The Origin and Development of the Nervous System

If the organism is a physicochemical system the mechanism of organismic integration and pattern must consist in the factors included under what we commonly call physiological correlations. Physiological or organis- mic correlation may be defined as the sum total of the physicochemical relations of organismic type between parts in the organism. It is necessary to make the dis- tinction clear between organismic and protoplasmic correlation. I have already pointed out that organismic pattern is of a different order of magnitude from pro- toplasmic pattern, and if we admit this it is evident that organismic correlation consists in the relations between different molar regions which may be separated by measurable and often very considerable differences. Chemical reaction between two protoplasmic constitu- ents, adsorption upon a colloid particle, the attraction or repulsion between ions or ionized colloid particles, these and similar relations considered individually are factors in protoplasmic rather than organismic correla- tion, but these same processes occurring in an orderly way in sufficient quantity may become organismic. Organismic correlation is concerned with masses of pro- toplasm, cells, molar regions and organs, with the production of substances in mass, their transportation over directly measurable and often considerable dis- tances and their action upon regions and organs as wholes, and with the transmission of dynamic changes, also over directly measurable and often considerable distances. The particular physicochemical processes involved in organismic correlation are of course proto- plasmic processes, but the mass, the order, and the distances concerned are of a different order of magnitude from those concerned in strictly protoplasmic relations. At the boundary line between organism and protoplasm, if such a line exists even hi the simplest living individuals, there may be difficulty in distinguishing between proto- plasmic and organismic correlation, but nowhere else is this the case. The house represents a pattern, an

integration of a different order of magnitude from the patterns of its constituent materials, whether these be lumber, bricks, stone, or cement, and it is the orderly mass arrangement of the material according to a certain plan which constitutes the house. Similarly the organ- ism represents a pattern which involves the orderly arrangement and relation not of protoplasmic con- stituents but of protoplasmic masses, cells, and organs. In order to answer the question concerning the nature of organismic pattern, and more particularly the possi- ble role of quantitative factors in the origin and develop- ment of this pattern, we must determine what the different sorts of physiological organismic correlation are, how they originate, and what part they play in organismic integration.

For present purposes it is convenient to group the correlative factors under three heads: the mechanical or contactual, the chemical or transportative, and the dynamic or transmissive, and to inquire concerning the possible role in integration of each of these groups. The mechanical or contactual factors include all those which involve direct mechanical action, pressure, or tension through direct or intermediary contact. While they may play a part in determining size of organs, direction of growth, or flow of fluids, and indi- rectly, in certain cases, the irritability or metabolic activity of protoplasm, it is difficult to conceive, in view of the fact that the energy of living protoplasm is largely chemical in origin, that they are primary or fundamental factors in physiological integration. Moreover, in order that they may act in a definite orderly way, differences of some sort must already be present between the differ-

ent regions or parts concerned, or the differences must arise through the direct local action of some external factor. The role of these mechanical factors is mani- festly secondary and incidental and is limited to organ- isms in which pattern of some sort has already been established and is in process of development. Chemical correlation, so called, perhaps more properly transportative correlation, includes the movements and exchanges of substance between the various parts of the organism. The internal secretions, hormones in general, and also the movements and exchanges of nutritive sub- stances, water, electrolytes, and waste products of metabo- lism, fall under this head. Transportative correlation, in short, includes the material exchanges and movements, the commercial relations, so to speak, within the organ- ism. These transportative factors in organismic cor- relation are obviously of great importance, and the work of recent years upon the more highly specialized aspects of such correlation, the internal secretions, hormones, etc., has shown us the bewildering variety and com- plexity of this kind of correlation in the higher animals. Moreover, when we consider that every organ is to some extent and in some way concerned in transportative correlation and that such correlation plays an essential part in the growth, differentiation and maintenance of the various organs, its significance in organismic inte- gration becomes sufficiently obvious.

