Principles of General Physiology

PROFESSOR OF GENERAL PHYSIOLOGY IN UNIVERSITY COLLEGE, LONDON IN the preparation of courses of lectures dealing with various physiological processes I have found considerable difficulty, and spent much time, in the extraction from books and original papers, many of them not biological, of * material of fundamental importance in the proper treatment of the subject. The mechanism of reactions in heterogeneous systems may be mentioned. It seemed to me, therefore, that the results of this labour might be of use to others, whose work does not allow them sufficient time to read articles which do not appear to bear upon their particular domain of science. In arranging these facts, however, it became manifest that a somewhat wider treatment would be of more value, so that the book might be of service to all desiring a general, elementary, treatment of what may be called " abstract " physiology, as distinct from the "applied" physiology required by the agricultural, medical, or veterinary student for the purpose of his profession. In extenuation of my conduct in producing a work on physiology for the use, as I venture to hope, of all those who have any interest in science, I should like to quote a few words by Huxley to be found in his address, " On the Educational Value of the Natural History Sciences " (Huxley, 1902-1903, p. 59 — see Bibliography). He gives an answer to the question, " What is the range and position of . Physiological Science as a branch of knowledge, and what is its value as a means of mental discipline ? " as follows: "Its subject-matter is a large moiety of the universe — its position is midway between the physico - chemical and the social sciences.

Its value as a branch of discipline is partly that which it has in common with all sciences — the training and strengthening of common sense ; partly that which is more peculiar to itself — the great exercise which it affords to the faculties of observation and comparison ; and, I may add, the exactness of knowledge which it requires on the part of those among its votaries who desire to extend its boundaries." One would like to add also, the great experimental skill demanded, owing to the complexity of the phenomena studied.

The name of "general" physiology, which I have chosen as my title, corresponds very closely with what my honoured teacher, Burdon-Sanderson, used to speak of as " elementary " physiology, defining it as " the study of the endowments of living material," from which he expected the greatest advances of the future to proceed (Burdon-Sanderson, 1911, p. 217). This is practically the same view as that taken by the great Claude Bernard, who was professor of "physiologic generale" in the University of Paris from the foundation of the chair in 1854 until he died in 1878 (see Bernard, 1866, p. 8). In the lectures which he gave he insisted on the fact that

physiology, U-ing the science of life, is to be regarded as an autonomous and independent study; in other words, that it is to be cultivated for its own sake, and not merely for its applications to the practice of medicine. If we look at the subjects with which he dealt, and which were in part published under the name of "Lemons sur les phe'nomenee de la vie c<miniuns aux animaux et aux vegetaux," we obtain some idea of what Bernard understood by general physiology. We find fermentation, nutrition, combustion, protoplasm, irritability and contractility, respiration, and so forth, all treated from a wide and comprehensive point of view.

A notable passage from Sprat's "History of the Royal Society" (17--, p. l'4."i) is of interest in this connection. The book is, it may be remembered, in great part an apology for the existence of a society for the purpose of making experimental "It is stranger that we are not able to inculcate into the minds of many men the necessity of that distinction of my Lord Bacon's, that there ought to be experiments of iiyht, as well as of fruit. It is their usual word, What solid good will come from thence ? They are indeed to be commended for being so severe exactors of goodness. And it were to be wished that they would not only exercise this vigour about i;q» runouts, but on their own fires and actions, that they would still question with themselves, in all that they do ; what solid good will come from thence ? But they are to know that in so large and so various an art as this of c.' [>• rlm> ids, there are many degrees of usefulness: some may serve for real and plain /» /<-/// without much delight : some for teaching without apparent profit, some for light now, and for use hereafter ; some only for ornament and curinalh/. If they will persist in contemning all experiments, except those which bring \\ith them immediate gain and a present harvest, they may as well cavil at the providence of God, that he has not made all the seasons of the year, to be times of moiuing, reaping, and vintage." A particularly striking case of the practical value of pure abstract laboratory work is to be found in the electric waves of Hertz, which were referred to in the first edition of Karl IVaisi.ii '> " Grammar of Science " as of no practical application, but before the second edition appeared, they were used for wireless telegraphy (see Pearson, 1911, p. 30). Again, Tyndall points out (1870, p.

