Principles of General Physiology

Poisons. — Many interesting substances of this class are to be met with, sometimes produced for the capture of food, sometimes for defensive or offensive purposes against enemies. The rnason wasp injects, with its sting, a toxic substance into the nerve ganglia of its prey, spiders. This produces paralysis, while the spiders still remain living and ready for food when wanted. The wasp, in fact, deposits an egg in proximity to the paralysed spider, so that, when the grub hatches, it finds fresh food, living but powerless, ready for it to consume Warburton's "Manual," 1912, p. 124).

Henze (1913) shows that the poison used by cephalopods to paralyse their prey, especially crabs, can be extracted by alcohol from the posterior " salivary glands. The active substance is found to be para-hydroxy-phenylethvlaiiiiiie, which was shown by Barger and Walpole (Barger and Dale, 1910, p. 31) to be produced from tyrosine, by removal of CO.,, in the putrefaction of meat. The chemical relationship of this substance to adrenaline is of interest in view of the production of this latter in the organisms. Thus : —

It is also interesting to note that Sepia, one of the cephalopods, makes use of tyrosine in another way, to form the black pigment of its inky secretion, as mentioned above. Salivary glands in the snakes have been differentiated into organs for the formation of extremely powerful poisons. These are of two main classes : some, such as that of the Australian black snake (Pseiidechis porphyriaca), investigated by C. J. Martin (1894), act on the blood, causing intra vascular clotting; some of this class also contain hsemolytic substances. The other class, typified by the Cobra, act on the central nervous system, causing paralysis of respiration (Laiult, 1903). Further details may be found in the papers quoted as also in those of Fraser and Gunn (1909 and 1912).

The meaning of the enormous variety of toxic and other alkaloids produced by plants is very difficult of explanation. It would seem that, if their presence were merely to avoid being eaten by animals, one or two distasteful substances would have sufficed. It may be that they are in many cases, as it were, accidental byproducts of metabolism, although the possibility of some hitherto unknown action on nutritive processes must not be forgotten. Hirudin. — It has long been known that the blood sucked by the leech into its alimentary canal remains liquid, and it was found by Haycraft (1884) that there are certain unicellular glands, close to the mouth of these animals, which secrete a substance which has the power of depriving blood of its coagulating property. This it does both when injected into the blood vessels of a living animal, or when added to the blood in vitro. The leech appears to benefit from the arrangement in two ways : there is no risk of blocking of the fine incision made by its teeth in the skin of the animal attacked and from which it is sucking blood, and the blood in its alimentary canal is naturally more accessible to the action of enzymes than if solidified.

The substance, which can be obtained in solution by extracting the heads of the leeches with water, either directly, as in Abel's method (1914), or after drying with alcohol, as in that used by Haycraft, has been of great service in experiments where it is necessary to collect blood from the veins of organs or to measure its rate of flow. This applies both to organs in situ and to artificial perfusions. The blood rendered non-coagulable by this means appears to be more normal than if defibrinated by whipping ; rabbits are killed by injection of

their own defibrinated blood, but are unaffected by extract of leeches. A dry commercial preparation of great activity, known as " hirudin," which is made by the method described by Franz (1903), is much used. Franz regards the active constituent as being a kind of albumose. Abel finds that it is in colloidal solution in water. Silk and the similar substance of spiders' webs are very interesting products of secretion. They are of protein nature and are formed in the liquid state by special glands. The liquid is forced through fine apertures and rapidly sets in contact with air. By opening up the silkworms, a considerable quantity of the liquid secretion can be obtained, which can then be used for making fibres of greater thickness than those made by the insects themselves. These threads are of great strength, and are valuable for fish lines, ligatures, etc.

