Principles of General Physiology

It is evident, to begin with, that some change is produced in the blood, by which the tissue cells are affected. In different animals, the actual symptoms vary according to the particular organ most sensitive to these changes in the blood. In the guinea-pig, the bronchial muscle is most affected, in the dog, the liver and intestine. We have seen that a considerable time is necessary for these changes to be produced in the blood, but, once produced, the blood of a sensitised animal can bring about anaphylactic shock in a normal one, immediately, as was shown by Manwaring (1910). At the same time, the anaphylactic substance, or influence, becomes fixed or adsorbed on the tissue cells, so that, as Dale shows, the excised and washed uterus of an anaphylactic animal, suspended in Ringer's solution, is itself sensitive to the antigen. Fig. 258 shows the effect, together with the striking " specificity " of the reaction. The organ was taken from a guinea-pig, sensitised by an injection of horse serum, fourteen days previously. It gives no response to a small dose of the serum of

the sheep, cat, rabbit, dog, or man, nor to egg-white, but a powerful contraction to a similar dose of horse serum, the antigen itself. Now, there are two points to be cleared out of the way before we proceed. Fresh serum of all animals contains a toxic substance, which causes contraction of smooth muscle ; this property diminishes considerably as the serum is kept and has nothing to do with the anaphylactic reaction. A much larger dose has to be given ; but, in the testing of the anaphylactic phenomenon, the fact must be remembered. The curves of Fig. 258 show that the doses given have no effect of this kind. Secondly, it might be supposed that the normal guinea-pig uterus is particularly sensitive to horse serum, as compared with other sera. This is

Powerful contraction with the antigen serum, but with no other serum nor with egg-white. found not to be the case ; a dose of horse serum, just as large as that of any other serum, is required to cause contraction of the normal uterus. Although the specificity of the reaction appears to be so great, and is, in fact, under proper conditions, sufficiently so to serve as a delicate test for the antigen, there are some facts which show that it is really only of a quantitative nature, and also that the phenomena of specific immunisation share this characteristic. Dale finds (p. 188) that if the guinea-pigs are sensitised simultaneously to horse serum, sheep serum, and egg-white, as can be done, the sensitiveness to horse serum, although present, is comparatively low. To understand the further evidence, we must consider the fact of desensitisation. Suppose a uterus, sensitive to horse serum, has been tested with a fairly large dose and has given a powerful contraction, it is found to be incapable of response to a second dose. It is evident that some kind of reaction has taken place between the sensitised tissue and the antigen,

in which the sensitiveness of the tissue has been abolished. It appears that the antigen has fixed itself in such a way as to prevent the action of further doses. Take, next, the above uterus sensitised to three antigens. Treat it first with sheep serum, so as to desensitise it to this antigen. Its sensibility to horse serum is now also very small, but is unaffected towards egg-white. If, however, the uterus be first desensitised to egg-white, it is found to be desensitised to both the others. In another experiment, it was found that, by first treating with sheep serum (p. 189), the sensibility to egg-white was greatly diminished, though not abolished. Further evidence is afforded by the behaviour of the uterus of animals immunised by repeated doses of horse serum. It is, of course, well known that such animals are no longer sensitive to a small dose of the antigen. But the isolated uterus itself still remains capable of anaphylactic reaction. A series of ten injections of horse serum was given, at first at three days' interval, that is, during the "incubation period" of anaphylaxis. On testing the uterus, it was

Tested for anaphylaxis twenty-four days after the last injection. Perfused. A, 0'5 c.c. sheep serum causes contraction and subsequent desensitisation for a further dose at C. C, (After further change of bath) 0'5 c.c. sheep serum. R, Fresh Ringer solution. D, 0'5 c.c. horse serum (the first dose was not large enough to effect complete desensitisation). found to be sensitive to sheep serum, though less so than to horse serum. It was desensitised, however, to sheep serum in the process, so that the phenomenon was a genuine anaphylaxis (see Fig. 259). These facts seem to exclude explanation by specific " chemo-receptors." If there is a particular receptor for egg-white, for example, which is taken possession of in treatment with the antigen, why is the tissue thereby made insensitive to sheep and horse serum also ?

If three months were allowed to elapse after the last injection of horse serum, although the immunity of the whole animal was still present, the anaphylactic reaction of the excised uterus had nearly disappeared. This latter kind of immunity, by disappearance of sensitiveness, must not, of course, be confused with the immunity conferred by the presence of antibodies in the blood, which are supposed to neutralise the antigen before it has attacked the tissues.