The question at once arises whether transportative correlation is the primary and fundamental factor in organismic integration. A moment's consideration shows that the existence of definite and orderly trans- portative correlation implies the existence, first, of definite and orderly differences in different regions, and second, of some means of transportation between the regions, parts, or organs concerned. Between regions which are identical in protoplasmic constitution no definite and orderly transportative correlation of the organismic type is possible. Evidently organismic pattern of some sort must exist to some extent before transportative correlation can arise. In short, it is at once evident that, however important transportative correlation may be in the growth, differentiation, func- tion, and maintenance of parts or organs, it cannot con- stitute the first step in organismic integration, because this first step concerns the origin of the localized differ- ences which make transportative correlation possible. The material exchanges between the constituents of protoplasm involve, of course, electronic, atomic, or molecular transportation, but it is the ordering and localizing of these exchanges with respect to proto- plasmic or multicellular masses, regions, and organs that is the characteristic feature of organismic trans- portative correlation, and this is possible only on the basis of a pattern of a higher order of magnitude than the protoplasmic pattern.

The protoplasmic pattern alone does not seem to afford any mechanism for the origination of this larger pattern, but such a pattern may of course arise through the relation of protoplasm to external factors. When, for example, some portion of the surface of an Amoeba comes in contact with and ingests food, the reaction itself presupposes the existence of an organismic pattern in the Amoeba, but as a result of the reaction a new kind of organismic pattern arises temporarily, i.e., a food

vacuole appears, and since the processes going on in and about the food vacuole are different from those in the other regions transportative correlation between the vacu- ole and other parts becomes possible. For the appear- ance of this particular nutritional pattern in the Amoeba the external factor, the food, is the directly determining condition, the pattern arising from the reaction of the protoplasm to the food. Similarly, if one portion of the surface of the cell mass is exposed to an adequate oxygen supply while other portions are not so exposed, a regional difference in rate of oxidative activity may arise which may make possible transporta- tive as well as transmissive correlation. Of course organismic pattern in general arises, not in such purely fortuitous manner, but in some very definite and con- stant way for each form, but there seems to be no escape from the conclusion that transportative correla- tion is possible only when such pattern is already present, however it may have arisen.

The correlative factors of the third group, the dynamic or transmissive factors, consist in the trans- mission through protoplasm or along limiting surfaces of a dynamic change of some sort which is initiated in some particular region. While these factors may involve transportation of electrons or ions from one point to another, they differ from the transportative factors in that the correlative action of one part upon another is accomplished, not by the mass transportation of substance from one to the other, but by the passage of an energetic change which we call excitation or of some dynamic effect of excitation. Capacity for trans- mission of excitation is, so far as we know, characteristic

to some degree of all living protoplasm, except perhaps in certain quiescent conditions; moreover, protoplas- mic transmission may occur from one region to another, even though no differences, either qualitative or quantitative, existed between the two regions before the excitation of one of them by some external factor, i.e., the excitation- transmission pattern may arise, at least momentarily, through the excitation itself. The nature of the process of excitation and transmission is of course dependent upon protoplasmic pattern, but there is no reason for believing that this protoplasmic pattern can of itself give rise to local excitation in the absence of any external action. It appears then that the excitation-transmission pattern is in the final analysis the result of action of an external factor upon a protoplasm.

Since excitation and transmission undoubtedly occur in all protoplasms it is evident that, while the processes concerned may differ in certain respects in different protoplasms, the occurrence of excitation and transmis- sion is independent of the specific constitution of the particular protoplasm concerned and also independent of the nature of the exciting external factor. Viewed as a whole, the condition which we call excitation, however brought about, appears to be essentially an increase in the rate of living, or at least in the fundamental energy- liberating processes concerned in the life of any particular protoplasm, and transmission consists in the spread or passage of excitation from one region to another, cer- tain dynamic changes in an excited region being the exciting factor for adjoining regions. The excitation- transmission relation is then an energetic, nonspecific

or quantitative relation in a protoplasm, and it may therefore be regarded as the most generalized or most primitive organismic relation. This fact is, I believe, of fundamental, though not generally recognized, signifi- cance for physiology, and particularly in relation to the problem of organismic pattern. This consideration of organismic pattern has estab- lished certain points. First, organismic pattern is of a higher order of magnitude than protoplasmic pattern and involves the differential action, differentiation, and relation of regions or masses of protoplasm or cells. Second, although in every case a particular protoplasm with its specific constitution and pattern constitutes the substratum upon which organismic pattern arises and develops, there is no evidence that the protoplasmic mechanism is able autonomously, i.e., without the aid of environmental factors, to give rise in the first instance to organismic pattern. Third, organismic pattern, whether mechanical, chemical and transportative, or excitatory and transmissive, may arise, at least tempora- rily, through the action of external factors upon a proto- plasm. Fourth, the excitation-transmission relation being essentially quantitative and nonspecific appears to be the most generalized and most primitive factor in organismic pattern.

