t^» «• \v si* CORNELL UNIVERSITY. THE Basra elf #. movoev ^ibrarg^J THE GIFT OF ■/£&' ' c ROSWELL P. FLOWER ( <■■ FOR THE USE OF -V THE N. Y. STATE VETERINARY COLLEGE 1897 * _^ 8394-1 RV. r *# QP 145.S79T906" VerSKyUbrary Me «SliS , n*JSS!?l!B any lectures on recent adva 3 1924 000 041 669 The original of this book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924000041669 THE PHYSIOLOGY OF DIGESTION. MERCERS' COMPANY LECTURES ON RECENT ADVANCES IN THE PHYSIOLOGY OF DIGESTION Delivered in the Michaelmas Term, 1905,. in the Physiological Department of University College, London. BY ERNEST H. STABLING, M.D., F.E.S., jodsell professor of physiology. WITH TWELVE ILLUSTRATIONS. SECOND IMPRESSION. LONDON: AECHIBALD CONSTABLE & CO. LTD., 1906. ^tA. fair"] I+* Ho ^\w\ S79 J V ^fcfeRADBUBT, AGNKW, & CO. LD., PRINTERS, LONDON AND TONBBIDGE. * PKEFACE. In recognition of a generous gift by the Mercers' Company in aid of the work of the Physiological Department at University College, the Council of the College resolved that a course of Lectures should be given each year dealing with the original investigations made in the Department. In presenting this first course of Mercers' Company Lectures I have attempted, in the light of researches which have been carried out in this laboratory, to give an appreciation of the present state of our knowledge on certain aspects of the subject of digestion, in preference to describing at length the researches themselves, which can be read in the original papers enumerated at the end of this book. The great development in this branch of Physiology, which has taken place in recent years, owes its inception to the masterly series of researches carried out by Pawlow in the Institute of Experimental Medicine at St. Petersburg, researches to which I shall have repeated occasion to refer in the course of the following Lectures. Two other important lines of investigation have presented themselves as necessary to the proper understanding of the biological facts elucidated by Pawlow. The first of these is the study of the chemical and physical conditions which determine the digestive changes in the food-stuffs. As will be seen in the first two Lectures, we approach here a subject which must play a great part in all our future conceptions of intracellular mechanism, i.e., the study VI PREFACE. of chemical and physical changes in capillary and colloidal systems, where the modification of physical condition occurring at surfaces determines changes of quite another order to those which have so far formed the chief pre-occupation of physics and chemistry. The second line had its starting point in the discovery that the pancreas is normally excited to secrete, in response to stimuli originating in the gut, not, as Pawlow thought, by means of the nervous system, but by the dispatch of a chemical messenger or hormone from the seat of stimulation to the reacting gland through the blood-stream. Subsequent investigations have shown the existence of other chemical cor- relations of the same nature and suggest that, by the detection and isolation of such hormones, we may later be in a position to influence and control a number of the chief functions of the body. I trust that the publication of these Lectures may serve to interest a larger audience of students and medical men in the " growing border " of these important subjects and to give them some idea of the aims and objects of this branch of physiological research. EKNEST H. STABLING. Physiological Laboratory, University College, March, 190G. CONTENTS. r.ECTTRE PAGB I. THE FOOD-STUFFS AND THEIR CHANGES DURING DIGES- TION — THE MODE OF ACTION OF FERMENTS II. THE MODE OF ACTION OF FERMENTS (continued) III. SECRETION OF SALIVA IT. DIGESTION IN THE STOMACH V. PANCREATIC SECRETION VI. CHANGES IN THE PANCREAS DURING SECRETION VII. THE PROPERTIES OF THE PANCREATIC JUICE VIII. THE BILE IX. THE INTESTINAL JUICE X. THE MOVEMENTS OF THE ALIMENTARY TRACT 20 41 62 80 94 102 112 120 129 LIST OF ILLUSTKATIONS AND DIAGEAMS. 1. DIAGRAM SHOWING: (ffl) TOTAL BLOOD FLOW THROUGH SUBMAXILLARY GLAND, (b) TOTAL AMOUNT OF WATER TRANSFERRED FROM BLOOD TO GLAND. (c) TOTAr, SECRETION OF SALIVA (BARCROFT) . . . . 52 2. COMPARISON OF CHANGES IN VOLUME OF SUBMAXILLARY GLAND WITH THE OUTFLOW OF SALIVA PRODUCED BY STIMULATION OF THE CHORDA TYMPANI NERVE (BUNCH) . . . . . . . . .52 3. TRACING OF VOLUME OF SUBMAXILLARY GLAND, SHOW- ING EFFECT OF STIMULATION OF THE CHORDA AFTER ADMINISTRATION OF 10 MG. ATROPINE . ... 53 4 . TRACING OF VOLUME OF SUBMAXILLARY GLAND SHOWING DECREASE ON EXCITATION OF CHORDA ... 54= 5. TRACING OF VOLUME OF SUBMAXILLARY GLAND, SHOW- ING EFFECT OF CHORDA STIMULATION AFTER OBSTRUC- TION OF THE DUCT .55 6. DIAGRAM SHOWING THE MANNER IN WHICH THE STOMACH IS DIVIDED INTO TWO CAVITIES, SEPARATED ONLY BY A DIAPHRAGM OF MUCOUS MEMBRANE, AND STILL IN • MUSCULAR AND NERVOUS CONTINUITY ... 65 7. REPRODUCTION OF PLATE FROM RENE DE GRAAF'S TREATISE "DE SUCCO PANCREATICO," REPRESENTING A DOG IN WHICH HE HAD ESTABLISHED BOTH P.D. b ' X LIST OP ILLUSTRATIONS AND DIAGRAMS. FIQCBE. PAOE SALIVARY AND PANCREATIC PISTOLS, SMALL GLASS PHIALS BEING ATTACHED TO EACH TO COLLECT THE SECRETIONS 81 8. EFFECT OF INJECTION OF -ACID INTO LOOP OF SMALL JNTEsTINE AFTER DESTRUCTION OF ITS NERVOUS CONNECTIONS . . . . . . .87 9. EFFECT OF SECRETIN PREPARED BY THE ACTION OF DILUTE ACID ON INTESTINAL MUCOUS MEMBRANE WHICH HAD BEEN EXTRACTED WITH HOT ABSOLUTE ALCOHOL 89 10. FORMATION OF ISLET OF LANGERHANS FROM SECRETORY ALVEOLI 100 11. EFFECT OF INJECTION OF SECRETIN ON THE FLOW OF PANCREATIC JUICE AND OF BILE . . . .117 12. DIAGRAM (FROM CANNON) SHOWING THE APPEARANCE OF A LENGTH OF GUT FILLED WITH FOOD CONTENTS 140 13. RHYTHMIC CONTRACTIONS OF THE WALL OF THE SMALL INTESTINE (DOG) RECORDED BY INSERTING A RUBBER BALLOON INTO THE LUMEN OF THE GUT, AND CON- NECTING IT BY A TUBE WITH A PISTON RECORDER . 141 THE PHYSIOLOGY OF DIGESTION. LECTUEE I. THE FOOD- STUFFS AND THEIE CHANGES DURING DIGESTION THE MODE OF ACTIQN OF FERMENTS. Physiology deals with the sources and the transformations of energy in the living organism. In animals the whole of the energy available for the vital processes is obtained by the combustion of the food-stuffs, i.e., the union of their carbon and hydrogen with the oxygen taken in from the surrounding atmosphere. The office of digestion being to prepare the food- stuffs for absorption into the fluids of the body and for utilisa- tion by its constituent cells, the chapter in physiology dealing with this subject logically precedes all others. In the following lectures I propose to deal with the changes undergone by the food in the alimentary canal, and especially with the mechanisms by which these changes are brought about. The time at our command will not allow me to enter into full details in every part of the subject ; I shall therefore devote my chief atten- tion to those questions which are at present being most actively discussed by physiologists, and to the solution of which I am able to bring the experience of work which has been carried out in this laboratory. In the bewildering variety of foods that are at- the disposal of civilised man, it would seem at first sight hopeless to attempt P.D. B 2 THE PHYSIOLOGY OF DIGESTION. to give a description of the principles' "which underlie the diges- tion of each one of them. A chemical examination of these food-stuffs, however, reveals the possibility of