It has been already mentioned that the blood of an anaphylactic animal can produce the state in a normal one, so that Dale made experiments to see how far a normal uterus could be sensitised by treatment with serum of a sensitised animal. It was found comparatively easy to resensitise an anaphylactic uterus which had been desensitised. Mere contact for some hours with not too dilute a serum of a sensitised animal was sufficient. Perfusion of a normal uterus with diluted serum from sensitive animals also conferred a decided sensitisation. It is evident, then, that interaction with other organs is not necessary for the reaction in the guineapig, and it was found that the bronchial spasm could be produced even when the liver and intestines were removed. In the dog, the reaction in the liver produces some secondary reactions, by which toxic substances are sent into the blood, causing exaggeration of the symptoms.

Certain theories have been suggested in explanation of the phenomenon. That there is some sort of interaction between the antigen and some constituents of the serum is indicated by the results of Anderson and Frost (1910), who found that serum from, a sensitised animal, after digestion with antigen, produced symptoms resembling anaphylactic shock when injected into normal animals. Experiments of this kind led to the theory of a kind of proteolytic digestion, but Doerr (1912, p. 337) has shown that similar effects can be obtained from serum that has been digested with kaolin or kieselguhr. Further, Doerr and Moldovan (1912) find that many of the symptoms of anaphylactic shock can be obtained by intravenous injection of some inorganic colloids, such as silica.

According to Dale, these latter experiments indicate the direction in which to look for a more satisfactory explanation than the protein digestion theory. In addition to the facts mentioned, the absence of any perceptible latent period, the sudden onset, and the gradual decline are quite unlike any enzyme action. The effect, in fact, is like that of a powerful stimulating drug, such as /2-iminazolylethylamine. The action of inorganic colloids is usually to give rise to mutual precipitation or aggregation, when mixed with protein solutions. Dale's experiments, as he points out, show that the colloidal interaction must take place on the muscle fibres themselves and need not actually go so far as precipitation. In the light of the work of Lillie and others (page 398), on the increase of permeability in the state of excitation, it seems highly probable that the contraction resulting from the interaction of the sensitised muscle fibre with the antigen is a . consequence of increased permeability of the cell membrane. This view is supported by the fact that the presence of calcium salts tends to oppose the reaction, as would be expected from their relation to colloidal processes. As Dale says (p. 221), "The action of the antigen in extreme dilutions, the saturation of the antibody (desensitisation), the cessation of the effect when the union of the antibody and antigen may be supposed to be complete, all find their reasonable explanation."

I have spent some time in the description of these experiments because they apply not only to anaphylaxis, but to immunity in general. In connection with them, the fundamental paper by Wooldridge on "Chemical Protection" (1888) should be referred to. The main result of this work was to show that a solution of a " tissue-fibrinogen " could confer specific immunity. The solution was prepared from the thymus of normal rabbits ; it was partly coagulated by boiling and pressed through fine linen, so as to obtain a very fine suspension. When injected, this suspension was found to confer immunity against anthrax. Thus, it was shown " that immunity can be obtained, not, as had previously been supposed, only by the inoculation of attenuated micro-organisms or their products, but by the administration or introduction into the system of a chemical substance which had never come into relation with or was in no sense a product of the life of a micro-organism " (Introduction to " Collected Papers," p. 28).

Certain specific substances have been described which are supposed to increase the taking up of micro organisms by leucocytes. This is said to be done by an action of the micro-organisms of such a nature as to make them attractive to their devourers. The work of Ledingham (1912), already referred to (page 3), has shown that mere agglutination is sufficient for the purpose. Further evidence against the necessity of assuming specific " opsonins " is given by Savchenko and Aristovsky (1912). They show that the optimum reaction of the medium for phagocytosis is the same as that most favourable for the adsorption of the " alexin " by the object of phagocytosis ; and that phagocytosis, as showing itself by the mutual attraction (relative surface tension) of the leucocytes and the object, and by the moistening of the object by the protoplasm of the leucocyte, depends on the adsorption of the alexin by the object of the phagocytosis. The meaning of the " alexin " requires further investigation.

There are a large number of substances, acting powerfully in minute amount, which are of great importance in physiological processes. One class of these consists of the hormones, or chemical messengers, which are produced in a particular organ, pass into the blood current, and produce effects in distant organs. They provide, therefore, for a chemical co-ordination of the activities of the organism, working side by side with that through the nervous system.

The most typical instance of this kind is the pancreatic secretin. Methods of preparing active secretin solutions, free from the depressor substance, are given in the text. There is evidence that a similar substance is produced from the pyloric mucous membrane, and excites the secretion of gastric juice. The internal secretions, formed by ductless glands, as well as by other tissues, belong to the class of hormones. The remarkable relationship of the medulla of the suprarenal glands and its secretion, adrenaline, to the sympathetic system is discussed in the text.