The Gas Bladder of Fishes. — Since the substance of which the body of fishes is composed is of a higher specific gravity than that of sea water, it is obviously of advantage to them to possess a float, containing gas which, present in the appropriate amount, will reduce their weight to that of an equal bulk of water, thus removing the necessity of muscular movement in order to keep themselves from sinking. An organ of this kind actually exists in the teleosts. But it is clear that the gas will be compressed as the fish sinks, thus becoming of a greater specific gravity, and more must be produced to restore proper compensation. Conversely, when the fish rises again, the gas will expand and displace other tissues, as in fact happens when deep sea fish are brought to the surface rapidly. In some fish, there is a duct to the exterior, via the oesophagus, which can be opened to allow of escape of gas ; and in others, where the duct has become solid, in a special region, the "oval," the wall of the gas bladder has the power of absorbing the gas. This oval can be shut off from communication with the gas bladder when nob required. At first sight, it might seem strange that the gas is found to consist almost entirely of oxygen, but if it has to be secreted and absorbed, the advantages are obvious. Oxygen can easily be obtained from oxyhsemoglobin and can be used up either by combination with reduced haemoglobin or by oxidation of some reducing substance. Woodland (1911, 1 and 2) has made an interesting investigation of the structure and physiology of the gas bladder, and the reader is referred to his papers, which contain also a list of other papers. A remarkable vascular organ is found in the course of the blood vessels supplying the gland in the gas bladder which secretes oxygen.

This organ is what is called a rete mirabife, in which the artery divides into a number of fine arterioles, which lie closely, side by side, with the corresponding finely divided veins carrying blood from the gas gland. These vessels do not join each other, but allow of free interchange of diffusible constituents of the blood, and have, obviously, an important function in relation to the secretion of gas. It would seem that some chemical substance must be produced in the gland cells, which is not desirable in the general circulation. As this substance returns in the veins, it diffuses out into the blood of the arterioles in the rete and is, for the most part, sent back to the gland. It is probably something which enables oxyhsemoglobin to give up its oxygen readily ; that there are substances of this kind will be seen in Chapter XXI. It is not a hsemolysin, since there is no evidence of the presence of such a substance, nor is there haemoglobin in the cells of the gland itself. The gas must therefore be given off by the corpuscles in much the same way as to other tissue cells. The preparations of Woodland show that the gas gland possesses large cells, similar in appearance to those of a typical secreting gland, and, according to Bohr (1894), the vagus nerve supplies secretory fibres, since, after section of the intestinal branch of this nerve, no further secretion of gas takes place, even when the bladder is emptied of gas, a procedure always resulting normally in renewed formation of oxygen.

The protozoan, Arcella, forms bubbles of gas and raises itself to the surface of water by this means. According to Bles (1910), these bubbles consist of oxygen. The stimulus to secrete the oxygen bubble appears to be, curiously enough, the want of oxygen in the depths of the pond water; the animal thus floats itself to the surface. In order to sink again, the animal must absorb the oxygen, since it cannot escape to the air, owing to the shell on the animal.

Luminous Substances. — There are many organisms known which are capable of secreting substances which give off light. Very little is known of the chemical nature of the reaction concerned, but it is evidently an oxidation process of some kind, since the luminosity disappears in the absence of oxygen. According to the work of Raphael Dubois (1913 and literature cited therein), there are two substances concerned, neither of which is luminous alone. The one is of the nature of an oxidising enzyme, or peroxidase, the nature of which we shall have to discuss in Chapter XX. This can be replaced by solution of a permanganate, or by some other oxidising enzyme. It is called " luciferase." The substance oxidised is called " luciferine " ; its chemical nature is unknown, but it appears to have some of the properties of proteins. A remarkable fact about the light produced is that the radiation contains only a very small percentage of the longer wave lengths, known as heat rays, and is almost entirely composed of "light" rays. It has hence been designated " cold light " and indicated as the ideal illuminant. Further details will be found in Chapter XIX.

