Protoplasmic Action and Nervous Action

SCIENCE SERIES, established by the Trustees of the University, owes its origin to a belief that there should be a medium of publication occupying a position between the technical journals with their short articles and the elaborate treatises which attempt to cover several or all aspects of a wide field. The volumes of the series will differ from the discussions generally appearing in technical journals In that they will present the complete results of an experiment or series of investigations which previously have appeared only In scattered articles, If published at all. On the other hand, they will differ from detailed treatises by confining themselves to specific problems of current Interest, and In presenting the subject In as summary a manner and with as little technical detail as Is consistent with sound method. They will be written not only for the specialist but for the educated layman.

Biologist, Nela Research Laboratories, Cleveland; formerly Professor of Biology, Clark University What am I, Life ? a thing of watery salt. Held in cohesion by unresting cells . . . . ? The present volume is based in part on lectures delivered in Clark University and the Marine Biological Laboratory, on the physico-chemical basis of the more general or fundamental properties of living matter. Common to all forms of living matter are certain properties or modes of action which are absent or imperfectly developed in non-living matter. The chief of these are (i) the property of specific growth, and (2) a unification or integration of activities, of such a kind as to secure the continued existence of the living system in its environment. The question of how the living system must be constituted (in the physico-chemical sense) in order to exhibit such properties is the fundamental one for physiology.

Of late years the analytical investigation of the living organism and its products has made great advances; on the synthetic side, however, progress has been relatively shght. The precise manner in which certain special physico-chemical materials and processes are combined so as to produce life still remains largely obscure. It may be expected that properly directed experiment will throw light on this problem, as it has on many others apparently equally difficult, but at present we are at a stage where exact or scientific knowledge is only in its beginning.

In this book I have made no attempt to consider in detail the many special problems of pure physics and chemistry which are presented by the organism. It is assumed that these problems are of the same kind, and to be approached by the same methods, as other problems of physics and chemistry. This point of view seems the only one possible for the scientific investigator. The organism exhibits a regularity which, although of a special kind, is obviously based upon and presupposes the regularity of its component physico-chemical processes. Investigation of the latter requires the use of the exact methods developed by modern analysis; and these have been shown to yield the same constant and reproducible results in organisms as in non-living systems. In fact, one of the most striking features of organic processes is their exactitude, which is frequently safeguarded by regulatory devices of the utmost delicacy. The investigation of many such processes is purely physico-chemical in its method and results.

It must be remembered, however, that in living organisms we are dealing with synthetic products of a higher order. When the materials and energies of the surrounding world unite to constitute the organism, new qualities and modes of activity inevitably come into existence; these special properties of living beings form the subject-matter of the biological sciences, as distinguished from the physical sciences. For this reason the physical and chemical characterization of the constituents, reactions, and processes whose combination or synthesis produces life is not in itself sufficient; the biological interest centers in the conditions and special mode of this combination, and in the nature of the resulting unity. The problem of the nature of vital organization remains the fundamental one for biology.

We may safely assume that all qualitative phenomena, including those of the living organism, are subject to quantitative laws; but the determination of these laws, while an essential object of scientific investigation, cannot be regarded as its only object. The biologist is primarily interested in the phenomena which are peculiar to life and in the conditions under which these originate and manifest themselves. As already indicated, growth, development, and an integrative correlation of activities are the chief distinguishing characters of organisms. Underlying and determining these properties are the fundamental or universal properties of protoplasm. The essential problem in the physiology of growth (and ultimately of development and heredity) is the problem of the conditions of specific chemical synthesis in protoplasm. And the problem of integration resolves itself largely into the problem of the conditions under which protoplasmic processes, although spatially separated, mutually influence one another; i.e., the problem of transmission. For the solution of these problems we require first of all a knowledge of the special conditions under which the chemical reactions in protoplasm proceed and influence one another.

