Popular Science Monthly/Volume 75/September 1909/The Theory of Individual Development

by Frank Rattray Lillie

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THE THEORY OF INDIVIDUAL DEVELOPMENT^[1]

By Professor FRANK R. LILLIE

UNIVERSITY OF CHICAGO

ORGANIC development presents two aspects: that of the individual and that of the race, ontogeny and phylogeny (evolution). These are not two separate and distinct series of phenomena; on the one hand, the individual development is to a certain extent a record of the past history of the race, and the promise of future racial development; on the other hand, evolution is not a series of completed individuals but a series of individual life, histories; for the only road from one generation to the next is by way of a complete life history. Individual development is, therefore, not something distinct from evolution; it is a part of the process of evolution itself; the development of the individual is a chapter in the history of the race.

The development of the individual may be pictured as a steadily broadening stream that takes its source in the fertilized ovum and flows on until death. In this analogy the individual would be represented as a cross-section of the stream at whatever stage we were examining. Though such an analogy limps, inasmuch as individual development is never before us as a unit, as a stream may be conceived to be, and can indeed be said to exist only as the successive cross-sections (its past having disappeared and its future yet unborn), nevertheless, it represents very well the steady, unbroken progress of development from the ovum to old age. There may be crises in the development of the individual, as, for instance, when the chick leaves the egg or the pullet lays its first egg, but there are no breaks in its continuity. Successive generations may be pictured as new streams, each taking its source from a particle—a germ cell—from some cross-section of the preceding generation; and evolution may be represented by placing the new source at a different level than the original. For evolution studies we compare cross-sections of different developmental streams (generations) at comparable distances from the sources, and for evolutionary explanation we must examine the entire series of processes involved in the origin of the new source and in the conditions and inherent character of the new developmental stream.

We can not be said to have actual experience of any other form of development than individual development; evolution or racial development is an inference from innumerable facts and series of phenomena, all of which are bound up together and rendered intelligible by the theory of common descent. We therefore find that the founders of theories of evolution turn to individual development as the court of last. resort, as the place where evolution may be detected in actual process. For here is found the link that binds successive generations, here variations arise, whether they be mutations or of the ordinary fluctuating kind, whether they be germinal or acquired; here in the individual life history the Lamarckian must look for the reflection of the experiences of the individual back upon the germ; here the adherents of orthogenesis must find their crucial evidence.

In his theory of natural selection Darwin accepted as given the data of individual development. But he saw clearly that the fundamental phenomena of heredity and variation had their seat in the individual development, and he experienced the need of framing a conception that would bind together the phenomena of hybridization, the various forms of variation, atavism, telegony, regeneration, inheritance of acquired characters and the like; and in his volumes on "Animals and Plants under Domestication" he framed the provisional hypothesis of pangenesis to include them all. I shall not attempt to present the details of this theory, but I may be permitted to say that, as a matter of logical arrangement of the assumed data, under the circumstances of existing biological conceptions and of the state of knowledge of the time, the theory was well worthy of its illustrious founder. In its way, it was as original as the theory of natural selection, though some of its fundamental ideas had certainly been anticipated by previous writers.

Nor shall I attempt a critical estimate of the value of the theory in the history of science; but I may be permitted to call attention to certain features. In the first place, the theory was overburdened with certain unnecessary conceptions such as inheritance of acquired characters, atavism and telegony. The elimination of these conceptions immensely simplifies the theory of individual development. In the second place, it rested upon a fundamental conception, that of representative particles, which amounts to a denial of the reality of individual development. And in the third place, it assumed certain biological processes—the existence of specific vital particles of ultramicroscopic dimensions, their radiation from parent cells, and their aggregation in other specific cells in a definite architectural pattern—for which there is not only entire absence of evidence, but which are wholly inconsistent with the known facts of cellular physiology. For these reasons the theory had only provisional importance, as indeed Darwin recognized in naming it the provisional hypothesis of pangenesis.

