, respectively, while the parents are II and III.]

In the transfusion of blood from one individual to another, that is
sometimes necessary, it is essential that the blood corpuscles of the
donor are not agglutinated by the serum of the recipient. Thus it is a
matter of great importance to select a donor that does not bring about
such a catastrophe. The simple rules are that individuals belonging to
the same blood group (I, II, III, or IV) do not agglutinate each other’s
blood, but the blood corpuscles of an individual represented by AA or Aa
will be precipitated if the donor contains the agglutinin represented
by aa, and conversely the blood corpuscles of an individual represented
by BB or Bb will be precipitated if the donor contains the agglutinin
represented by bb. Inspection of the diagram will show that group II
(with serum bb) precipitates III and IV, and group III (with serum aa)
precipitates II and IV. Further the serum of group I (aa bb) precipitates
all of the other groups; while the serum of group IV precipitates none of
the others.

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
rôle. 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.

[Illustration: FIG. 10. Above (A) normal adult hen-feathered Campine
cock. Below (B) castrated cock about one year after operation. The
castrated bird has developed the secondary sexual characters of
cock-feathering.]

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.

[Illustration: FIG. 11. To left (a) hen-feathered Sebright cock. To
right (b) castrated Sebright cock that has developed characteristic
cock-feathering.]

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.

[Illustration: FIG. 12. Cross between hen-feathered Sebright cock and
black-breasted game female belonging to a race with cock-feathered males.
The offspring (F₁) are hen-feathered males and normal hens. These inbred
give 3 hen-feathered to 1 cock-feathered son.]

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 (or their
secretions) 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.

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.

[Illustration: FIG. 13. Diagram showing inheritance of immunity to
cancer. (From Tyzzer and Little.)]

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.

[Illustration: FIG. 14. Diagram showing inheritance of a sex-linked
recessive lethal (“tumor”) factor in _Drosophila melanogaster_. Here, in
the center of the diagram, the sex-chromosome that carries the lethal
factor is represented by the black rod. A female with the tumor-factor,
normal wings and red eyes, in one of her sex-chromosomes and with the
factors for yellow wings and eosin eyes in the other is bred in each
generation to a male with yellow wings and eosin eyes. In the next
generation there are twice as many daughters as sons, since all the sons
that carry the black chromosome die. The half of the daughters (_i.e._,
those not yellow eosin) that carry the black chromosome repeat the same
history. The linkage of yellow and eosin enables one to pick out in each
generation those daughters that carry the tumor-factor.]

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.

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 (owing to imperfect
separation) 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 (into which the serum was injected) 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 F₁ 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.