a very simple classification. All the foods which serve to us as sources of energy are themselves derived from living beings, either plant or animal. The chemistry of the food-stuffs is, therefore, iden- tical with the chemistry of the tissues of living organisms. The substances which are utilised in the building up of a plant or animal fall into one of three main groups, which are also the groups into which our food-stuffs are divided. These groups are — (1) Proteids — nitrogenous bodies such as those forming the greater part of meat or white of egg. These can be split up' readily by hydrolytic agencies into a whole series of mono- amine- and diamino- acids, derived chiefly from the fatty series but partly also from the aromatic series. They also contain sulphur as an integral part of their molecule, chiefly in the form of cystin, which itself is derived from two amino-acid groups. (2) Carbohydrates, including the starches and sugars. (3) Fats, which are compounds of glycerin with fatty acids. I have spoken of these foods as sources of energy to the body. Is this their sole significance ? The energy value of food is easily determined by finding how much energy in the form c-f heat a given weight of it will evolve when burned in an atmo- sphere of oxygen. In this way we might find the following heat equivalents for the three classes of food-stuffs, namely — Proteids ... 5*5 kilocalories. Carbohydrates ... ... 4*1 ,, Fats 9-5 One gramme of fats, for instance, when burned in an atmo- sphere of oxygen to C0 2 and H 2 0, will evolve an amount of heat which is sufficient to warm 9'5 kilogrammes.of water from 0°C. FOOD-STUFFS AND THEIE CHANGES DTJEING. DIGESTION. 3 to 1*C. If the energy value of a food-stuff represents its whole value to the organism, we should expect that the animal would be able to nourish itself and discharge its normal activities at the expense of any one of these food-stuffs, provided that this were given in proportion to its energy or heat value. Within limits this is the case. If an animal be made to do more work, or be exposed to external cold, so that it needs more heat to main- tain its normal temperature, the amount of food which it takes must also be increased, and it seems to be a matter of indiffer- ence to the organism which class of food-stuffs is used to furnish this excess. From the energy point of view the value of a food is the amount of heat which it will evolve when burned to CO2 and H 2 0. From this point of view the nitrogen in the proteid molecule is practically valueless, and it is only the C and H atoms in the proteid which can be regarded as furnishing energy to the body. If an animal be corn- spelled to satisfy a large call on its energies by taking increased proteid food, the useless nitrogen in the molecule, which is set free by the utilisation and combustion of the carbon and hydrogen, must be discharged from the body, and as a matter of fact we find that, with increased proteid diet, there is corre- sponding increase in the output of nitrogen in the form of urea. As a source of energy, proteid cannot be regarded as presenting any advantages over carbohydrate and fat. In fact, it suffers from the disadvantage that, for the utilisation of its energy, nitrogen has to be split off, probably in the form of ammonia, and a certain amount of useless work has to be done in the transformation of this nitrogen into urea and its excretion from the body. Although, however, the nitrogen in the food is useless as a source of energy, its presence is an essential con- dition for the utilisation of the energy of the other food-stuffs, and it must be regarded, therefore, as one of the most important constituents of all living organisms. In fact, the protoplasm, b2 4 THE PHYSIOLOGY OF DIGESTION. the active part of the organism, consists almost entirely of proteids or allied bodies. Fats and carbohydrates, where they occur in the living organism, are found only to a slight extent in combination in the living protoplasm itself, the greater part of them being laid down as store material for the future wants of the active growing protoplasm. Many facts show that the combustion and utilisation of the energy of the carbon and hydrogen of the food take place in the protoplasm itself, the oxidisable molecules being linked on to the central living nucleus ; and it seems that nitrogen plays an important part both in this linkage, and in bestowing on the complex thus pro- duced the lability or instability which is a necessary condition of the vital processes themselves. Essential functions of all living beings are those of growth, repair, and in the higher animals death. No act can go on without involving some degree of disintegration of the living nitrogenous framework of the tissue, and the consequent need of repair. In every living cell, therefore, we may speak of two kinds of chemical changes, or of two destinations of the food- stuffs. In the first place there are the changes which furnish the energy necessary for vital manifestations, movement, warmth, etc. As sources of this energy, all three classes of food-stuffs can be employed, their value being given by their heat equivalents when taken as food. In the second place we have the changes which are involved in the disintegration, repair, and growth of the living . protoplasm itself. In this nutritional metabolism proteids play the most important part, and are absolutely essential for the continuance of life. An animal, therefore, can theoretically be nourished on a diet of pure proteid, but it would be impossible to keep an animal alive on a diet consisting either of pure fat or of pure carbohydrate. These three classes of food-stuffs being essential constituents of all our foods, the use of the processes of digestion is to FOOD- STUFFS AND THEIR CHANGES DURING DIGESTION. 5 render them fit for absorption into the blood, by which they may be carried round to all parts- of the body. In most cases they cannot he utilised in their original form by the living cells. It must be remembered that, when we nourish ourselves at the expense of an animal or plant, we are taking in, not only the current coin of the organism which is being used for the supply of energy to its vital processes, but also, and to a much larger extent, the framework forming the machinery of the organism, as well as its stores of carbo- hydrate or fat. The food-stuffs therefore, as we ingest them are in the most inactive form possible. Practically all pf them are colloidal, free from taste or chemical reaction, and presenting no tendency to unite with oxygen, or indeed to undergo any change whatsoever, apart from the interference of living organisms such as bacteria. In a starving animal, the stores of carbohydrate and fat and the proteid structure of the living cells have - to be converted into a soluble form, transformed, so to speak, into currency, before they can be utilised by other living cells for the discharge of their normal functions and the maintenance of the life of the animal. In the same way, when we take these colloidal or insoluble stable substances into our alimentary canal, they have to be dissolved and rendered diffusible, in order to allow of their easy transference across the wall of the gut into the blood and their transport to the tissue cells. On fats and carbohydrates, therefore, the effect of digestion will be to render them soluble and diffusible, and to reduce them to a condition