The determinant hypothesis of Weismann, contained in his theory of the germ-plasm, includes the assumptions of the pangenesis hypothesis, with those eliminated that were made necessary by the conception of the inheritance of acquired characters. For Weismann's gemmules, or determinants, the assumption of somatic origin was unnecessary, and thus, as Professor Whitman states, the entire centripetal migration of Darwin's theory was eliminated, but the entire centrifugal process was retained. The origin of every character of the individual was explained in the Weismannian theory, as in the Darwinian theory, by the unfolding (it can not be called development) of representative particles. Nevertheless, the theory of the germ-plasm played an important role in the development of biological knowledge, for it framed a set of ideas in a manner sufficiently logical and definite to serve as veritable working hypotheses or bases of attack. The immense effect of Weismann's writings on the theory of individual development should not be underestimated.

 

Physiology of Development

The theories of individual development that we have mentioned bear all the marks of provisional or formal hypotheses. Although extremely ingenious and logical, they are based only in small part on analysis of the actual processes and they offer no real explanation of the phenomena themselves; for they really include all the elemental phenomena and merely sum them up; they are definitions that include the matter to be defined; they amount to a denial of the reality of individual development as truly as did the preformation theories of the eighteenth century.

As a series of processes occurring in nature and accessible to experience, the development of the individual is capable of resolution into simpler biological processes, and these presumably into physico-chemical events in the usual sense. All attempts to make such analyses come under the head of Physiology of Development; and this plan of attack on the problems of individual development, known in Germany as developmental mechanics, is one of the most actively pursued lines of biological investigation at the present time. Physiology of Development deals primarily with specific problems, and the results constitute a critical basis for the appreciation of general theories of both individual and racial development. We shall examine some results and principles of these studies, and consider their application to some theories of heredity and evolution.

1. Embryonic Primordia and the Law of Genetic Restriction.—In the course of development the most general features of organization arise first, and those that are successively less general in the order of their specialization. Thus the directions of symmetry of the future organism—the oral and aboral surfaces, right and left sides, anterior and posterior ends—are the earliest recognizable features of organization of bilateral animals, and they appear while the germ is still unicellular. The distinction between outer, intermediate and internal organs next makes its appearance, each at first as a single tissue. The outer tissue then separates into an epidermal and a nervous tissue, the inner tissue into the intestinal and yolk-sac epithelium, the middle tissue into muscle-forming tissue, connective tissue, skeleton-forming tissue, blood-forming tissue, excretory tissue, peritoneal tissue, etc.

For every structure, therefore, there is a period of emergence from something more general. The earliest discernible germ of any part or organ may be called its primordium. In this sense the ovum is the primordium of the individual, the primitive outer tissue the primordium of all structures of the skin and nervous system, the primitive inner layer of the intestine and all structures connected with it, etc. Primordia are, therefore, of all grades, and each arises from a primordium of a higher grade of generality.

The emergence of a primordium involves a limitation in two directions: (1) it is itself limited in a positive fashion by being restricted to a definite line of differentiation more special than the primordium from which it sprang, and (2) the latter is limited in a negative way by losing the capacity for producing another primordium of exactly the same sort. The advance of differentiation sets a limit, in the manners indicated, to subsequent differentiation, a principle that has been designated by Minot the law of genetic restriction. This in a merely descriptive way is one of the general laws of individual development, and in it is involved the explanation of many important data in the fields of physiology and pathology.

But, though primordia are thus restricted, they nevertheless have the very important property of subdivision, in many cases at least, each part retaining the qualities of the whole. Thus, for instance, in some animals two or several complete embryos may arise from parts of one ovum. Similarly, two or more limbs may be produced in some forms by subdividing a limb bud. Thus frogs with six hind legs have been produced by Gustav Tornier by the simple process of dividing the primordia of the hind legs with a snip of the scissors, in which case he found that on each side one part of the primordium produced a complete pair of legs and the other the normal leg of that side. This capacity for subdivision of primordia explains large classes of pathological facts—at the same time it furnishes a problem to the student of the physiology of development which has proved a serious stumbling block.

2.Principle of Organization.—I have already indicated the existence of direction and localization in the primordial germ of the individual, the unsegmented ovum; the ovum, as we say, is polarized, and, not only so, but, in bilateral animals, it is bilaterally symmetrical. This is not usually indicated in the form of the ovum, which is typically spherical, but in the disposition and developmental value of its parts. Here we have one of the most fundamental and least comprehended facts in embryology. It has, moreover, been shown that this property of direction and localization resides in the homogeneous, transparent, semifluid matrix that suspends all the visible particles of the protoplasm of the egg. It is probable that primordia of all grades possess similar properties, and, if this is so, we have a principle that goes far to explain the orderly localization of processes in morphogenesis.