43), in reference to the great practical use now made of Faraday's electrical discoveries, " that if Faraday had allowed his vision to be disturbed by considerations regarding the practical use of his discoveries, those discoveries would never have been made by him." Although most of the problems treated in the present volume are common to tall living organisms, a few are included on account of their importance to a very large number of organisms, notwithstanding the fact that they are not, strictly speaking, of a "general" nature. The fundamental properties of the nervous system may be instanced.

It will be seen that the scope of general physiology is not identical with that of comparative physiology. This latter is sometimes apt to become in great part a description of functions peculiar to certain lower organisms, even when they throw no light on the activities of the human body, which are, after all, the most vitally interesting and important problems presented to the physiologist. Practically all the questions dealt with by general physiology apply both to man and to all living creatures, animal, or plant. In

treatises on comparative physiology, copious details of alimentary or digestive mechanisms will be found, but no discussion of the general nature of the action of enzymes. In speaking of higher and lower organisms, it is well to make it clear that 110 invidious distinction is intended to be made. Both are equally well adapted to their environments. The higher are so called because they are affected by a greater variety of changes in their environment arid respond to these ^iii a more complex manner.

A certain amount of repetition is unavoidable, since the same process has different aspects and, owing to the interaction and interdependence of the phenomena observed in the more highly developed organisms, it is impossible to avoid references in the general treatment to activities which are also described as parts of complex actions in later chapters. The reader who is unable to follow the meaning of the text in places in earlier chapters, owing to reference to matters discussed in detail in later chapters, will usually find in tlje index the pages on which this description occurs, and can make himself familiar with them before proceeding further. A better course would be to read the earlier chapters a second time, after the later pages have been mastered.

An elementary knowledge of physics, chemistry, and biology must be assumed, unless the book is to become altogether unwieldy. It is indeed impossible to insist too strongly on the importance of at least an elementary knowledge of these three basal sciences for every one, much more for those pursuing the study of any branch of science whatsoever. At the same time, it has been thought useful to enter into some detail with respect to conceptions with which the student of physiology frequently finds difficulty, such as catalysis, the tension of gases, and some of the laws of hydrodynamics.

Vital phenomena being essentially dynamic, the study of physiology consists in the investigation of changes. As Jennings (quoted by von Uexkiill, 1909, p. 30) says, " It is of the very greatest importance for the understanding of the behaviour of organisms, to look upon them chiefly as something dynamic — as processes rather than as structures. An animal is something that happens." The velocity of reactions and the conditions affecting it, together with the energy changes involved, are, therefore, more essential than the chemical structure or physical properties of the reacting substances or the resulting products, although the knowledge of certain of these properties is, of course, necessary. To use an illustration, inadequate as it is, that of a petrol motor, the problem of the physiologist is analogous to that of the investigation of the amount of fuel consumed in relation to the work done, when the engine is working under various conditions. The greater number of the chemical and physical properties of the materials used in the construction of the engine are of no importance, such as the valency of the iron or the smell of the lubricating oil, while others are fundamental, such as the heat of combustion of the fuel and the insulation of the ignition circuit. Even the exact chemical nature of the fuel is of subsidiary importance, so long as it is sufficiently volatile, and capable of giving an explosive mixture with oxygen. Moreover, the precise form of many parts, such as the heads of bolts, is immaterial, just as many structural details of living organisms or the precise chemical composition of connective tissue have,

at all events at present, an insignificant physiological interest. In making this statement, it is far from my intention to undervalue in any way the work of the organic chemist or the morphologist. Structure is the indispensable basis of function, and all structures, chemical or morphological, will, IK i doubt, ultimately have their function assigned. But, in these pages, space cannot be spared for description of such as have no functional importance suggested up to the present.