in which they can be directly assimilated by the cells of the body. These latter cannot deal, for example, with all kinds of carbohydrate. Many an animal cell will starve when presented with starch, dextrin, or any of the disac- charides, such as maltose, lactose, or cane sugar. It is necessary, therefore, that all the carbohydrates shall be 6 THE PHYSIOLOGY OF DIGESTION. reduced in the alimentary canal or in its walls to the form of monosaccharides. As regards proteids, the processes of digestion have a different significance according as we are dealing with their value as givers of energy or their value as builders up of the living protoplasm. If the proteids of the food are to be oxidised and utilised as a source of energy, it is only necessary to render them soluble so as to assist their absorption. If, however, they are to be- built up as integral parts of the living cells, to take the place of molecules which have been destroyed in the wear and tear of the processes of life, a much more profound change is necessary. The proteids of the cells from different parts of the body have different molecular constitutions. Not only do they differ among themselves, but they differ very largely from many of the proteids which may be taken in with the food. A child is able to obtain material for the growth of his brain cells, his muscle cells, his liver cells, from a diet containing proteid in the form of caseinogen, of vegetable gluten, of meat fibrin, or vegetable proteid, such as edestin. A reference to the following tables will show the striking difference in com- position between the various proteids of the food and the proteids which have to be formed from them in the living tissues. We may take for example the manner in which the nitrogen is combined in the different proteids. For purposes of classi- fication the nitrogen can be divided into three fractions, accord- ing, to its behaviour in the product of the acid hydrolysis of the proteid. These fractions are — (a) The portion which is driven off as ammonia by heating the acid mixture with alkalies or magnesia, the so-called ammonia- or amide-nitrogen ; (b) That contained in the form of monoamino-acids ; ■(c) That contained as diamino-acids, or as bases such as FOOD-STUFFS AND THEIR CHANGES DURING DIGESTION. 7 guanidine, histidine, or arginine, etc., known as basic nitrogen and precipitated on addition of phosphotungstic acid. In the following table* is given the relative distribution of the nitrogen in various proteids among these three groups : — Proteid. Amide N. Basic N. Monamino-N. Crystallised serum albumin . . 6-5 344 60:2 Crystallised egg albumin 8-5 21-3 67-8 Crystallised edestin . . 10-2 38-1 55-0 Caseinogen of milk 10-4 ' 23-9 62-0 Serum globulin 8-9 25-0 68-3 Still greater differences are noticeable when we examine the content in certain individual constituents of the proteid molecule, thus : — Proteid. Arginin. Lysin. Hietidin. Tyrosin. Cystin. Edestin 14-07 — — — — Caseinogen 4-84 5-80 2-59 4-5 — Blood fibrin — — — 3-82 1-17 Gluten fibrin (wheat) 3-05 — 1-53 — — Zein (maize) 1-82 — 0-81 _v Egg albumin — — — 1-5 0-29 ' r 2-15 Serum albumin — — — 2-0 It is evident that to form serum albumin, for instance, out of wheat gluten, an entire reconstruction is necessary. This can only be accomplished by taking the proteid molecule to * From Hofmeister, " Ergebnisse der Physiologie," I., i. (1902), p. 777. 8 THE PHYSIOLOGY OF DIGESTION. bits, and by selecting certain of its constituent parts and building these up in the proper proportions to form a new proteid molecule. For the purposes of nutrition the changes in the proteid molecule in the intestine must be profound, and the extent of the change must be greater the more variation there is in the composition of the proteid of the food from the- composition of the proteids of the tissues. In primitive alimentary canals, every cell lining the canal may be endowed with amoeboid properties and capable of devouring food particles, the subsequent changes in the food particles to fit them for their journey through the rest of the body being performed in the body of the cell itself. In all the higher animals, however, including ourselves, the greater part of the preparation of the food is accomplished extra- cellularly in the lumen of the alimentary canal, and the changes are effected by means of special digestive juices, which are formed by the activity of masses of cells produced as outgrowths from the wall of the canal. The digestive juices attack the food-stuffs by means of ferments, and in every case the action of these ferments is hydrolytic, the food- stuffs taking up one or more molecules of water and under- going dissociation into simpler molecules. Since each class of food-stuff requires a different ferment, a great variety of ferments are concerned in the processes of digestion. In the following list the ferments of the alimentary canal are enume- rated, together/ with the substances on which they act and their ultimate products : — Food-staff. Ferment. Product of action. Proteids (all) Pepsin Albumoses and peptones (ammo-acids after pro- longed action). Trypsin . . Peptones, amino - acids and bases (complete hydrolysis). FOOD-STUFFS AND THEIR CHANGES DURING DIGESTION. Food-stuff. Ferment. Product of action. Hydrated proteids and Erepsin Amino-acids, etc. certain coagulable proteids such as fibrin and caseinogen Carbohydrates — Starch Amylase of saliva . . „ of pancrea- tic juice Dextrin and maltose Maltose . . Maltase Glucose. Cane sugar Invertase Glucose and fructose. Milk sugar Lactase Glucose and galactose. Fats Lipase (steapsin) . . Patty acids and glycerin. It will be seen that, as the end result of digestion, the enormous variety of food taken by man is reduced into a fairly small number of simpler bodies. These end products are : — (1) Carbohydrates. The monosaccharides: glucose, fructose or Isevulose, and galactose. (2) Fats : fatty acids, or (in alkaline medium) soaps, and glycerin. (3) Proteids. Here we have a great variety of mono- and diamino- acids, which may be enumerated as follows : — MONOAMINp-ACIDS — Glycine (aminoacetic acid) . . ... . \ Alanine (aminopropionic acid) Serine or oxyalanine (oxyaminopropionie acid) \ Aminovalerianic acid . . . . .1 Leucine (aminoisobutylacetic acid) Isoleucine (aminocaproic acid) . . . . . . J Aspartic acid • Glutamic acid Phenylalanine Tyrosine (oxyphenylalanine) Proline (pyrrolidine carboxy lie acid) .. Oxyproline (oxypyrrolidine carboxylic acid) . . Tryptophane (indol-aminopropionic acid) Monobasic acids of fatty series. Dibasic acids. Benzene (aromatic) derivatives. Heterocyclic compounds. 