Apparently there is no escape from the conclusion that organismic pattern is not inherent in protoplasm, but arises in the final analysis from the relation of protoplasm to external factors, and it seems also to be true that the excitation-transmission relation is the most generalized and most primitive component in organismic pattern. The conclusion that organismic pattern arises in the final analysis through the relation between protoplasm and environment does not of course exclude the possibility that such pattern once estab- lished may persist through processes of reproduction, i.e., may be inherited.

Before accepting this conclusion, however, it is necessary to examine briefly certain aspects of the problem of pattern which have not yet been considered. Except perhaps in the simplest organisms, protoplasm exists in the form of cells with differentiation into nucleus and cytoplasm, the nucleus being commonly regarded as the fundamental portion of the cell. The cell itself represents an organismic pattern and is primarily an organism, though it may undergo integra- tion with other cells into the pattern of the multicellular organism. While there is every reason to believe that the factors concerned in the origin of cell pattern are essentially the same as those concerned in the origin of other organismic patterns, we may for the moment accept cell pattern as given and inquire whether the pattern of multicellular organisms is inherent in the cells. The investigations of recent years in the fields of genetics and cytology have led to the postulation of definite chromosome patterns differing for different chromosomes, and many biologists believe that the totality of chromosome patterns in the nucleus of the germ cells of a species represents in some way, and con- stitutes the basis of, the organismic pattern which appears in the development of the individual.

Cytological investigation, however, has established beyond question the fact that every cell of the indi- vidual body possesses normally the full complement of chromosomes, and therefore, supposedly, the complete nuclear pattern of the fertilized egg. Nevertheless different cells of the body become different and differ- ent kinds of organismic correlation arise between them. Boveri recognized this fact years ago and admitted that local conditions rather than the nuclear pattern must be responsible as activating factors for the origin of these differences between the cells, but many biologists have either not discussed the question or have failed to recognize the fact that if all the cells are originally alike they cannot of themselves become different. Loeb, in his book The Organism as a Whole, evades the entire problem with the statement that " the egg is the embryo in the rough" and makes no attempt to show how the egg has attained this condition, and Morgan in his recent discussion of the organism as a whole (Morgan,1 1919, pp. 241-46) fails completely to account for the fact that cells, which are originally alike as regards nuclear pattern, become different in a definite and orderly way, and is very evidently helpless before the problem of the organism as a whole. Moreover, even if we maintain that a cytoplasmic pattern is determined in the egg by the nuclear or chromosomal pattern and that the pattern of the multicellular organism results from the distribution of the components of the cyto- plasmic pattern of the egg among different cells in development, we have attained no solution but merely a formulation of the problem of organismic pattern in the purely preformistic terms of nuclear pattern, and the problem of nuclear pattern remains. But there is

still another difficulty involved in this conception. If nuclear pattern is the fundamental factor in determin- ing cytoplasmic pattern, and if the cytoplasmic pattern of the egg represents the pattern determined in this way, as this conception apparently assumes, we should expect each cell which arises with a full complement of chromosomes from the egg gradually to approach the cytoplasmic pattern of the egg, even though different cells originally received different components of the egg pattern. In other words, since they all possess the same nuclear pattern the different cells should tend to become more and more alike instead of more and more different. But since they do become more and more different it is necessary to assume either that cytoplasmic pattern once established may continue to exist independently of, or in spite of nuclear pattern, or else that such cytoplasmic pattern may influence and alter nuclear pattern, and either of these assumptions amounts to an abandonment of the original hypothesis of nuclear pattern as the determining factor. In short, it is evident that even when we start with the cell conceived in terms of the theories of nuclear pattern, something more, viz., the action of an external factor, is necessary to account for the pattern of the multicellular organism.