This principle is not farther analyzable at present; but, as it may be found intact in parts of primordia no less than in the whole, it probably rests on a molecular basis. The most ready analogy in simpler phenomena is that of crystallization. The study of fluid crystals has furnished us examples of inorganic molecular aggregates in which direction and localization are given in the whole and also reappear rapidly in the parts when the whole is subdivided.

3. The Rôle of Cell-division in Development.—The individual organism begins as a single cell, from which all cells of the developed organism trace their lineage by the process of cell-division. This has been regarded as one of the most fundamental factors of the individual development in the theories of Weismann, Hertwig and others. But important as the process of cell-division undoubtably is in development, I believe that it is impossible to ascribe to it in principle more than an indirect effect: Considerable complexity of development is possible among Protozoa, whose body is unicellular, and some ova may carry out under experimental conditions a considerable part of the early development without a single cell-division. Moreover, the same kind of differentiated structure may be composed of one cell or of many, or of variable numbers of cells.

The physiological value of cell-division is no different in principle in developing than in functioning tissues (using these terms in the usual sense). The general law of relative reduction of surface in proportion to increasing mass imposes a size limit on cells, which can be regulated only by cell-division; an internal principle of regulation of cell-size has also been stated by R. Hertwig and Boveri, viz., a certain relationship characteristic of each species between the amounts of nuclear and cytoplasmic matters, so that increase of initial volume of the former involves increase of the latter, and vice versa. Corresponding to these principles, we find that individuals of different sizes of the same species vary not in the size, but in the number of the cells; and this is regulated by variation in the number of cell-divisions in different individuals.

Cell-division must necessarily, therefore, have an immense {{hws|func|functional} functional significance in development, owing to the principle of relation of functional area to mass. It has also another very important function as an isolating factor. The localizations that arise, owing to the organization process of which we have spoken, are rendered relatively stable and permanent by the formation of cell-walls. Thus the elements of the mosaic are isolated, and each isolated part has the opportunity to grow into a new mosaic. Cell-division is thus an important factor in progressive differentiation, not as a cause, but as a means.

4. Environment.—Environment must be conceived in a somewhat broader sense than usual in considering the individual development. The developing embryo has an environment in the usual sense, consisting of all those external conditions that surround it, some of which enter into its development. But in addition to this extra-organic environment there is an intra-organic one; the developing embryo is not merely a unit on which an extra-organic environment operates, but it is a living mosaic, each element of which may conceivably enter into the development of any other in the sense of being a factor in the process. Each part of the embryo, therefore, has an intra-organic environment consisting of all the other parts, 6ome of which constitute relatively immediate environmental factors, others relatively remote ones.

To illustrate: nerves arise in the embryo from certain centers and grow out in the embryonic tissues, much as roots grow out in the soil; the muscles arise separately and the nerves grow to them and make the proper connections. Is this due to an innate tendency of each nerve to grow in particular paths and branch according to definite laws, or, on the other hand, is it due to a directive stimulus exerted on the growing nerve by developing muscle tissue? The answer can be given only by a suitable experiment: If an abnormal innervation area were brought into the field of growth of a developing nerve, would the nerve entering the abnormal area follow its normal mode of branching, or the one characteristic of the normal nerves of the transposed area? To be specific: the bud of a leg of a tadpole that has as yet no nerves may be transplanted to any region of the body (Braus and Harrison), and it develops as a leg; but it receives its innervation from the nerves of the region to which it has been transplanted, and the mode of branching of the nerve is that of the leg nerves. We may generalize this statement by saying that any nerve may be made to depart from its normal mode of branching and to branch like leg nerves, by bringing a leg bud into its innervation area at the time that the nerve is still growing.

It will be seen that if this is generally true, the constancy of distribution of peripheral nerves is not due to the transmission of nerve-branching determinants from generation to generation, but is a function of the intra-organic environment in each generation.