10 THE PHYSIOLOGY OF DIGESTION. DlAMINO-ACTDS AND THEIR COMPOUNDS Lysine (diaminooaproic acid) . . . . ■ ■ \ „, Arginine (guanidinaminovalerianic acid) . . > , hexQne bases _> Histidine (a pyrimidine derivative) . . / Diaminotrioxydodeeoic acid . . derived from a 12 carbon acid. . ( Sulphur - containing Cystin (derived from aminotniolactic acid) . . j hodv The -whole of these digestive changes in the food-stuffs are to be ascribed, to the action of ferments. "When, following the food through the walls of the intestine, we have to deal with the processes by which it is assimilated into the living cell, and the processes by which it undergoes oxidation or disinte- gration and so furnishes energy to the body, as well as the processes by which one cell may be nourished at the expense of other less important cells, in every -case we find that ferments are involved. It is impossible, therefore, to proceed further with our study of the digestive juices,, without trying to form some conception of the manner in which these bodies, the most important factors in the maintenance of life, effect their changes. It is important to note that all the changes wrought by the digestive ferments on the food- stuffs are hydrolytic in character. Thus the proteids are transformed by the action of pepsin or trypsin into the hydrated proteids, albumoses or peptones, and these again by the further process of hydration into the amino-acids. Starches take up water with the formation of maltose. Each molecule of the disaccharides takes up one molecule of water, and is converted into two molecules of a monosaccharide. Each molecule of neutral fat takes up three molecules of water to be transformed into glycerin and the corresponding fatty acid. If the food-stuffs are placed in contact with water, either at ordinary tempera- tures or at the temperature of the body, and bacteria be excluded from the solution, they undergo practically no - THE MODE OF ACTION OF FERMENTS. 11 change. If the solution be warmed, a slow progress of hydra r tion takes place, which is quickened by rise of tempera- ture, so that in water heated above boiling point hydration occurs with considerable rapidity. We may say, then, that the action of the ferments is to quicken a process of hydro- lysis which, without their presence, would take an infinity of time for its accomplishment. In this respect their action is similar to that of acids, and indeed of a whole class of bodies which are spoken of as catalysers and catalysts. A catalyser is a substance which will increase the velocity of a reaction without adding in any way to the energy changes involved in the reaction, or taking any part in the formation of the end products. Since the catalyser is unchanged in the chemical process which it brings about or hastens, a very small quantity is able to influence reactions involving large quantities of other substances. By adding acids to a watery solution of the food-stuffs, the process of hydrolysis is quickened in proportion to the strength and concentration of the acid. The effective catalytic agents in this process appear to be the hydrogenions of the free acid. There are many other substances besides the free acids, which may act" as catalysers, and a study of the conditions under which catalysis takes place may throw some light on the essential nature of the action 'of ferments. The velocity of almost any reaction in chemistry can be altered by the addition of some or other catalytic agent, and there are few of the ordinary reactions in which catalysis does not play some part. Among such processes we may instance the action of spongy platinum on hydrogen peroxide. Hydro- gen peroxide undergoes slow spontaneous decomposition into water and oxygen. If, however, a little spongy platinum be added to it, it is at once seen to decompose rapidly with the evolution of bubbles of oxygen, and the action does not cease 12 THE PHYSIOLOGY OF DIGESTION. until the whole of the hydrogen peroxide has been destroyed. Spongy platinum is able in the same way to quicken a very large number of chemical reactions. Thus sulphur dioxide and oxygen when heated together will combine very slowly ; the combination becomes rapid if a mixture of the two gases be passed over heated platinum. The same reaction, namely the combination of sulphur dioxide with oxygen, may be quickened by the addition of a small trace of nitric oxide, and this fact is made use of in the manufacture of sulphuric ;acid on a commercial scale by the ordinary lead chamber process. Hydrogen peroxide and .hydriodic acid slowly inter- act with the formation of water and iodine. This reaction may be quickened by the addition of many substances, among -which we may mention molybdic acid. It might be thought, however, that, although there is this superficial resemblance between the action of catalysers and that of ferments, certain important characteristics of the ferments might serve to make a wide cleavage between the two processes. Thus among the ferments we find a marked specificity. We may take as examples the ferments which act on the disaccharides. Any of the disaccharides, whether natural or artificial, can be readily converted by treatment I with acids into the corresponding monosaccharides. Thus ' -cane sugar treated in this way gives equal parts of fructose and glucose. Lactose will give equal parts of glucose and galactose. Maltose is entirely transformed into glucose. When we come to the ferments, however, we find that inver- tase, which quickly transforms cane sugar into fructose and glucose, has not the slightest action on either of the other disaccharides. In order to split up lactose we have to make use of a special ferment, lactase ; and similarly for the con- version of maltose into glucose we must employ the ferment maltase. The action of these ferments is not, however, so THE MODE OF ACTION OF FERMENTS. 15 specific as would appear when we confine our attention to tha food-stuffs themselves. Thus invertase not only breaks up cane- sugar, but also causes hydrolysis of raffinose and gentianose. Lactase, in addition to its action on lactose, or milk-sugar, has. the property of hydrolysing all the y3-galactosides. Emulsin hydrolyses the /?-glucosides (i.e., most of the natural glucosides),, as well as the /3-galactosides, including milk-sugar. Maltase not only converts maltose into glucose, but also hydrolyses. all the a-glucosides. On the other hand, although some sub- stances such as platinum, especially in the finely divided form of platinum black, can influence a very large number of: reactions, they cannot influence all chemical reactions. Potas- sium bichromate will act as the catalyser for the oxidation of hydriodic acid by bromic acid, but not for the oxidation of the same substance by iodic acid. Iron and copper salts in minute traces will quicken the oxidation of potassium iodide by potassium persulphate.but have no influence on the course of the oxidation of sulphur dioxide by potassium persulphate.. Tungstic acid increases the velocity of oxidation of hydriodic- acid by hydrogen peroxide, but has no effect on the velocity of oxidation of hydriodic acid by bromic acid, and these: examples may be multiplied to any extent. One cannot, therefore regard the limitation of action of the ferments as. justifying any fundamental distinction being drawn between the action of this class of substances and that of catalysts. Another contrast has been drawn between the effects of rise of temperature on these two classes of phenomena. Whereas, the influence of most catalysers on the velocity of a reaction increases rapidly with increase of temperature, in the case of' ferments this increase occurs only up to a certain point. This point is spoken of as the optimum temperature of the ferment action. If the mixture be heated above this point the action of the ferment rapidly slows off and then ceases. This.. 14 TEE PHYSIOLOGY OP DIGESTION. contrast again is only apparent. The ferments are unstable bodies easily altered by change in their physical conditions, and destroyed in all cases at a temperature consider- ably below that of boiling water. We may say, therefore, that ferment actions, like catalytic actions, are quickened by rise