We may then not only reaffirm the conclusion that so far as the evidence goes, organismic pattern does not appear to be inherent in protoplasm, but we may go a step farther and maintain that the pattern of multicel- lular organisms cannot be inherent in nuclear pattern. Assuming that this conclusion is correct, organismic pattern must originate in the first instance in the relations between protoplasm and its environment, or else it must be dependent upon a non-mechanistic principle, as the vitalists maintain.

Leaving out of consideration the purely contactual or mechanical relation as obviously not of fundamental importance in this connection, there remain two chief categories of relation between protoplasm and its environment, the material or chemical and the dynamic or excitatory. These two types of relation appear in all organisms, the one being concerned with nutrition, respiration, excretion, i.e., the material exchange in general, the other with behavior in the broad sense. I have pointed out that the excitation-transmission rela- tion is apparently the most generalized and most primitive factor in organismic pattern (p, 17). Lest this statement be misunderstood it may be pointed out that it does not mean that in the relations between protoplasm and the environment excitation is any more primitive or fundamental than the material relation. Material exchange between protoplasm and environ- ment is of course necessary for the continuance of life in protoplasm, and there can be no doubt that in nature material exchange and excitation are closely associated. I would merely maintain that the excitation- transmission relation, whether it arises in connection with material exchange or through a purely dynamic action of external factors is a more generalized and more primitive factor in the organismic pattern arising on the protoplasmic substratum. Material exchange is primarily a matter of protoplasmic pattern and not necessarily organismic, but the excitation-transmission relation is always

organismic when it exists. Moreover, it is not primarily the material exchange between protoplasm and environ- ment, but the ordering and controlling of this change in definite ways which constitute the fundamental charac- teristic of organismic pattern. In short, however it may arise, organismic pattern is not simply the pattern of the material exchange between protoplasm and environment but rather a definite behavior pattern of different regions, cells, or cell groups. The fundamental factor in determining protoplasmic behavior of organis- mic character is the nonspecific, quantitative factor of excitation, and with excitation transmission is associated. In view of all the facts, then, the logical procedure in attacking the problem of the origin of organismic pattern is to determine whether, or to what extent, excitation and transmission are actually concerned in determining this pattern. And since the data of both ontogeny and phylogeny indicate that organismic pattern once estab- lished undergoes progressive complication, it is evident that we must first of all attempt to discover the simplest terms in which organismic pattern appears in nature. The following chapter is devoted to a consideration of this question.

The cell is primarily an organism, though it may be integrated with other cells to form a part of a multicel- lular organism. While we have no positive knowledge concerning the origin of cell pattern, the structure of the cell in general suggests that it is primarily what we may call a surface-interior pattern. If this is true, the differentiation of nucleus and cytoplasm from the primi- tive protoplasm, possessing in some degree the functions of both, must have resulted in the first instance from differences and relations between exterior and interior. Some organisms appear to be even simpler in pattern than the ordinary cell, but most of them are so minute and show so little differentiation of parts that our knowledge of their pattern is very fragmentary. Even in the simplest organisms, however, we should expect to find at least a surface-interior pattern. In the absence of any positive data, further discussion of the origin of cell pattern and of still simpler patterns is of value only in the light of what we can learn concerning other organismic patterns and is therefore postponed (see p. 60) .

The surface-interior pattern is primarily a com- pletely radial, spherically symmetrical or centered pattern and, assuming that organismic pattern arises through relation between protoplasm and environment, it represents such relation in its most general and primitive form. While some cells and some still simpler organisms may possess this pattern alone, it is certain that most organisms, including all multicellular forms, at least many unicellular forms and probably some of those simpler than cells, possess not only a surface- interior pattern but also an axiate or polar pattern and primarily either a radial or bilateral symmetry with asymmetric modifications in various cases. Both the course of organismic evolution from very early stages as well as the development of the individual are based upon this axiate pattern. I have already pointed out (see p. 8) that the general similarities of organismic pattern in different protoplasms suggest that such pattern is, at least as regards its fundamental features, in large measure independent of the differences in the specific constitution of different protoplasms and therefore essentially quantitative, i.e., it apparently represents a primarily quantitative relation in a specific protoplasm. It now becomes necessary to examine the data of observation and experiment with reference to the question of the nature of the axiate pattern.