Certain drugs, such as nicotine and pilocarpine, produce a part of their effects - by stimulating the secretion of adrenaline into the blood. The respiratory centre is stimulated by the increase of hydrogen ion concentration in the blood, due mainly to carbon dioxide, a parahormone, in Gley's sense. There is no satisfactory evidence of its acting as a specific hormone. The various hormones arising from the sexual glands are responsible for the development of the secondary sexual characters, 'ihese hormones appear to be produced by the interstitial cells, not by the generative cells themselves. The corpora lutea of the ovary are responsible for the first stages of uterine hypertrophy and for the growth of the mammary gland.

There are certain " ductless glands," pituitary, thyroid, and thymus, which have a marked influence on growth in general. Complete removal of the pancreas results in the production of severe diabetes. The structures responsible for the " antidiabetic " hormone are the islets of Langerhans. There are interrelations between certain of these internal secretions, but, at present, their nature is still very obscure. Some evidence exists of the production of hormones in plants.

The mode of action of drugs is discussed in the text. The conclusion arrived at is that the chemical structure alone throws very little light on their action. The theory of " chemo-receptors " or special receptive side-chains in the cell is found to be contrary to many facts, and to be generally inappropriate. While the cells take up certain alkaloids, such as atropine, which can be regained from them, they do not take up any detectable amounts of strophanthin, which acts in direct proportion to its concentration outside. It is probably adsorbed at the cell membrane.

In the explanation of " specific " action, phenomena due to surface action, and other physical forces, have to be taken into account. In fact, many of the supposed cases of extreme specificity have been found, on inquiry, to be due to factors other than specific chemical relationship. The properties of certain individual drugs, of physiological interest, are described in the text. Such are, acetyl-choline, strychnine, nicotine, pilocarpine, atropine, hyoscine, veratrine, and ergotoxine.

Certain substances of colloidal nature, probably all of protein constitution, such as the bacterial toxins and foreign proteins, give rise to the production in the blood of antibodies which are capable of neutralising, in various ways, the action of the antigen injected. If an interval of not less than eight to ten days elapses after an injection of one of these substances, the animal is found to be supersensitive to the antigen (anaphylaxis). If an antigen usually innocuous, such as egg-white, is injected in this sensitive state, severe symptoms are produced.

Under certain conditions, the state of anaphylaxis is very specific, an isolated organ reacting only to the actual antigen alone. But results obtained by Dale indicate that the property is merely one of degree. Organs sensitised by one antigen, under particular conditions, may react to a different substance. The theory of specific chemo-receptors does not give a satisfactory account of the phenomena. The explanation appears to be in a colloidal precipitation process at the surface of the sensitive cells, by which their semipermeability is more or less destroyed.

Results have been obtained by Wooldridge, which show that tissue extracts from normal animals can be obtained, which are capable of conferring immunity in a similar way to the specific antitoxin obtained by bacterial inoculation. The facts connected with the increase of phagocytosis by the so-called " opsonins " are, in all probability, to be explained by adsorption, causing changes in surface tension. They are only to a limited degree specific. Note. — In the transcription of Russian names, it is usually the custom to adopt the German form. Although this is correct for the German reader, it is not so in English. With the aid of my Russian friends, Prof. Babkin and Dr Anrep, I have, therefore, adopted a spelling which gives, as far as possible, the Russian pronunciation, using the English letters. For instance, there is a single letter which has to be reproduced in German as " Tsch," but the sound of this letter can be simply given in English as " ch " in " which." The name frequently given as " Pawlow " ought to be written " Pavlov " in English, and so on.

The same remarks apply to many Japanese names, which are frequently given in their German spelling. This practice applies, of course, only to languages which do not use the Latin characters ; in those languages which do so, French, German, Italian, etc., the names are spelled in their original form. In order to shorten the titles of journals, I have made use of a certain number of abbreviations, whose meaning will generally be obvious ; but their significance will, in any case, be found in the following table : —

Anat. , Anatomy or anatomical, or similar. Ann., Annalen, Annales, Annals. Anz., Anzeiger. Arb.f Arbeiten. Arch., Archives, Archiv. Beitr., Beitrage. Ber., Berichte. Bioch., Biochemical, Biochemisch. Bot., Botany, Botanical, etc. Chem., Chemical, chemisch. Chim., Chimie. Chem. Ber., Ber. der Deutschen chem. Ges. Clin., Clinical, Clinica. Compar., Comparative. C. R., Comptes rendus de 1'academie Entwickl., Entwicklungsmechanik. Exper. , Experimental. Fol., Folia, (res., Gesellschaft. Hyg., Hygiene.