The treatment of the subject in the way here attempted undoubtedly has its difficulties. Important points have most probably escaped reference. I shall be very grateful to readers who will inform me of these omissions, and also for criticism in general. I feel that I may, in some places, perhaps, have laid myself open to the charge of neglecting statements which are in opposition to the }>oint of view adopted. I consider myself justified in certain instances in doing this, on account of the disagreement of these statement* with a large mass of knowledge otherwise obtained, ami in tinbelief that further investigation will explain the apparent contradiction. As Sir Thomas Browne says (1672, vol. i. p. 115): "For what is worse" (that is, than new knowledge being but reminiscence), "knowledge is niailc by oblivion, and to purchase a clear and warrantable body of Truth, we must forget ami part with much we know. Our tender Enquiries taking up Learning at large, and together with true and assured notions, receiving many, wherein our reviewing judgments do find no satisfaction." In other cases of omission, my ignorance must serve as an excuse. But, as Bacon has well pointed out, truth is more likely to come out of error, if this is clear and definite, than out of confusion, and my experience teaches me that it is better to hold a well-understood and intelligible opinion, even if it should turn out to be wrong, than to be content with a muddle-headed mixture of conflicting views, sometimes miscalled impartiality, and often no better than no opinion at all. One is tempted to quote Browning: —

" Stake your counter as boldly every whit, Venture as warily, use the same skill, Do your best, whether winning or losing it, If you choose to play ! — is my principle. Let a man contend to the uttermost For his life's set prize, be it what it will ! Is — the unlit lamp and the ungirt loin, Though the end in sight was a vice, I say, You of the virtue (we issue join) How strive you? De te,fabida" But, at the same time, there must never be the least hesitation in giving up a position the moment it is shown to be untenable. It is not going too far to say that the greatness of a scientific investigator does not rest on the fact of

his having never made a mistake, but rather on his readiness to admit that he has done so, whenever the contrary evidence is cogent enough. In the present book I venture to lay down no expression of opinion as to the problem of "Vitalism," although it is scarcely possible to hide my feelings on the matter. I take it that there is no serious difficulty as to the kind of phenomena to be classed as "vital," and no dispute as to what are the problems with which the physiologist has to deal. If asked to define " life," I should be inclined to do as Poinsot, the mathematician, did, as related by Claude Bernard (1879, p. 23), " If anyone asked me to define time, I should reply : ' Do you know what it is that you speak of ? ' If he said ' Yes,' I should say, ' Very well, let us talk about it.' If he said ' No,' I should answer, ' Very well, let us talk about something else.' " The great physiologist, in another place (1878, pp. 116-117), describes what seems to me to be the most profitable attitude to take with regard to the question of vitalism ; he says, " There is in reality only one general physics, only one chemistry, and only one mechanics, in which all the phenomenal manifestations of nature are included, both those of living bodies as well as those of inanimate ones. In a word, all the phenomena which make their appearance in a living being obey the same laws as those outside of it. So that one may say that all the manifestations of life are composed of phenomena borrowed from the outer cosmic world, so far as their nature is concerned, possessing, however, a special morphology, in the sense that they are manifested under characteristic forms and by the aid of special physiological instruments." It must be remembered, of course, that the special systems referred to are not to be understood as outside the laws of physics and chemistry.

All that we are justified in stating is that, up to the present, no physico-chemical system has been met with having the same properties as those known as vital ; in other words, none have, as yet, been prepared of similar complexity and internal co-ordination. A further point, with regard to which Claude Bernard's attitude is far more inspiring than that of those who regard living things as in perpetual conflict with external nature, may also be given in a translation of his own words (1879, p. 67): "It is not by struggling against cosmic conditions that the organism develops and maintains its place ; on the contrary, it is by an adaptation to, an agreement with, these conditions. So, the living being does not form an exception to the great natural harmony which makes things adapt themselves to one another ; it breaks no concord ; it is neither in contradiction to nor struggling against general cosmic forces ; far from that, it forms a member of the universal concert of things, and the life of the animal, for example, is only a fragment of the total life of the universe." (See also Kropotkin's attractive book, " Mutual Aid.")