The case of the determination of nerve-branching by intra-organic relations does not by any means stand alone. The same principle undoubtedly holds for the development of the blood-vessels, which grow along paths determined by the arrangement of organs and tissues and not according to a predetermined law given in the blood-vessels themselves. Color patterns have been shown in some cases to be determined by intra-organic variable relations, as in Loeb's experiments on the determination of the color pattern of the yolk-sac of a fish, which he demonstrated to be due to the positive attraction of the circulating blood for migratory cells that bear pigment. The development of any color pattern was therefore dependent upon blood-circulation, and the form of the pattern upon the pattern of the blood-vessels. The primordia of the eye or the ear transplanted to strange locations in the embryo induce formations in surrounding tissues that are strange to them and characteristic of the normal eye and ear environment. The origin and growth of motor nerve cells has been shown in my laboratory by Miss Shorey to be dependent in the chick on normal muscle development; so that the anatomy of the central nervous system, no less than the peripheral system, is dependent to some extent on the environment. Regeneration of lost parts is dependent for its completion to some degree on innervation, and the normal development of muscle tissue beyond a certain stage is likewise so dependent. These examples might be increased by others, which, taken together, would show that an immense part of what we call inheritance is inheritance of environment only, that is, repetition of similar developmental processes under similar conditions. The bearing of all this on the doctrine of determinants, that characters of the adult are represented by germs of a lesser order in the germ of the entire organism, is obvious.

Many of the problems of heredity, so-called, are not capable at present of such resolution. We may note some instances of this kind and then attempt to analyze the whole matter briefly. The example cited of transplantation of a leg-bud is of this kind: the transplanted leg-bud does not develop into an arm if it be transplanted to the region of the arm, but into a right or left leg, as the case may be, and this is true no matter how early the stage at which the transplantation may be made. It is not possible to change the specificity of such a primordium by any means yet employed. Moreover, there are many other experiments which show that the primordia of a great many structures are definitely specified even before they can be detected by any method of pure observation. Thus if a portion of the medullary plate of a frog embryo be cut out so as to include in the cut part the region that would form an eye in the course of time, and if then this piece be replaced inverted, it is found that the subsequent development of this area is inverted, not restored to the normal, although no trace of organs was present at the time of the operation (Spemann). In this case, then, the eye appears in an abnormal position.

Correlative Differentiation.—We have cited a series of cases that illustrate two apparently contradictory principles known as the principles of correlative differentiation and of self-differentiation. The part that these play in embryonic development should be analyzed. The data of correlative differentiation may be placed in two categories, one of behavior and one of metabolic relations. Considering these separately:

Behavior.—Any case of behavior involves a stimulus, and a response; these imply irritability and reaction capacity. To take a simple case, for instance, the contraction of a muscle, the stimulus may be of a variety of kinds, nervous, chemical, electrical, thermic, mechanical; in any case the response is contraction. The nature of the response is given in the system and is limited by its reaction capacity. The muscle cell does not contract for one kind of stimulus and secrete in Response to another.

This principle is elementary in physiology and psychology and it must apply also in the physiology of development. It appears to me that it has not been sufficiently borne in mind by students of the subject. Herbst, for instance, divides developmental stimuli into directive, trophic and formative. The first kind of stimulus determines the direction of growth or migration, and so plays an important part in development, a really great part illustrated in two of the cases cited, viz., the mode of branching of nerves, and the direction of migration of wandering cells. Trophic stimuli are those that affect the rate or :amount of growth without altering its specific character.

The conception of formative stimuli implies, if it has any meaning whatever, that the nature of a developmental process is determined %y the nature of a stimulus. A case often cited is as follows: the two most fundamental parts of the eye, lens and retina, develop from two entirely distinct primordia, the retina from the embryonic brain and the lens from the epidermis. The retina first grows out from the wall of the brain and reaches the epidermis to which it becomes fused. The latter then produces a lens. Now it was shown for some amphibia, that, if the retina fails to reach the epidermis, no lens forms; therefore, it was argued that the production of the lens is due to a formative stimulus exercised by the retina on the epidermis. But in some other cases the lens forms even if the retina be absent; which does not prove that it arises without stimulus, only that this specific stimulus is not needed. And the fact that transplanted optic vesicles stimulate lens formation in strange localities from the epidermis merely shows that this form of reaction of embryonic epidermis is widespread at this stage of development.