The mollusc, Pholas dactylus, which bores its way into hard mud on the sea coast, is frequently to be found and has a brightly luminous secretion. The work of Molisch (1904) on luminous bacteria will be found of much interest. The article by Mangold (1910) on the production of light by organisms may also be consulted. Electrical Organs. — In the electrical fish, Malapterurus, found in the Nile and known to the ancient Egyptians, the electrical organ is evidently developed from skin glands. We have seen that the process of secretion is accompanied by electrical changes and it is curious to note how this has been made use of for the purpose of defence and perhaps of benumbing prey. In other electrical fish, the organ seems to have been formed from muscular tissue and will be referred to in Chapter XXII.

In a general way, all living cells may be said to give off to the surrounding medium products of the chemical reactions taking place within them. But the name of secretion is especially given to those cases in which the products are made use of for purposes of importance to the organism as a whole. Under the name are also included processes in which the function of the cells is to separate from the blood products of the metabolism of the organism as a whole. These waste products would be deleterious if allowed to accumulate, and there are arrangements produced in order to reject them to the exterior of the organism. This process is sometimes called "excretion," and is the particular function of the kidney, although the epithelium of the alimentary canal takes part in the excretion of foreign substances under certain conditions.

Secreting organs, or glands, may either discharge their products by means of a special channel, the duct, into a cavity such as the alimentary canal, which cavity is, in a sense, outside the organism itself ; or their products may diffuse into the blood vessels and in this way affect distant organs. Glands of this latter kind are known as those with internal secretion. The products of glands with external secretion, such as the pancreas, are given out, for the most part, dissolved in water, so that the first problem is the way in which the cells produce a current of water through their substance in order to wash out, as it were, the chemical compounds which they have formed.

The filtration of pure water from a solution of the molar concentration of blood is impossible by pressures directly available in living organisms. If, however, the liquid to be filtered off consists of blood minus its colloids only, the arterial pressure is higher than the osmotic pressure of these colloids and can filter off a solution of this kind. The process actually occurs in the glomerulus of the kidney. Since it is found that the pressure under which secretion is possible is higher, in some cases, than that of the arterial blood, osmotic forces are indicated as the

source of the energy required. Certain possibilities are indicated in the text as to the way in which these osmotic forces are available. But, in the end, the production of osmotically active material must be ascribed to what, in our present ignorance, we call " protoplasmic " activity, by means of which the chemical energy derived from oxidation of food is converted into the various other forms of energy required. In most cases, the process of secretion is found to be accompanied by the

disappearance of certain granules, " zymogen," from the cells of the gland. These granules appear to be a stage in the formation of the constituents of the secreted fluids. The production of osmotically active substances, together with changes in the permeability of the cell membrane, appear to be the chief factors in the actual process of secretory activity. The first stage in the formation of urine is the filtration in the glomerulus of a liquid which is identical with blood-plasma minus its colloids ; so that the rate of secretion under a given pressure is inversely proportional to the osmotic pressure of these colloids in the blood, and if the blood pressure is lower than this osmotic pressure, no filtration takes place.

The work done in secretion is, in the main, of two kinds, although the ultimate source of both lies in chemical energy utilised in cell processes. The work done in producing a secretion of higher osmotic pressure than the blood can be calculated by the method given in the text. That done in the various chemical reactions can only be estimated approximately by the amount of oxygen consumed. The work in glomerular filtration is not derived from the kidney itself, but from the contractions of the heart muscle.

The measurements of oxygen consumption give some indications as to the nature of the cell process. The increase is found to take place, not only during the secretory process, but for some time afterwards. This obviously means that energy from some reaction is being stored up during rest and in a form available for the next period of activity. There does not appear to be any storage of " intramolecular" oxygen, since the secretory activity is greatly dependent on the supply of oxygen in the blood at the time of secretion itself.