Many different lines of evidence agree in indicating that axiate pattern in its simplest form is essentially quantitative in character and consists in graded differ- ences in the rate of the fundamental dynamic activities of protoplasm and in the conditions associated with these activities. These graded differences in physio- logical state have been called axial gradients because, so far as the evidence goes, they are the primary indi- cations of the existence of an axiate pattern (Child, They have also been called metabolic gra-

dients, not because it is assumed that they are purely or primarily metabolic in character, but because our knowledge of protoplasm in general indicates that metabolism, and more specifically oxidation, is a funda- mental factor in life and the chief source of the energy of living organisms and because the data of observation and experiment indicate that differences in the rate of metabolism and particularly of oxidation are character- istic features of these gradients. Protoplasm is a system in which the chemical reactions of metabolism are so intimately associated with other factors, e.g., colloid dispersion, active mass of enzymes, permeability of limiting surfaces, electrolyte, and water content, etc., that to attempt to distinguish one particular factor rather than another as primary is at present impossible. The axial gradients are not simply oxidative or meta- bolic gradients but gradients in the general physiological state of the particular protoplasm concerned, and in this physiological state oxidation and associated with it other metabolic reactions are important factors. The term " metabolic gradient" as used in this connection means only that the metabolic factor is a characteristic feature of the gradients. The term "physiological gradient," which avoids all specific implications, might be substituted for it.

In the development and differentiation of the axiate pattern the apical region or head of the organism arises from the region of greatest activity or highest metabolic or oxidative rate, the "high end" of the major or polar gradient, and other organs at different levels of the gradient. The simplest forms of radial symmetry in axiate organisms in which there is no differentiation between different radii are in reality nothing more than apico-basal or polar pattern, together with a surface- interior pattern. In the more complex forms of radial symmetry a number of radial axes or gradients arise, and the radially arranged parts differentiate in relation to these. In bilateral patterns there is not only a gradient along the longitudinal or polar axis, but bilateral gradients are also present. In at least most bilateral invertebrates the high region of these bilateral gradients is apparently represented by the median ven- tral region and in the vertebrates by the median dorsal region. The evidence indicates that the chief axial gradients appear primarily in the superficial regions of the cell or multicellular body. In many of the simpler organisms, e.g., many Protozoa (Child, 19146) and plant cells, they are present throughout life only or chiefly in the superficial regions, but where definite localized internal organs with an axiate pattern exist these also show axial gradients in all cases examined, though these organ gradients do not necessarily coincide in direction with the primary gradients. As was pointed out nearly five years ago (Child, 1915^, pp. 54, 60) the primary gradient or gradients may persist throughout life, but do not necessarily do so. They may undergo modifica- tion and complication in various ways during the course of development: the originally quantitative relations may become qualitative, new gradients may arise in certain parts or organs, in some cases pre-existing gradients may be broken up, obliterated, or reversed, one kind of axiate pattern may be replaced by another, and so on. In all cases, however, the sequence of events is definite and orderly, and many features of it can

already be interpreted in physiological terms, and usually the pattern even in the fully developed organism shows a very definite relation to the primary gradients. The evidence for the existence of metabolic or physiological axial gradients is varied and extensive and only a brief summary is possible here. The evi- dence, as it stood five years ago, was briefly discussed in the book Individuality in Organisms, but since that book was written other methods of investigation have been developed and many new data obtained, so that a review of the subject is necessary at this time.

First of all many eggs and embryos show an apico- basal gradient in protoplasmic structure and content, e.g., the gradient in yolk accumulation in many animal eggs and embryos, and the gradient in protoplasmic density and vacuolation in many plant embryos, and in the vegetative axes of many of the simpler plants. A gradient in the rate of cell division, growth, and differ- entiation in relation first of all to the primary of apico- basal axis, later in relation to other axes, is a very general feature of at least the earlier stages of develop- ment. This gradient appears first in the rate of cell division and size of cells along the apico-basal axis in a large proportion of both animal and plant eggs and in many plant axes, as a gradient in rate of division and cell size from the growing tip basipetally. It also appears in the progress of morphogenesis and differen- tiation along the axes, particularly in animals, although in plants, except for the fact that the growing tip itself remains embryonic, the course of differentiation is also