of temperature, but this effect of temperature is finally put a stop to by the destruction of the ferment. The same effect of temperature is observed in the case of inorganic catalysers whose physical state is susceptible, like that of the ferments, to the action of heat. By the passage of electric sparks between two platinum terminals immersed in distilled water, minute ultra-microscopic particles of platinum are thrown off into the fluid, so that a colloidal solution of platinum is obtained. This colloidal platinum exerts marked catalytic effects on various reactions, e.g., on the decomposition of hydrogen peroxide and on the combination of hydrogen and oxygen. The effect, however, presents an optimum tempera- ture, owing to the fact that the colloidal platinum is altered, coagulated, and thrown out of solution when this is heated to near boiling point. We may therefore employ either class of reactions in trying to form some conception of the processes which are actually involved. Very many theories have been put forward to account for this action of catalysers or of ferments. Many of them are merely transcriptions in words of the processes which actually occur, and fail to throw any light on their real nature. The essential phenomena involved fall directly into two classes. In the first place, it must be remembered that the molecules of any liquid or gas, which are situated in the surface layer in contact with some other substance, are in a different condition from those in the interior of the fluid, In gases this difference results in a diminution of the pressure or of the translatory velocity of the molecules in the surface, THE MODE OF ACTION OF FERMENTS. 15 and therefore to a condensation of the gas here. After a glass vessel has been evacuated by means of a mercury pump, it is found that the vacuum slowly diminishes, owing to the gradual giving off by the glass of the so-called occluded gas, i.e., gas which has been adherent to its surface, and perhaps in actual solution in its superficial layers. The glass gives up this occluded gas very slowly, and in order to make a perfect vacuum the process of evacuation has to be repeated several times, and the glass must be heated considerably during the operation. In many cases the combination of gases can be hastened by increasing the surface to which they are exposed, as by passing them over broken porcelain or powdered charcoal. The power of a solid to condense gases on its surface varies with the nature of the solid and the nature of the gas. It is very marked in animal charcoal, especially in the case of gases such as ammonia or sulphur dioxide. Metals also have some power of occluding or condensing at their surfaces. Thus both platinum and palladium will absorb a very- large amount of hydrogen. In the same way silver has the power of occlud- ing oxygen. That this effect is a surface phenomenon is shown by the fact that the power of these metals or sub- stances to occlude gases is in proportion to their state of subdivision. The same proportionality holds between the surface of these substances and their catalytic power. Thus the efficacy of platinum in hastening the combination of hydrogen and oxygen is in direct proportion to its fineness of subdivision, and is best marked when the metal is reduced to ultra-microscopic dimensions, as in the colloidal solution of platinum. Every colloidal solution must be regarded as presenting an enormous surface in proportion to the mass of substance in solution. Thus a sphere of 10 cubic centi- metres with a surface of 22 square centimetres, if reduced to a fine powder consisting of spherules about 0-00000025 cm. 16 THE PHYSIOLOGY OF DIGESTION. in diameter, will have a surface of 20,000,000 square centi- metres, i.e., nearly half an acre.* There is a direct proportionality,- therefore, between the power of a substance to condense a gas on its surface and its power to quicken the velocity of chemical changes in which the gas is involved. The same process of condensation occurs with dissolved substances. Just as the pressure of a gas in immediate contact with a solid body is diminished, so the osmotic pressure of a substance in solution is diminished at the surface. Hence there is a diffusion of dissolved substances towards the region of lower osmotic pressure i.e., a concentration of dissolved substances at the surface of contact. It was suggested by Faraday that the catalytic pro- perty of surfaces was due to this condensation of molecules, and the consequent bringing of the two sets of molecules within each other's sphere of influence. Whether this is the sole factor involved is doubtful, since mere compression of gases or increased concentration of solutions does not in the majority of cases result in such a quickening of the velocity of reaction as is brought about by the effect of the surface. It is possible that this condensation effect may in every case be combined with the second factor, which we must now consider, namely, the formation of intermediate products. If we take an alkaline solution of indigo, and boil it with some glucose, the indigo is reduced, giving up its oxygen to the glucose. The mixture therefore becomes colourless. On shaking with air, the colourless reduction product of the indigo absorbs oxygen from the atmosphere and is re-trans- formed into indigo. These two processes can be repeated until the whole of the glucose is oxidised, and the process can be made continuous if air or oxygen be bubbled through a hot * V. Mellor's, "Chemical Statics and Dynamics" (Longman's, 1S04), esp. pp. 245 et seq. THE MODE OF ACTION OF FERMENTS. 17 alkaline solution of glucose containing a small trace of indigo. In this case the indigo does not add to the energy of the reaction. It appears unchanged among the final products, and a small amount may be used to effect the change of an infinite quantity of glucose. It therefore may be said to act as a ferment or catalytic agent. Instead of an alkaline solution of indigo, we may use an ammoniacal solution of cupric oxide for the purpose of carrying oxygen from the atmosphere to the glucose. This is reduced to cuprous hydrate on heating with sugar, but cupric hydrate can be at once re-formed by shaking up the cuprous solution with air. It has been thought that a large number or all of the catalytic reactions occur in the same way by two stages, i.e., by the formation of an intermediate product. Thus in the ordinary process for the manufacture of sulphuric acid the nitric oxide may be supposed to combine with the oxygen of the air to form nitrogen peroxide. This interacts with sulphur dioxide, . giving sulphur trioxide and nitric oxide once more. The nitric oxide, which we alluded to before as the catalyser, may in this way be regarded as the carrier of oxygen from air to sulphur dioxide. It has been suggested that the action of spongy platinum or colloidal platinum rests on the same pro- cess, and that in the oxidation of hydrogen, for instance, PtO or PtOa is formed and at once reduced by the hydrogen with the formation of water. There is a certain amount of experimental evidence in favour of this hypothesis. According to Engler and Wohler,* platinum black, which has been exposed to oxygen, in virtue of the gas which it has occluded, has the power of turning potassium iodide and starch blue. This power is not destroyed by heating to 260° in an atmosphere of C0 2 , or by wash- ing with hot