The general physical conditions under which chemical reactions are initiated, accelerated or retarded, and influence other reactions at a distance are undoubtedly the same in living as in non-living matter; but the special features of composition and arrangement in the protoplasmic system often render detafled analysis difi&cult. Under these circumstances the study of "models" — simple artificial systems in which the action of single factors may be isolated and observed — may be of great

service, and I have made use of this method in a number of instances. For example, the transmission of the effects of stimulation in nerve and other irritable forms of protoplasm resembles closely certain types of chemical transmission or distance-action in metal-electrolyte combinations; many biocatalytic reactions are identical with those induced by colloidal platinum or charcoal; there are also instructive analogies between organic growth and certain types of inorganic growth. Many fundamental physical processes which play an important part in protoplasm are independent of the special chemical composition of the material; thus the influence of radiation and electricity on living matter is a special case of the general influence which these agents exercise under appropriate conditions upon all chemical reactions. The detailed nature of the conditions in protoplasm can be determined only by special investigation.

The more special sections of this book have reference to the two fundamental problems above defined. The structural and physico-chemical organization of living matter, the modifiability of its rate of reaction under varying conditions (irritability), and its transmissive property (so highly developed in nervous tissues) are considered in some detail; and their probable relation to the polyphasic and film-partitioned character of the protoplasmic system is indicated.

I. Introduction — General Characteristics of Living Matter i IV. General Peculiarities of Protoplasm as a Physical System 48 V. Physical Nature of Protoplasmic Structure: Im- portance of Surface Conditions 66 VI. Protoplasmic Structure {Continued): Permeability and Other Properties of Protoplasmic Membranes 98 X. Catalysis in Relation to the Chemical Processes in Living Matter 217 It is a peculiarity of living matter, as distinguished from non-living matter, that it is never found in a diffuse, unorganized, or formless state, but always composing definite individualized systems or organisms, of which there are many kinds or species, each with definite and, on the whole, highly constant physicochemical, structural, and active characters. These organisms form a class of natural systems which, considered quantitatively, is a very small one in comparison with physical nature as a whole. This fact in itself implies that living systems are highly special developments; they represent a higher order of synthesis, and it is to be expected that they should exhibit properties and activities which are absent in non-living systems. Hence the existence of a sharp contrast between the living and the non-living — i.e., between organism and environment — is not in itself surprising. We know, however, that continuous transitions from the one to the other have existed and stilL exist; life has evolved from non-living matter in the past; and in the present every living organism is the seat of a continual transformation of non-living into living matter. The chief problem of general physiology is to trace the steps of this transition; i.e., to determine the nature of the synthesis by which the living matter, protoplasm, is

built up from the non-living material which it incorporates from the surroundings. Physiology regards the living organism solely in its objective aspect as a physical object in external nature; many aspects and manifestations of living beings do not form directly a part of its subject-matter, and the general philosophical question of the essential significance of life in the cosmos — the question of vitalism or antivitalism — is not one which it makes any pretensions to answer. It observes simply that certain systems, living organisms, exist in the external world, presenting a remarkable combination of properties not found in other natural systems; and its task is the analysis of these systems in the terms and by the methods of physical science.

These special or distinguishing peculiarities of living organisms may be grouped under several general heads, as follows: (i) metabolism, (2) growth, automatic selfmaintenance, reproduction and heredity, (3) irritability, (4) regulation and adaptation, (5) spontaneous activity, having reference to future as well as present conditions. The essential character and implications of these various properties will first be briefly considered. The essential peculiarity which places organisms in a class apart from most non-living objects is that their properties and manifestations depend on their continued chemical activity; in other words, they are metabolizing systems, formed, maintained, and perpetuated by processes of chemical transformation. The production of new chemical compounds by transformation of other compounds taken from the surroundings, and the