The instance is valuable as proving that stimuli are important in development, but useless as an example of a formative stimulus. Morphogenetic behavior, like behavior in other fields, is not a function of the stimulus as to its specificity, but it is prescribed and limited by the reaction capacity of the system. One example is as good as many. We shall not find this principle contradicted by any of the known data of the physiology of development.^[2]

Metabolic Relations.—When we consider to what an extent the nature of every biological character is given in its chemical composition, it can be readily understood that, to some authors, physiological chemistry should seem the complete basis of heredity. The characters of every tissue of the body are absolutely dependent on their chemical composition, and even slight variations in chemical composition may completely alter function, appearance or form. For such a statement examples are entirely unnecessary.

The development of characters in the individual is dependent upon the occurrence of definite chemical reactions, upon their rate and upon their degree of completion. It has been shown that the law of acceleration of embryonic development in correspondence with rise of temperature is the same in principle as the law of acceleration of chemical reactions by temperature increase. Numerous experiments have been made on the character of development in the absence of one or other or combinations of the elements normal to protoplasm, with the aim of determining their rôle in development. Herbst, for instance, has made a series of experiments on the development of larvae of the sea urchin in artificial sea waters, in the composition of which definite elements are wanting. He shows, for instance, that in sea water made up without calcium the skeleton fails to develop, and that the form of the larva resulting is profoundly modified from the normal. In other experiments the potassium or sulphur, or iron, etc., is omitted from the solution, and the effect on the development noted. Other experimenters have maintained that the presence of specific chemical elements in excess has definite morphological consequences.

As regards complex substances and their rôle in morphogenesis, but little is actually known. Recent results indicate that the egg contains substances of complex chemical composition which are essential for the development of specific parts or tissues. Thus certain experiments consist in the removal of definite parts of the egg containing specific materials; and in the subsequent development specific parts of the embryo are wanting. In other experiments, by Conklin, the transference of definite substances from their normal location by means of centrifugal force is followed by the development of corresponding specific structures in the abnormal location. These experiments strongly suggest, even if they do not rigorously prove, that such substances are essential ingredients in definite developmental processes. I am indebted to Dr. Riddle for the following illustration: The various colors of mammals, such as black, brown, red, yellow, are due to chemical substances known as melanins. The chemistry of these substances starts out from a simple colorless base or chromogen, from which the series of colors, yellow, red, brown, black, is derived as successive stages of oxidation. The chromogen base is found in all mammals; the color then would appear to be due to the varying powers of the cells of different individuals to oxidize the given base. Tornier has shown in his experiments on the coloration of Amphibia that the particular color developed is a function of nutrition, varying in the order of oxidation value (as was later ascertained) according to the degree of nutrition. The development or inheritance of color, therefore, can certainly not be due to the presence of black or brown or red or yellow determinants in the germ, assumed for theoretical purposes by some students of heredity, but to a specific power of oxidation of the protoplasm. This faculty in its turn is no doubt capable of resolution into other physiological terms.

We are only at the beginning of the study of correlations of embryonic metabolism. The role that the internal secretions of the embryo may play in the processes of development is practically unknown; but we may expect to find here biological reactions of fundamental significance, especially when we consider such phenomena of the adult as the influence of pregnancy on the organism, the possibility of inducing lactation, with all that this implies, by injection of fœtal tissues; the relations between the sex organs and secondary sexual characteristics and indeed the entire habitus of the organism; the influence of a small gland like the thyroid, or the pituitary body, etc. Biochemical reaction runs through every phase of development and is unquestionably the decisive factor in the appearance of many characters of the organism.