Glands are set into activity either by means of chemical substances circulating in the blood, such as drugs or the natural " hormones " such as secretin, or by the agency of nerves supplying the gland cells. This statement does not exclude the possibility that the final link in the chain of excitation processes may be the same chemical substance in all cases. Evidence, taken as a whole, indicates that there are two kinds of nerve fibres to glands ; one kind, the " secretory " of Heidenhain, presides over the secretion of water, together with diffusible substances present in blood, and must, therefore, affect both permeability of cell membrane and the osmotic pressure of cell contents. The other set, "trophic" of Heidenhain, are concerned with the production of the specific solid constituents and have little or nothing to do with the phenomena connected with the production of a flow of water.

The combination of various facts indicates that during rest gland cells form, by means of reactions which are reversible, certain substances which are preliminary stages of the constituents of the actual secretion formed on stimulation. When the gland is excited to activity, a current of water is set flowing through the cell by a combination of increased permeability of the outer end of the cell with the splitting up of some cell constituent into smaller molecules and thus raising the osmotic pressure. This current of water washes into the duct various substances stored in the cell, sometimes after these have been changed by the excitation process, before being given off. As these substances are removed, further formation takes place by the cell reactions in order to re-establish equilibrium.

The results of experiments on artificial perfusion of salivary glands show that some constituent of blood is necessary for the production of secretory activity by stimulation of nerves. In the case of the pancreas, the combination of at least three agents is necessary for secretion : oxygen (in greater amount than can be dissolved in saline solutions), electrolytes, and secretin. Whether any other constituent of blood, such as protein, is necessary is uncertain. It is obvious that prolonged activity is only possible when materials for the formation of the constituents are supplied.

The electrical changes of gland cells when excited are of two kinds with opposite sign. That associated with the secretion of water has an opposite direction to that associated with the formation of the organic solids which are characteristic of the secretion. The kidney requires special consideration. The glomerular filtrate, as it passes along the tubules, undergoes three changes. Its total concentration is increased by loss of water, on the one hand, and by secretion into it of waste products, such as urea, etc., on the other hand. At the same time, it may lose, by reabsorption, a large part of those solutes which are valuable to the organism, such as sodium chloride, glucose, and amino-acids, but which are unavoidably present in the filtrate. Foreign salts, such as iodides, appear to be excreted in the tubules.

Most diuretic substances act by diminishing the osmotic concentration of the blood colloids ; some, by a specific action of some kind, perhaps by decreasing absorption of water, etc., by the tubules. The formation of certain special secretory products is briefly discussed in the text. These are acid and alkali, sepia, poisons, hirudin, silk, oxygen, luminous substances, and electrical charges. THE great majority of the materials taken in as food by animals require treatment of some kind in order to enable them to be carried by the blood or other fluids to the various organs requiring them.

In the green plant, the food-stuffs do not require treatment of this kind, but, even here, stored products such as starch and protein require the action of certain enzymes before they are again available for the use of the cells, or to be conveyed to distant growing parts. In the animal, the conversion of food-stuffs into diffusible or assimilable substances is known as digestion, and is carried on in the alimentary canal, chiefly by means of enzymes secreted into the cavity by the various glands opening into it or situated in its walls. In the digestion of certain food-stuffs, especially that of cellulose in the herbivora, bacteria play an important part.

To describe the great variety of digestive mechanisms met with in the animal kingdom would take far more space than is permissible here. It may be said in general that the object of these mechanisms is to ensure the effective action of the digestive enzymes, and the due absorption by the blood or lymph of the products of their activity. Details of these mechanisms may be found in the article by Biedermann (1911). In the unicellular organisms the whole process takes place within the one cell. The food-stuffs are taken in, a vacuole containing liquid is formed around them, and the necessary enzymes secreted into this vacuole. Material undigested is extruded through any part of the cell. Although raw starch appears difficult of attack by protozoa, the fact that boiled starch is hydrolysed shows that they possess an amylase. They also store glycogen, a fact indicating the reversible action of an amylase. But, in any case, 'protein appears to be their chief food, obtained in the main from bacteria and algte. According to the work of Nierenstein (1905), the reaction of the contents of the food vacuole is at first acid to neutral red, and subsequently becomes alkaline. During the acid period, no digestion takes place, but the reaction seems to be connected with the killing of the bacteria taken as food. The actual digestion occurs during the alkaline stage. Mouton (1902) prepared an enzyme from a large number of amoeba-, and found that it would not attack living bacteria, but dead ones rapidly, so that the preliminary killing in the acid stage is of importance. The enzyme acted best in a medium alkaline to litmus, but acid to phenolphthalein, that is, faintly alkaline ; it produced tyrosine and is, accordingly, to be considered as a trypsin.