water. On exposure of the platinum black to hydrochloric acid, a certain amount is dissolved, and the substance loses its effect on potassium iodide. The amount dissolved corresponds with the amount * Quoted by Mellor, loc. cit., p. 269. P.D. 18 THE PHYSIOLOGY OF DIGESTION. of iodine liberated from potassium iodide, and also with the amount of oxygen occluded, the (soluble) platinum and oxygen being in the proportions necessary to form the compound PtO. But why should a reaction take place more quickly if it occurs in two stages instead of one ? The formation of an intermediate compound can only be regarded, as Ostwald has pointed out, as a sufficient explanation of a catalytic process, when it can be demonstrated by actual experiment that the rapidity of formation of the intermediate compound and the rapidity of its decomposition into the end-products of the reaction are in sum greater than the velocity of the reaction without the formation of the intermediate body. In the case of one reaction this requirement has been fulfilled. The ' catalytic action of molybdic acid on the interaction of hydriodic acid and hydrogen peroxide has been explained by assuming that the first action which takes place is the formation of permolybdic acid, which then interacts with the hydrogen iodide, to form water and iodine. Now it has been actually shown — (1) that permolybdic acid is formed by the action of hydrogen peroxide on molybdic acid ; (2) that permolybdic acid with hydriodic acid produces water and iodine ; (3) that the velocity with which these two reactions occur is much greater than the velocity of the interaction of hydrogen peroxide and hydriodic acid by themselves. Although we may find it difficult to explain why a reaction should occur more quickly in the presence of a catalyser by the formation of these intermediate bodies, certain simple analogies may help us to comprehend how a factor which introduces no energy can yet assist the process. Thus a man might stand to all eternity before a perpendicular wall twenty feet high. Since he cannot reach its top at one jump, he is unable to get there at all. The introduction of a ladder will not in any way alter the total energy he must expend on raising his body THE MODE OF ACTION OF FERMENTS. 19 for twenty feet, but will enable him to attain the top. Or we might imagine a stone perched at the top of a high hill. The passive resistance of the system, the friction of the stone and its inertia, will tend to keep it at rest, even though it be on a sloping surface and, therefore, tending to slide or roll to the bottom. If, however, it be rolled to the edge, to a point where there is a sudden increase in the rapidity of slope, it may roll over, and, having once started its downward course, its momentum will carry it to the bottom. The amount of energy set free by the stone in its fall will not vary whether the course be a uniform one, or whether it falls over a preci- pice at one time and rolls down a gentle slope at another. It is evident that, by a mere alteration of the slope or, in the case of a chemical reaction, of the velocity of part of its course, a change in the system may be initiated and brought to a conclusion which, without this alteration, would never take place. We have, therefore, to inquire in the case of enzymes or ferments how far their action is to be explained by surface phenomena, or by the formation of intermediate compounds between the ferment and the substance it acts upon (which is generally known as the substrate). This discussion we may defer until the next lecture. c2 LECTURE II. THE MODE OP ACTION OF FERMENTS {continued). We have seen that catalytic phenomena may be explained, in part at any rate, by the formation of an intermediate com- pound between the catalyst and the substance or substances which are undergoing change (the substrate) ; and the question arises whether the action of ferments may not be accompanied by the formation of some such intermediate compound. Since the action of ferments, like that of catalysts, consists essentially in the quickening up of processes which would otherwise occur at an infinitely slow velocity, we must first inquire whether the study of the velocity of the reaction will throw any light upon the number of substances taking part in the reaction, and, therefore, upon the question whether the ferment is itself involved at some stage of the reaction. It is well known that the velocity of a reaction does depend on the number of substances involved. As an illustration, we may take first the case of a reaction involving a change in one substance. If arseniuretted hydrogen be heated, it undergoes decomposition into hydrogen and arsenic. This decomposition is not immediate, but takes a certain time, and the velocity with which the change occurs depends on the temperature. At any given temperature the amount of substance changed in the unit of time varies with the concentration of the substance. If, for instance, one-tenth of the gas be dis- sociated in the first minute, in the second .minute a further tenth of tbe gas will also be dissociated. Thus, if we start THE MODE OF ACTION OF FERMENTS. 21 ■with 1,000 grammes of substance, at the end of the first minute 100 grammes will have been dissociated, and 900 of the original substance will be left. In the second minute one-tenth again of the remaining substance will be dissociated, i.e., 90 grammes, leaving 810 grammes. In the third minute 81 grammes will be dissociated, leaving 729 grammes. We see, therefore, that the amount changed in the unit of time will always bear the same ratio to the whole substance which is to be changed, and will, therefore, be a function of the concentration of this substance. Put in the form of an equation, we may say that , the amount changed in the unit of time, will be equal to KC, where K is a constant, varying with the substance in question and with the temperature, and C represents the concentration of the substance. The equation = KC applies to a unimolecular reaction. If, however, two substances are involved, the equation will be rather different. In this case the amount of change in a unit of time will be a function of the concentration of each of the substances, and the form of the equation will be \j> = K (C x X C y ). In the case of the unimolecular reaction, halving the concen- tration of the substance will halve the amount of substance changed in the unit of time. In the case of a bimolecular reaction, halving each of the substances will cause the amount of change in the unit of time to be reduced to one- quarter of its previous amount. If now either a unimole- cular or a bimolecular reaction be quickened by the addition of a catalyser or ferment, and the ferment enter into com- bination with one of the substances at some stage of the reaction, it is evident that our equation must take account also of the concentration of the ferment or catalyser. In the case of the catalytic effect of molybdic acid on the interaction between hydrogen peroxide and HI, which we studied in the 2'2 • THE PHYSIOLOGY OJ? DIGESTION. last lecture, we saw that there was definite evidence of a reaction taking place between the molybdic acid and the peroxide, resulting in the formation of an intermediate com- pound, namely, permolybdic acid. Brode has shown that the interaction of the molybdic acid is revealed in the equation representing the velocity of the reaction. Without the