organization of these compounds in new structural and chemical relationships, constitute the fundamental activities of all living matter. Hence a consideration of the general features of metabolic processes must come first in any discussion of the nature of protoplasmic action. Under the term metabolism are included primarily the nutritive and energy-yielding chemical processes in protoplasm, and secondarily the other chemical processes subserving or underlying these. The application of the term is usually clear; but metabolic processes comprise chemical reactions of all kinds, many of which are in no sense peculiar to organisms, while others are not met with elsewhere in nature. The traditional distinction between constructive and destructive metabolism remains an essential one; what the organism is at any time is a resultant of the effects of these two large and, in general, oppositely directed groups of chemical reactions. Broadly speaking, the constructive reactions represent the nutritive processes, and the destructive reactions the energy-yielding processes. Constructive metabolism includes the synthetic (anabolic) reactions underlying growth, self-maintenance, and reproduction. In any species the end-products of the constructive sequence of reactions consist largely of certain colloidal compounds, highly individualized and specific in their chemical constitution, the proteins; the other synthetic products (carbohydrates, fats, lipoids, etc.) are chemically nonspecific; i.e., not confined to the species in question; these form, together with the specific compounds, water and various dissolved substances, a complex and highly organized system, or organic individual, which is specific

(i.e., definitely characterized and unique) in its structural and active characters. This building-up, by means of metabolic construction, of a complex system, specific in chemical composition, structure, and activity, out of relatively simple non-specific materials taken from the surroundings (food, water, salts) is the fundamental general peculiarity which distinguishes living organisms from non-living systems. Constantly associated with the constructive group of reactions is the destructive or catabolic group by which substances contained in the protoplasm are broken down, usually oxidized, to yield the energy freed in vital activity. A great diversity of compounds are thus utilized by protoplasm as sources of energy; the catabolic process is non-specific; i.e., sugars, fats, and proteins are metabolized to yield the same endproducts (CO2, water, urea, etc.) and energy in organisms of all kinds.

It is essential at the beginning of any study of fundamental vital properties to recognize the dependence of the various phenomena designated by the four terms above upon the fundamental process of specific constructive metabolism. In every organic individual normal self-maintenance, by which the material lost as a result of metabolic destruction is replaced by new construction, involves the same specific synthetic reactions as those concerned in growth. And growth is obviously a highly specific process; this becomes evident whenever a seed or an egg ''grows into" the specifically organized adult. Organic growth thus involves or implies ''hered-

ity"; and since growth is the foundational life-process — that by which all living matter is brought into existence — we see at once that the specificity of the underlying metabolic syntheses is the essential condition underlying organic specificity. When constructive metabolism ceases, not only does growth cease but life itself, since the continual formation of specific material is a prerequisite for normal maintenance. Each of the terms above, however, designates a feature or aspect of vital phenomena which is as a rule perfectly definite and distinguishable from the others. Organic growth is perhaps best defined as increase in the quantity of the specifically organized living material.^ Reproduction is the formation of new individuals by growth from the parent organism, or a detached portion of the latter (germ, gamete); in metazoa the replacement of outworn or senescent individuals is thus accomplished. Reproduction has been defined as ''discontinuous growth"; thus the growth of a plant-cutting is a reproduction, and many cases of asexual reproduction in animals illustrate the same phenomenon (reproduction by fission, regeneration). In the lowest organisms, e.g., bacteria, it becomes no longer a matter of practical interest to distinguish between growth and reproduction. Heredity, the resemblance of offspring or outgrowth to parent stock, is illustrated in all of these cases; the special problem of heredity, therefore, is reducible ultimately to the fundamental problem of the conditions determining the property of specific construction possessed by all forms

^ Cf. the discussion by Child, Senescence and Rejuvenescence, Chicago (1915), chap. ii. of protoplasm/ This consideration is overlooked in many '' theories of heredity/' which apparently take for granted the existence of the property which they are called upon to explain. Ids, pangenes, chromosomes, and the other representative particles of these theories are self-multiplying units; i.e., they possess ex hypothesi this automatic power of synthesizing material and structure of their own kind. It is well, therefore, to realize clearly the fundamental identity of the physiological conditions underlying all of the phenomena grouped under the foregoing head.