My object, then, is to discuss the physical and chemical processes which intervene in these phenomena, so far as they are known. It must be kept in mind that all the methods available for the study of vital processes are physical or chemical, so that, even if there were a form of energy peculiar to living things, we could take no account of it, except when converted into known forms of chemical or physical energy in equivalent amount. This fact was clearly insisted upon by Burdon-Sanderson (1911, p. 164). Where explanation on these lines fails as yet, I have usually been content to summarise the general laws of the

process, leaving it for the future to curry further the reduction to simpler laws. Nevertheless, I fear that I may in some cases have been unable to resist the temptation to suggest hypotheses, even where the experimental data are inadequate. May I venture to hope that some of these suggestions will help to indicate gaps and to excite research to fill them up ? If so, any labour involved in the writing of this book will be amply repaid. It should be unnecessary to point out that vital processes can only )>e investigated where they exist, that is, in the living organism, either as a whole or in its separate parts, when these can be prepared in such a way as not to interfere with their function, or, if so, only in a known manner. Such experiments, when vertebrate animals are concerned, are known sometimes as " vivisections," an objectionable and misleading name. 1 should not have thought it necessary to refer to this question, were it not that certain people, whom one might reasonably expect to possess better knowledge, appear to hold that the progress of physiological science is possible without such experiments. Vesalius stated that the simplest experiment on the living animal, as a rule, revealed more than a long study on the dead body. With another set of people, who see no value in physiology, and frequently also none in science of any kind, I have naturally no concern, except to remind them that a great artist like Leonardo da Vinci, whom they probably hold in some esteem, not only thought differently, but actually performed " vivisections."

Finally, nowhere is the admonition of St Paul to the Thessalonians (Hrst epistle, chap, v., 21), which I have placed on my title-page, more necessary than in physiological work, " prove " (or rather " test ") " all things, hold fast that which is good." Let me remind the reader, also, that the word translated " good " is KuAos, which also means " beautiful," and in the passage quoted implies " true." Let us try to imitate the ancient Greeks, and look upon all that is true as both beautiful and good. All science should be KaA?;, and not, as to many narrow minds, essentially ugly, although possibly necessary. It is not always easy, however, to take this pi »int of view. But some of the greatest artists of the past devoted much time to scientific investigations ; Leonardo has been mentioned already, and Christopher "Wren may be added.

With regard to the use of the word "good" as applied to experiments, the remarks of Claude Bernard (1875, p. 516) should be kept in mind by the physiological investigator : " In physiology, more than anywhere else, on account of the complexity of the subjects of experiment, it is easier to nuike bad experiments than to be certain what are good experiments, that is to say, comparable. This is the reason of the contradictions so frequent amongst experimenters, and it is one of the chief obstacles to the advancement of medicine and of experimental physiology."

NOTE. — I may take the opportunity here to thank those authors and publishers who have kindly allowed the reproduction of certain illustrations. Those to which no name is attached are by myself and, for the most part, were prepared especially for this work. Microscopic Vision - Ultra-violet Photography Intra-vital Staining - Fixation ----- Mathematics in Physiology 37 The Carbon Atom - 41 Effect of Temperature on the Rate of Re- action - 41 Animal Temperature 44 Effect of Temperature on Equilibrium 44 Summary - - - - 45 Literature 47

Emulsoids- Gels - Imbibition- Proteins - Complex Colloidal Systems Modes of Preparation of Colloidal Solutions 108 Summary - 108 Chemical Composition - - - - 129 Action of Toxic Substances - - - 136 The Nature of the Membrane - - - 136 Phenomena in which Changes of Permeability occur - - - 137 Phenomena in which Changes of Permeability occur — lontd. Narcosis Turgor of Vegetable Cells 162 Reaction of Smooth Muscle to Drugs 163 Methods of Measurement Ionic Conductivity - Hydration of Ions Further Evidence and Difficulties Dielectric Constant .... "Strong" Electrolytes and the