addition of molybdic acid, the equation would be = K (Ch 2 o 2 X C HI ) . After the addition of the molybdic acid, the equation becomes 4> = K (Ch 2 2 + y. CmolyMicacid) ChI, where y is another constant depending on the molybdic acid. If the ferments, which are engaged in the solution of the food- stuffs, act in a similar way by the formation of intermediate compounds, this fact should be revealed by a study of the velocity at which the ferment action takes place. Various methods may be adopted for the study of the velocity of ferment in action. If, for instance, we were inves- tigating the action of diastase upon starch, we should take solutions of starch and of diastase of known concentrations, keep them in a water bath at 38° C, or whatever temperature it is desired to study, and at a given moment add, say, 20 cc. of ferment solution to every 100 cc. of the starch solution. At periods of five or ten minutes after the addition had been made, 5 cc. of the mixture might be withdrawn by a pipette and at once run into boiling Fehling's solution. The precipitated cuprous oxide would be dried and weighed, and would give directly the amount of sugar formed in the action of the ferment. After obtaining a series of data in this way, a curve could be drawn, showing the amount of change of starch which had occurred in each unit of time. In the case of "the action of invertase on cane sugar the investigation is still easier. Since the change from cane sugar to invert sugar is accompanied by a change in the rotatory power of THE MODE OF ACTION OF FEEMENTS. 23 the solution on polarised light, it is only necessary to put the mixture of ferment and cane sugar into a polarimeter tube, ■which is l'f from gtud— 10 ^•■' —-, Water tort by K\ / / bio ad I •' . j* Saliva »5 I 1 1 *0 .25 \» It to ■Oi 'nit 1 I j j j j Fig. 1. — Diagram showing r (a) Total blood flow through submaxillary gland. (6) Total amount of water transferred from blood to gland, (c) Total secretion of saliva (Baroroft). the gland during secretion. In these experiments the whole submaxillary gland was placed in a plethy sinograph, and - s •Ml, \K1 tON C.C 1 ht '■> V s. "■V- /, 7 s r ~s U V ^ v *^\^ 5 io is ^o t$ so » the influence of the acid, we have called secretin. It can be ' prepared from the upper part of the intestine of any animal belonging to the class of vertebrata by scraping off the mucous membrane, pounding it up, and boiling with dilute hydrochloric acid. When the mixture is boiling it is nearly neutralised, so as to precipitate coagulable proteids, and then 8§ THE PHYSIOLOGY OP DIGESTION. filtered. The filtrate may be introduced into the veins of any animal, and will in every case produce a flow of pancreatic juice, whether the animal be frog, bird, or mammal, and what- ever be the origin of the secretin solution. We have not yet succeeded in isolating the secretin itself. The fact that it is not destroyed by boiling shows it is not a ferment. It is diffusible ; it is soluble in alcohol or alcohol and ether. It is. however very readily oxidised, and this fact makes it difficult to concentrate its solutions by evaporation. It is not thrown down by any of the reagents used for the precipitation of bases or proteids. Secretin may be formed from mucous, membrane by the action of any acids, or even by simply boiling the tissue with water. On the other hand mere extraction with" cold water or alcohol in which secretin is freely soluble, does not result in the production of an active solution. We may therefore conclude that the epithelial cells lining the gut contain a body — pro-secretin — which is insoluble in water,, alcohol, or salt solution, but which, under the influence of agents such as acids, undergoes hydrolysis with the splitting off of a new body — secretin (Fig. 9). That this chemical mechanism is normally involved in the production of pan- creatic secretion and is responsible for the flow obtained on the introduction of acid into the small intestine, is shown by the fact that its distribution in the gut exactly corresponds with Wertheimer's results. Thus, whereas extraction of the mucous membrane of the duodenum yields a very strong solution of secretin, a similar acid extract or decoction of the lower two feet of ileum yields a solution which has no influence on the pancreas. We have here an example of a type of mechanism which probably plays an important part in the correlation of activities of many organs of the body. In the normal life of the higher animals, which must be considered as a continuous series of PANCKEATIC SECRETION. 89 reactions to changes in the environment, ending only with the death of the animal, those reactions, which are carried out through the intermediation of the nervous system, play such a preponderant part, that we have almost forgotten the possibility of other means of co-adaptation among the different organs of the body. Yet, in the lowest organisms, before the appearance of any Fig. 9. — Effect of secretin prepared by the acuon of dilute acid on intestinal mucous membrane which had been extracted with hot absolute alcohol. The effect on the pancreas is the same as with the extract of fresh mucous membrane, but the alcohol has removed the substance responsible for the fall of blood pressure, which generally follows the injection of fresh extracts. central nervous system, it is by chemical means that any co-ordination of function is determined, either among the different organisms of a colony, or among the various cells making up a multicellular organism such as the sponge. In this case the mechanism, which determines the movement of phagocytic cells towards an irritant, the chase of food, the escape from noxious environment, or the approach of sexual 90 TIIE PHYSIOLOGY OF DIGESTION. cells, has been given the name of chemiotaxis. Since the application of these chemical stimuli depends on their diffusion through the medium bathing the cells, the process is neces- sarily a very slow one. So far as the communication of one cell with another in the same organism is concerned, the pro- cess could be quickened by the circulation of a common nutrient fluid such as the blood. Before the appearance of such a vas- cular system, however, we find that the "need for quick reactions has determined the setting apart of special reactive cells, endowed with a sensibility above tbat of their fellows, and united with the surface and the various tissues of the body by strands of protoplasm, specially endowed with conducting powers (nerve fibres). The whole history of the evolution of the higher types of animal henceforward centres about this nervous system. It is only in respect of the complexity of his nervous reactions that man himself has any advantage over the lower animals or plants. The development, however, of a special nervous system, adapted for the carrying out of quick reactions to changes in the environment, has not abrogated the more lowly and primitive method for co-ordinating the activities of different parts of the body. Where the necessity does not exist for a specially rapid reaction, as for instance in the adaptation of the activities of the digestive glands to the presence of food in the alimentary tract, one might expect to find, as we have found, that the connection between the part of the body receiving the stimulus and the part of the body which has to react to the stimulus should be by chemical means. Of these chemical messengers or hormones, as they may be termed (from bp^aw, arouse or excite), we already know several examples. The hormones determining gastric and pancreatic secretion we have dealt with in these last two lectures. We shall come across evidence later on for the existence of similar bodies, which determine the secretory PANCREATIC SECRETION. 