Phagocytosis. — We find the process of iritracellular digestion, similar to that of the amoeba described above, still present in the amoeboid cells of the higher multicellular organisms. The leucocytes of vertebrates require special attention. In these, Metschnikoff has shown that the taking up of living bacteria plays an important part in the defence against infection by micro-organisms. He called the process " phagocytosis." It is not confined to certain leucocytes of the blood, but is manifested by large cells found in the peritoneal cavity and elsewhere. The reader may consult the book by Metschnikoff (1901) for further details. The process of phagocytosis has been referred to previously (page 3) and Ledingham's work mentioned. According to this observer, the bacteria in the blood are not

taken up by pseudopodial processes of the phagocytes, since in the circulating blood current they are spherical cells ; when a bacterium comes into contact with a phagocyte, it is engulfed, killed, and digested. It will be clear that any influence which makes adhesion more certain on chance contact will increase the number of bacteria taken up, as will also, as Ledingham points out, any agglutination of the bacteria into clumps, since a large number will be taken up at a chance encounter instead of a single one. There does not seem to be any necessity for the assumption of such ill-defined chemical substances as "opsonins," which have been supposed to make the bacteria attractive or " tasty " to the phagocytes.

The process of phagocytosis is also met with in the absorption of larval organs, such as the tail of the tadpole. It plays a part in the formation of bone ; and certain cells in the liver, Kupffer's "star-cells," are phagocytes. In the extraordinary " disruption " of internal organs that takes place in the metamorphosis of the fly, wherein nearly the whole of these organs become broken up preparatory to the formation of the new organs of the adult, phagocytes play a considerable part.

Digestion in the Sea Anemone. — The process here deserves a little consideration, since it forms a kind of transition to that of the higher multicellular animals. Although there is what seems like a gastric cavity, no one has yet succeeded in showing the presence therein of any secretion with digestive properties. Nevertheless, animals of considerable size are actually digested by the anemone and in fact by a somewhat remarkable process. There are long filaments in great number attached to the septa, in this gastric cavity and these wind themselves all over the body of the animal taken in and into all depressions and cavities in it. This they do by a kind of pseudopodial movement, probably conditioned by surface tension, like that of the Amoeba. Where the cells covering the filaments are in contact with food material, they secrete digestive enzymes limited to the area of contact. These enzymes cause the tissues attacked to break up and the fragments are then taken in by the cells and dealt with further by the ordinary process of intracellular digestion. It appears that the enzymes can diffuse for a short distance, since food wrapped up in filter paper is digested, provided that the paper is moistened with meat extract. The presence of some chemical stimulant in the meat causes the secretion of enzymes in the cells of the mesenterial filaments at the places where they come into contact with it.

The alimentary canal may be said to consist of a long tube, with dilatations in places. In this tube the food is subjected to the action of a series of enzymes. The dilated sections are capable of being shut off from the neighbouring sections by means of rings of muscle, the sphincters, so that the food shall not be passed on to the next section prematurely. As a rule, arrangements exist by which the secretion of the digestive juice in a particular section is brought about by the presence of food in the preceding section, so that no delay in the process occurs. The food is kept in movement by muscular contractions of the walls of the canal and passed on by similar movements. These movements are partly provided for by nerve centres in the wall of the canal itself, but are under the control of the central nervous system. As regards the sphincters, it is usual to find that they close by a nervous reflex when a certain amount of material has been passed through to the next section.