Self-differentiation.—The conception of self-differentiation in morphogenesis is a vague and unsatisfactory one. In a sense it is a contradiction in biological terms, for assuredly environment enters into every biological process. On the one hand, the term covers the fact of the specificity of primordia, which means only a certain stability of metabolism and reaction capacity; on the other hand, it may have specific meaning in one large class of developmental phenomena, viz., polarization and localization. If, for instance, the term self-differentiation might be applied to the appearance of definite axes, angles, points and faces of a crystal, it would with equal propriety be applicable to the appearance of polarity, bilaterality, etc., the axes of embryonic development. But if the term should come to hold simply this restricted meaning, then all reason for its maintenance would be gone. It is not at all certain that it will be possible to reduce all the problems of the physiology of development to such categories as we have mentioned. The subject is full of unsolved problems, but so far as I can see no one has shown any real reason for assuming ultraphysical agencies in any of the events, and there is the same pragmatic reason for refusing to assent to such suggestions, which are made all too frequently, that there is in other fields of science. If we will be consistent, we are driven to the conclusion that the apparent simplicity of the germ is real, that the germ contains no gemmules, or determinants or other representative particles; that development is truly epigenetic, a natural series of events that succeed one another according to physicochemical and physiological laws; the explanation of the sequence consists simply in the discovery of each of its steps.

 

Applications

The problems of heredity and variation are included in a true physiological conception of the individual development; but some biological conceptions that have more or less status and reputation are inconsistent with it. Such are the inheritance of acquired characters, atavism, and the theory of unit characters. The first is a familiar problem that I shall not argue anew; the second logically implies the presence of ancestral representative particles in the germ, which is inconsistent with a physiological theory of development. But it is obvious that the facts united under the name of atavism or reversion take their place naturally in a physiological theory of development, as arrests of development, or modification of environment, or in other ways.

The theory of unit characters deserves more attention for it ia essentially a modern theory, and counts numerous adherents. This, conception has been most sharply formulated by De Vries in his Mutationstheorie. He says:

The properties of the organism are constructed of units which are sharply distinguished from one another. These units may be united in groups, and in related species the same units and groups occur. Intermediates between the units, such as the external forms of plants and animals exhibit so abundantly, are not found any more than between the molecules of chemistry.

Bateson's allelomorphs constitute a similar conception. Such hypothetical elements of organization must be conceived as distinct from the germ on. They can be shuffled about from one generation to another, and can, therefore, be introduced, removed or replaced in the germ cells. It must be admitted that these conceptions fit certain facts of inheritance in many hybrids fairly well, but the progress of discovery has made necessary the installation of subsidiary hypotheses, so that the most recent conceptions of unit characters are becoming extremely complex, and it would seem as though the system would soon fall of its own weight. The entire value of the hypothesis consists in the formal approximate expression of certain facts; when it is found that the hypothesis begins to fail even for the classes of facts for which it was originally intended, and that most of the known facts of development can not possibly be expressed in its terms, the entire conception is put on trial.

The weakness in the theory of unit characters is in the use and conception of the term "character.' The term has been prescribed to us by the systematic zoologists and botanists engaged in describing the differences between species; so that "character" really means any definable feature of an anatomical kind that differentiates species; by extension it also means any other differentiating features that can be defined. In the study of evolution and heredity, it is usually only anatomical characters that are in question. Now the study of the physiology of development teaches us that whatever else "characters" may be, they are not units; they simply represent the sum of all physiological processes coming to expression in definable areas or ways, and they may thus represent a particular stage of a chemical process, or a mode of reaction of some part. "Character" is essentially a static morphological term; in the study of heredity and development we are dealing with biological processes. To adapt a phrase of Huxley's: "characters" are like shells cast up on the beach by the ebb and flow of the vital tides; they have a more or less adventitious quality. To give them representation in the germ is equivalent to a denial of uniformity in biological phenomena.

Just as the exact position of each shell on a beach might be fully explained if we knew its full history, so each character has a certain kind of inner necessity as the result of a sequence of developmental processes. And just as in the history of the position of the shell on the beach we should certainly ascribe great importance to the tides and winds, so in the quality of each individual character we should find corresponding vital tides and winds, as regular and lawful as those of the ocean. We do not yet know the secrets of the vital tides; we maintain only that they are the moving forces in development and heredity, just as in physiology and pathology; and every fundamental contribution to the physiology of protoplasm is at the same time, and to the same extent, a contribution to heredity and the physiology of development.