The Action of Ions i n PhysiologicalProcesses Hydrogen and Hydroxyl Ions - Dissociation Constants and Mass Action Physiological Action Measurement of Concentration Indicators - (Jas Electrode - Electrode Potentials Use in the Case of Blood Hydrolysis of Esters and Cane-Sugar Reaction of Blood - • 202 "Buffers" - - 203 Practical Use of Phosphate Mixtures 203 Physiological Saline Solutions - _'t i."> The Work of Sydney Ringer 207 Relation to Sea Water - 209 Antagonism of Salts - - -212 Action of Salts in Particular Instances 214 On Various Processes - - 214 Calcium Salts - - 215 Magnesium Salts - - - - •_' 1 7 Sodium Salts- '.'IT Potassium Salts - - 217 Chlorine -JIS Carbon Dioxide - - -Ms Salts of Weak Acids with Weak Bases • 218 Amphoteric Electrolytes - - 219 Action of Electrolytes in Extreme Dilution - 221

Necessary Constituents - 247 Chemical Complexity of Food Stuffs Re- quired - - ... 248 Of Reversible Reactions In Heterogeneous Systems Enzymes as Catalysts Definition and Terminology - Relation to Final Products - Velocity of Reaction In Case of Enzymes Destruction of Enzymes Reversible Inactivation Autocatalysis - Concentration of Enzyme - Electrolytes Co-enzymes Anti-enzymes Concentration of Substrate Physical Properties of Enzymes - 325 Chemical Nature of Enzymes - • 325

Digestion in the Sea-Anemone General Plan in the Higher Animals Movements The Secretion of the Digestive Juices Digestion of Fats - Absorption of Fats - Absorption of Water and Salts - Summary - Literature Optimal Rates of Incidence of Energy - 400 Connection Between Nerve and The Cerebral Circulation - - 484 The Sympathetic and Other Parts of the Successive - - - - • • Irreversibility of Direction - Refractory Phase - Reciprocal Innervation - Peripheral - - - Double Reciprocal Innervation Rhythmic Reflexes The Action of Strychnine and

Spinal Reflexes — contd. Interaction of Reflexes Compound Reflexes Fatigue - Nociceptive Reflexes The Extensor Thrust Autototny - ••-> Methods Conditioned Reflexes Temporary Association Inhibition The Analysers Removal of Cortex Hypnosis and Sleep The Receptor Mechanism in General Miiller's Law- - - • • Analysers - The Adductor Muscle of Anodonta The "Catch" Mechanism in Smooth Muscle ..---- Optical Sensitisation - - - 555 Relation of Velocity of Reaction to In- tensity of Light .... 55(j

Guaiacum Reaction - - - 584 Oxidases - ... 535 Enzymes concerned with Reduction - - 53G Hydrolytic - oxidative - reducing Reactions 586 Relation to Catalysts Energetics of Oxidation in Cells The Oxidation Potential of Cells in the History of the Discovery of Oxygen - - 600 The Storage of Oxygen - - - 606 Relation of Oxygen Tension to Consumption 609 The Regulation of Respiration - - • 630 By Hydrogen Ion Concentration of the Smooth Muscle The Heart - Secreting Glands Electrical Fish Plant Tissues Summary Literature

Loveii Reflexes . - - - 698 Action of Strychnine and of Chloro- Reaction to Changes of Pressure Regulation of Supply to Organs AT the very outset of our studies we are faced by one of the most difficult problems with which the biologist has to deal, namely, the structure, chemical FIG. 1. AMOEBA PROTEUS(?). — Creeping in direction of arrow. Projecting in advance clear pseudopodia. The contractile vacuole is seen in the posterior end of the organism. Each division of the scale corresponds to 2-5 /*. (Leidy, 1879, PI. iv. fig. 22.)

and physical, and the elementary properties of protoplasm. This substance is met with in all living cells, but in various degrees of differentiation into more specialised structures. In its simplest form, as seen in the pseudopodia of the amoeba or the leucocyte, it appears, even under the highest powers of the ordinary microscope, as a clear, colourless, jelly-like stuff, not showing any structure, but nevertheless keeping itself distinct from the fluid surrounding

it, not mixing therewith, and also capable of changing its form in response to changes in its surroundings (see Fig. 1). fa The structureless nature of protoplasm in its most elementary form is also, in certain cases, to be seen after fixation, as is shown in Fig. 2, in which it will be noticed that the external layer and the pseudopodia are completely clear. Even in some of the simplest unicellular organisms special portions are differentiated off for the purpose of performing particular functions, the contractile vacuole, for example.