To prevent any possible misunderstanding, a few words may be added here concerning the nature of the physiological problems raised by the chromosome theory of heredity, which now seems to be established on a secure basis through the correlation of genetic and cytological investigation.^ All the evidence indicates that the chromosomes, the carriers of genetic factors or "genes," are the elements or units in a sorting and distributing mechanism, by means of which special formative metabolic processes are localized in definite regions of the growing and

^ Haldane's remarks in his British Association address of 1908 {Nature, LXXVIII, 555), "nutrition itself is only a constant process of reproduction" and "heredity is for biology an axiom and not a problem," do not dispose of the problem of heredity, but apparently assign it to a border-line position, somewhere between chemistry and biology. The property of automatic specific synthesis is the one to be explained. The original natural systems which exhibited this property were presumably the ones from which living organisms, as we find them, have evolved.

developing organism. The property of self-multiplication possessed by these units, on which the possibility of their special action depends, is, however, not peculiar to them, as already pointed out, but is a property of protoplasm and of protoplasmic structures in general.^ Once the chromosomes have been produced by this autosynthetic process, they are free to exercise their special influence and function. In this respect they are like other structures which are definite factors in the formative processes; they must first be synthesized by the fundamental growth processes before they can function. There are obvious analogies between the action of the chromosomes and the action of special form-determining chemical substances (or hormones) produced by various organs. Development at certain stages is demonstrably a consequence, as regards certain special features, of the previous development of the thyroid or the pituitary gland or the gonads. An even more general analogy may be pointed out here, since it illustrates the nature of many biological sequences. A prerequisite to the normal activity of the adult is the development of the normal adult structure; for example, the formation of hands must precede the construction of a house, but we do not explain the whole constructive process by reference to the hands, the tools for sorting and distributing the materials. How the chromosomes influence formative metabolism is the essential problem for physiology; this problem is at present unsolved, but there can be no doubt as to the existence of this influence.

^H. J. Muller has discussed the properties of the genes from this point of view in a recent paper in American Naturalist, LVI (1922), 32. It is characteristic of all organisms that they respond to changes in their environment (stimuli) by changes in their own activity (response). And since metabolic reactions underlie all vital activity, this fact implies that the chemical reactions constituting metabolism are subject to the influence of external agencies acting upon the protoplasm. Both constructive and destructive metabolism may be thus influenced.

In general, what we mean by irritability is this susceptibility to external influence; irritability, howxver, cannot be considered as a special property independent of the continual automatic, chemical, and other activity of the living system; its existence merely shows that the chemical reactions of protoplasm are subject to modification — e.g., acceleration or the reverse — under the influence of relatively slight changes of state, caused usually by the action of external agencies upon the protoplasm.

A peculiarity of most intact organisms is that the changes of activity thus induced are normally of such a character as to favor the continued existence of the individual or of the species in the environment; this general fact may be expressed by saying that the normal responses to stimulation, however varied in detail, have a regulative or adaptive character. Adaptiveness, however, is a peculiarity of the organism as a whole, not an inherent property of protoplasm in general; this is shown by the fact that isolated parts may show irritability quite independently of any adaptive reference; e.g., nerve or muscle. In this respect irritabihty may be compared with the chemical instability of explosives, which may also be applied adaptively.

These characters, while based on irritabihty, have a more distinctively organic or vital quality — are manifestations of a higher plane of organization — than the simple property of responsiveness to stimuli. Fundamentally they are related to the characteristic self-conserving property of the organic individual or species; this property is exhibited by all naturally occurring organisms; i.e., the structure and activity of the latter are of such a kind as to favor a permanent or stable existence in the environment. Under the terms regulation and adaptation, we include, in their broadest appHcation, all of those features of adjustment — structural, chemical, and active — which are especially characteristic of living as distinguished from non-living systems. The organism is "fitted" to its environment; the reciprocal relations between the two are so balanced or correlated that the species persists. In other words, the properties or activities which have special "survival value" are those which we designate as adaptive. Adaptations may be (i) of a static or morphological kind — non-temporal in their reference — e.g., when the structure of the organism shows a correspondence with the unchanging features of its environment. Perhaps the most general and widespread example of such static adaptation is seen in the general plan of bodily structure common to most freeliving animals — bilateral symmetry combined with antero-posterior and dorso-ventral differentiation.^ Or