in general basipetal. Moreover, in bilateral animals and plants a similar bilateral developmental gradient appears more or less clearly. In at least most bilateral invertebrates differentiation of the body wall and its organs progresses from the median ventral region laterally and dorsally and in vertebrates from the median dorsal region laterally and ventrally as a moment's examination of the chick embryo shows. The so-called law "of anteroposterior development is merely a recognition of the existence of this develop- mental gradient in the longitudinal axis and it is, more- over, only a partial statement of what might be called the law of axiate development. We also find evidences of the existence of a polar axial gradient in the rate of regulatory development, the positions and proportions of organs in isolated pieces from different levels of the body in various forms (Child, 19076, c, ignb; Hyman,

The existence of these gradients is perhaps most readily demonstrated through the susceptibility of organisms to the action of various external agents. It has been determined experimentally for many species 1 Figures of these structural and developmental gradients are given in Individuality in Organisms. Figures showing gradients in cell size, rate of division, and in some cases in protoplasmic structure are as follows: cleavage stages of the frog's egg, Figs. 10, u; early develop- mental stages of plants, Figs. 18, 19; growing tips and axes of plants, Figs. 20-36; adventitious buds in plants, Figs. 37-39. In chaps, iv and v of the Individuality some of the evidence for the existence of the gradients from regulatory development and its experimental modifica- tions is given. See also Figs. 13-17, of flat worm and chick on pp. 109 and in below.

of animals, including all the chief phyla and many of the smaller groups and nearly a hundred species of algae among plants, that axial gradients in susceptibility to the action of at least a wide range of external agents exist. The agents used in these experiments include cyanides, many anesthetics, such as alcohol, ether, chloroform, chloretone, some of the urethanes, etc., carbon dioxide, various acids, alkalies, neutral salts, certain alkaloids, vital dyes and physical conditions, such as extremes of temperature and the negative factor lack of oxygen.1 Potassium cyanide has been much used in these experiments first because very low con- centrations are effective and second because it has been found by a large number of investigators to be a power- ful inhibitor of protoplasmic oxidation and susceptibility to cyanide may therefore be regarded as to some extent a comparative measure or indicator of rate of oxidation in the parts, organs, or individuals or a particular species.2

2 There has been much discussion concerning the nature of the action of cyanides on living protoplasm. Some authors have believed that they act essentially as reducing agents and so retard or prevent the metabolic oxidations. Others hold that they inactivate oxidizing enzymes and still others that their action is primarily on the state of the colloids. The literature of the subject has recently been discussed Comparison of the data on susceptibility with data obtained by other methods has shown that a general nonspecific relation between susceptibility and physio- logical condition exists, at least in the simple organisms and early developmental stages, where the differentia- tion of organs is not so far advanced that a more or less specific action of particular agents or particular organs is involved. This relation is as follows: to a certain range of concentrations or intensities of the agents used, which is experimentally determined to be above the limit of acclimation or tolerance for the particular species examined, susceptibility varies directly with, though not necessarily proportionally to, the general physiological activity of the protoplasm. To a certain

by Hyman (1919). Notwithstanding the differences of opinion con- cerning the way in which the effects are produced, and it is not improb- able that all the views are correct, practically all investigators agree that cyanides decrease intracellular respiration to a marked extent, except in very low concentrations, which may produce some accelera- tion. As regards Planaria, for example, Allen (1919) and Hyman (1919) have shown that KNC decreases oxygen consumption 80-90 per cent and that this decrease is reversible. I have found that it also decreases CO2 production and its action is to some extent additive to that of lack of oxygen (Child, I9i9c). Lund (1918) has reported that KNC does not decrease oxygen consumption in Paramecium, but his data are not conclusive, because the concentrations used by him are highly alkaline and produce extreme stimulation and intense motor activity, often continuing for hours, before the inhibiting action of the cyanide appears. Since he failed to reduce the alkalinity to a point approximately that of the normal environment of Paramecium, at which the solutions produce no stimulation, the total oxygen con- sumption observed by him does not represent the action of the cyanide alone, but includes the stimulating effect of the alkali. There is then at present no reason to alter the conclusion that susceptibility to cya- nides is to some extent a measure of physiological condition, so far as intracellular respiration is concerned,