But if these principles are accepted, how are we to explain the facts on which the theory of unit characters depends? The main difficulty lies not in the facts of mutation, for the physiology of this phenomenon already begins to appear from the experiments of Tower and MacDougal, who show that mutations may result from action of environment directly on the germ cells. The most fundamental phenomena in the unit character theory are unquestionably the segregations of characters that appear in the offspring of hybrids in so-called Mendelian inheritance. In the most typical cases, grandparental characters reappear in definite proportions of the progeny of the hybrid generation. The interpretation, according to the theory of unit characters, is in the hypothesis of purity of the germ cells of the hybrid generation with respect to the segregated characters; which means that the germ cells of the hybrid generation are pure with reference to the contrasting characters united in the soma; in other words, that corresponding contrasted characters can not both remain in the same germ cell, but are segregated in different ones and may thus appear pure in the descendants of a hybrid generation.^[3]

We may well doubt that absolute purity of grandparental characters in the offspring of the hybrid generation occurs, and the results unquestionably vary with the environment; but I believe that we have to admit the general principle of segregation. However, the theory of segregation of unit characters in the germ cells is in no way necessary to explain the results; it is in fact inconsistent with the highly variable result; if unit characters were segregated in the germ, we should expect very definite constant results.

If we take our stand on the epigenetic basis and regard the germ cells as no more complex than direct investigation would lead us to suppose, then we have to admit that segregation in the germ cells can involve only constituents of the germ cells themselves. But any variation thus induced in the germ cells would be a factor in each process of the development, and would hence tend to influence every character that appears. Such a hypothesis involves the conception that germ cells contain elements capable of segregation; and this is so. Even if the principle of segregation of characters in inheritance had never been discovered, the principle of segregation of germ-cell elements would still hold, for the two discoveries were made absolutely independently.

I refer to the work of Guyer and Montgomery on the chromosomes, which has been followed by a long series of very exact studies. These studies certainly suggest segregation of parental chromosomes in varying proportions in different germ cells. Indeed, I know of no other interpretation of chromosome behavior that is consistent with the facts. Whatever value we may attribute to the chromosomes in cellular physiology, the variable relations established by their differential segregations, even if only quantitative differences are concerned, must involve endless secondary effects in the long series of cell generations that make up the individual life history.^[4] It is not impossible that other segregations than those of the chromosomes form part of the germ-cell behavior, but of this we know nothing as yet. In any event, the principle of segregation of actual visible elements of the germ cells has a firm anatomical basis.

It must not be forgotten that the germ is the entire organism and that it passes through development as the same individual; continuity of individuality is preserved throughout development. Therefore, if we discard determinant hypotheses and take our stand on a strictly physiological theory of development, it follows of necessity that the transmitted factors of heredity included in the organization of the germ cells must be factors in the development of the entire organism. The so-called Mendelian factors must therefore be of this character, as I have argued elsewhere. That is to say, the segregated factors must be general constitutional conditions effective as factors in the development of every part of the organism. It can readily be seen that specific intensity of metabolism, or of reactivity, and variation in constitutional size of cells may be such conditions. Others no doubt exist, of which sex may be one. The essential thing to recognize is that the heritable and segregable factors, being conditions of the germ cells at the start, can never be anything less than factors of the entire organism at all stages.

Our conclusion is that the theory of individual development must more and more come to be regarded as a branch of physiology proper. The theory of representative particles must be relegated to the class of formal hypotheses whose usefulness is largely outlived. While it may still play a part in speculations on heredity, I believe that it will come to be generally recognized by those who use it as a mere matter of convenience of terminology, and not as an explanation of the phenomena described in its terms, in the sense of being a verifiable part of the sequence of processes in development.

1. One of the series of Darwin Anniversary addresses given under the auspices of the Biological Club of the University of Chicago, February 1 to March 18, 1909.
2. Stimuli in the sense in which we use the word involve merely the impinging of energies on the stimulated system; if substantive additions are involved we have more than a mere stimulus, to the extent that substances are added to the system.
3. Recent modifications of the theory of purity of the germ-cells do not essentially modify the argument.
4. This general argument would stand even if the chromosomes be regarded merely as indices of organization. They at least give us a clue as to what "the organism" is doing at the time in question. This is indeed all we can say of any characters at any period if we consider the matter in a strictly logical sense.