^I have discussed more fully the general conditions that render this type of structural plan adaptive in a paper on purposive and adaptive behavior in the Journal of Philosophy, Psychology and Scientific Methods, XII (1915), 589. they may be of an active kind; such are classed as regulations. In this case the activity of the organism or of its parts changes in such a way as to resist or compensate departure from the normal; i.e., from the physiological or other conditions required for continued life. The automatic regulation of food-intake, gaseous exchange or temperature, the protective and other self-conserving reactions or instincts, and the phenomena of form-regulation are examples. Since in all such cases the persistence of the organism in the environment is the condition promoted or secured, and since persistence in external nature implies equilibrium, we may characterize regulations as reactions of an equilibrating type; i.e., regulation corresponds essentially to equilibration. In a sense it is obvious that the structure and activities of an organic species must be such as to secure persistence in the environment, since the alternative is extinction; nevertheless the universal presence of regulative modes of activity is a peculiar and highly remarkable feature of living as distinguished from non-Hving systems, and requires special consideration. Regulations or automatic equilibrations are also met with in many non-living systems (regulators in machines or other artificial systems), but for the most part these are of a relatively simple type.

The conception of organic integration is closely related to that of regulation; the maintenance of a definite and unified structure and activity in any complex system consisting of many parts requires the mutual interaction and control of the different parts in such a manner that the activity of each is subordinated to that of the whole. This integration presupposes the transmission of chemical and other influence between different regions, and in higher organisms is effected chiefly through the nervous system in co-operation with a chemical control exercised by special substances (hormones and other metabolic products) transported from place to place in the circulation/ The possibility of these two forms of integration rests ultimately on mechanical or structural factors, shown in the permanence of morphological form and organization; hence some authors speak of a mechanical integration (or correlation) in addition to the other two.^

The chief vital phenomena classed under this head are characteristic of the organism in its action as a whole, rather than of its special parts, although many of these are spontaneously active; e.g., the heart. They are especially developed in animals, and include spontaneous activity and trains of activity (instincts) directed toward the external world and having usually some definite future reference; purposive and conscious action, in their physiological aspect, also belong here. All such characters are based upon, or presuppose, the other more fundamental characters; i.e., they are not general protoplasmic properties but appear at a higher level of vital synthesis; hence they do not form, strictly speaking, a part of our present subjectmatter.

^ Cf. Sherrington's Integrative Action of the Nervous System. ^ Cf . Child, The Origin and Development of the Nervous System from a Physiological Viewpoint, University of Chicago Press (1921), chap, i, p. 12. The first four groups of characters appear to be common to all forms of living matter; i.e., they are the expressions of the general or fundamental properties and activities of the living substance or protoplasm wherever found. We class as ''living" all natural systems exhibiting these properties in combination; and general physiology has for its object the study of the essential composition and activities of such systems.

From this point of view the distinction between animals and plants becomes one of minor importance. This difference is essentially one of method of nutrition; in plants the processes of constructive metabolism start with more elementary and widely diffused materials than in animals. A brief reference to the main points of distinction seems relevant here, since it may assist in defining the essential problem under consideration. It is evident that all organisms require for their normal growth and activities the presence of energyyielding (chiefly oxidizable) materials in the protoplasm, as well as materials for building up protoplasmic structure; the chief representatives of these two classes of substances are, respectively, the carbohydrates and the amino-acids. The main differences between plants and animals relate to the methods by which these materials are obtained or rendered available. In green plants they are synthesized from simpler compounds which in their unaltered state cannot serve as sources of energy — CO2, salts, water. In animals the chief ''food " materials are already complex compounds of high chemical potential which are not synthesized in the organism but are prepared outside of the latter (ultimately by

plants), and are introduced into the organism from without by its own special activities. In both groups, however, the active living substance or protoplasm consists chiefly of compounds of the same general chemical type, which in both cases undergo similar transformations. The fundamental physiological processes of plant and animal cells are thus closely similar. Hence, in general physiology, whose aim is the analysis of the vital process, wherever occurring, organisms of both groups come equally under consideration.