Immun., Immunitatsforschung. Inst., Institute. Internat. , International. Jahrb., Jahrbuch. Jl., Journal. Landw. , Landwirtschaft. Med., Medicine, medical, etc. ologie, physiologisch. Pharmac. , Pharmacology. Pharmakol. , Pharmakologie. Phil. Trans., Philosophical Transactions of the Royal Society. Proc., Proceedings. Protist. , Protistenkunde. Psychol. , Psychology, etc. Quart., Quarterly. Rec. , Recueil. R. S., Royal Society. Sci., Science, Scienze. Sitz. Ber., Sitzungsberichte. Soc., Society, Societe, etc. Soc. Biol. , Societe de Biologie. Trans., Transactions. Trav., Travaux. Vergl., Vergleichende. Verb.., Verhandlungen. Vers., Versuchsstation. Veter., Veterinary, etc. Wiss., Wissenschaften, wissenschaftlich. Woch., Wochenschrift. Zbl., Zentralblatt. Zool., Zoology, Zoologie. Zs., Zeitschrift. Ztg., Zeitung.

- und Oskar Frank (1910). — "Weiterer Beitrag zur Frage nach der Verwerthung von tief abgebauten Eiweiss im tierischen Organisinus." Zs. physiol. Chem., 64, 158-163. - und O. Kapfberger (1910). — "Serolog. Studien init Hilfe der optischen Aspergillus niger bei verschiedener Stickstoffquelle." Zs. physiol. Chem., — (1910, 2). — "Weitere Untersuchungen iiber die Verwendbarkeit des Seidenpeptons zum Nachweis peptolytischer Fermente." Zs. physiol. Chem.,

Removal of Diffusible Substances from the Circulating Blood of Living Animals by Means of Dialysis." Trans. Assoc. Amer. Physicians, 6th May, 1913, 4 pp. Jl. of Pharmacology, 5, 275-316. Abel, Williamina (1909). — "The Development of the Autonomic Nervous Mechanism of the Alimentary Canal of the Bird." Proc. R. S. Edinburgh, (1913). — " Wedenskij Inhibition in Relation to the ' All-or-None ' Principle - and Keith Lucas (1912). — "On the Summation of Propagated Disturbances

Alsberg, Carl L., and W. M. Clark (1914).— "The Solubility of Oxygen in the Serum of Limulus • polyphemus and in Solutions of Pure Limulus Hajmocyanin." JL Biol. Chem., 19, 503-510. (1904). — "La disparition du bios de Wildiers dans les cultures des levures." Ancel, P., et P. Bouin (1910). — "Recherches sur les fonctions du corps jaune gestatif. I. Sur la determinisme de la preparation de 1'uterus a la fixation de 1'ceuf." JL de Physiol. et de PathoL, 12, 1-16.

Ancel, P., et P. Bouin (1911). — "II. Sur la determinisme du developpement de la glande mammaire au cours de la gestation." Jl, de Physiol. et de PathoL, Anderson, John J., and W. H. Frost (1910). — " Studies upon Anaphylaxis with special reference to the Antibodies Concerned." Bull. No. 64, Hyg. Lab., U.S. Pub. Health and Mar. Hosp. Serv., Washington. 56 pp. Anrep, Vassilie von, and Napoleon Cybulski (1884). — "On the Physiology of the Vaso-dilators and Vaso-constrictors." (In Russian.) Petrograd. See Hofmann und Schwalbe's Jakresber., 13, 49-55.

Arisz, L. (1913). — "Ueber Hysteresis in Gelatinlosungen." "Resumes des Communications, IXme Congres internat. des Physiolog." Groningen. Armstrong, Edward Frankland (1904, 1).— "The Rate of Change conditioned by Sucroclastic Enzymes and its bearing on the Law of Mass Action." Proc. K S., 73, 500-516. (1904, 2). — "The Influence of the Products of Change on the Rate of Change (1908). — "Hydrolysis, Hydrolation, and Hydronation as Determinants of Enzymic Change in relation to Narcosis, etc." Proc. R. S., 82s,

(1911). — "The Function of Hormones in Regulating Metabolism." Ann. of - (1913). — "The Nature of Enzymes and their Action as Hydrolytic Agents." (1913). — "Herbage Studies. II. Variations in Lotus corniculatus The Correlation of Synthetic and Hydrolytic Activity." Proc. R. S., 88B, Arrhenius, Svant6 (18S9, 1). — "Ueber die Dissociationswiirme und den Einfluss der Temperatur auf den Dissociationsgrad der Electrolyte." Zs. physikal. Chem., 4, 96-116.

(1889, 2). — "Ueber die Reaktionsgeschwindigkeit bei der Inversion von (1899, 2). — "Ueber die Anderung der Stiirke schwacher Sauren durch (1914).— "Faraday Lecture. The Theory of Electrolytic Dissociation." (1910, 1). — "Die innere Sekretion der Nebenniere und deren Innervation." - (1910, 2). — "Ueber die Unabhiindigkeit der Gefasserweiterung von spezifischen Stoffwechselprodukten nebst Beinerkungen iiber die Lymphbildung." Pfliiger's Arch., 136, 421-428.