91 activity both of the liver as well as of the intestinal glands. The suprarenal bodies manufacture in their medulla a substance — adrenalin — which, travelling over the whole body, seems to be a necessary condition for the excitation of any sympathetic nerves. In the absence of this substance there is a fall of blood pressure which is fatal within a very short time. The thyroid gland in the same way manufactures some sub- stance, perhaps thyro-iodin, which is necessary for the ptfoper growth of the tissues of the body and especially for the discharge Of the cerebral function. The foetus during - pregnancy appears to secrete into the maternal blood some chemical substance which excites the growth of the mammary glands. It is probable that with increasing knowledge the list of these messenger substances will be largely extended and that, with their isolation, we shall have at our command means of influencing the growth and activity of the majority of the organs of the body. It is worthy of note that these substances do not belong to the group of physiologically active agents of complex and indefinite chemical composition, such as the ferments and toxins, but are in all probability well defined chemical substances, highly unstable in most cases, but capable of analysis and, in some cases at any rate, of artificial synthesis. They are comparable in many respects to the[ alkaloids and other substances of definite chemical composition* I which form the drugs of our pharmacopoeia. The practice of drugging would seem therefore to be, not an unnatural device of man, but the normal method by which a number of the i ordinary physiological processes of the organism are carried 1 out. The question now arises whether this chemical mechanism is the only means employed in the body for the excitation of pancreatic secretion. We have seen that the action of the most effective method for procuring a flow of pancreatic juice, i.e 92 THE PHYSIOLOGY OP DIGESTION. the introduction of acid into the small intestine, is entirely due to the splitting off of secretin under the action of the acid, and have given reasons for regarding this as a hydrolytic process. There are certain substances, however, which may produce pancreatic secretion when introduced into the intestine, but do not form secretin when rubbed up with the mucous membrane. Thus a flow of juice may be obtained by the introduction, into a loop of small intestine, of oil or of irritant substances, such as ether or oil of mustard, which have no effect in producing secretin from the scraped off mucous membrane. Some light on the action of oil is thrown by the observations of Fleig, who showed that, if the mucous membrane be rubbed up with a solution of soap, the resulting mixture contains secretin, and will evoke a pancreatic secretion on introduction into the blood stream. This observer regards the secretin produced in this way as different from that produced by the action of acid, and therefore christens it ' sapocrinin ; ' but, apart from its mode of, preparation, there is no evidence of any difference between the two. Wertheimer, moreover, has shown that if oil of mustard be introduced into a loop of intestine, and the blood from this loop be led into the veins of a second dog, a flow of pancreatic juice will occur in the latter, showing that the blood flowing from the loop contains secretin. It is possible that the action of oil may be due to the formation of a certain amount of soap as the oil comes in contact with the mucous membrane, and that this soap is responsible for the formation of the secretin. The action of oil of mustard can only be explained as a formation of secretin by a process of hydrolysis in the over-stimulated cells of the small gut, perhaps a,s one of the stages in the death of the cells. Whether the vagus can still be credited with any direct secretory action on the cells of the pancreas must be regarded as highly doubt- ful. The normal effect of stimulating the vagtis is to cause PANCREATIC SECEETION. 93 movements of the stomach, and either relaxation or contraction of the pyloric orifice. The first effect, therefore, of stimulating this nerve may he to cause a flow of the contents of the stomach into the duodenum, and the contact of the acid contents with the mucous membrane will give rise to the production of secretin and therefore set the whole chemical mechanism going. When proper precautions are taken to prevent the escape of fluid from the stomach into the duodenum, the effect on the pancreas of stimulating the Vagus is so insignificant that it can hardly be regarded as evidence of the presence of secreto-motor fibres in this nerve. We see therefore that, whereas in the mouth the reaction, which must be rapid, is entirely nervous, in the stomach there is a mixture of the nervous mechanism with the more primitive chemical mechanism. The nervous secretion preponderates in this viscus. When we come to the pancreas, the primitive chemical mechanism, namely the formation of hormones and their circulation through the blood to the reactive tissue, suffices to account for the whole activity of the gland, and it is doubtful whether in this activity the nervous system plays any part whatsoever. LECTUEE VI. CHANGES IN THE PANCREAS DURING SECRETION. Our study of the submaxillary gland taught us that the act of secretion involves the expenditure of energy, which has its seat in the cells lining the secretory alveoli. This expenditure of energy is necessary, not only for the formation of the specific con- stituents of the saliva out of the blood, but also for the separation of a fluid having a smaller molecular concentration than the plasma. In addition to this osmotic work, mechanical work must be performed in raising the pressure in the duct, if there is any hindrance to the flow of the saliva. Under these cir- cumstances the pressure within the duct may rise to a height which is double that of the blood in the arteries supplying the gland. We concluded that this energy must be determined by the changes in the structure of the cells, which give rise to a formation of granules from the protoplasm, and later on to discharge of these granules and their conversion into the fully formed secretion. The chemical changes, that are concerned in the transforma- tion of the food materials supplied to the cells of the pancreas into the specific constituents of the pancreatic secretion, may also be expected to involve an expenditure of energy. In the case of the pancreas, however, there is no evidence of work done in changing the molecular concentration of fluid or in the production of a secretion pressure. If the duct be occluded, the pancreatic secretion ceases at a pressure of a few centi- meters H 2 0, owing no doubt to the ease with which any fluid CHANGES IN THE PANCEEAS DURING SECKBTION. 95 formed by the gland cells escapes through the alveoli into the surrounding lymph spaces. The molecular concentration of pancreatic juice, as judged by its freezing point, is almost identical with that of blood plasma. That -work is done in the process of secretion is shown by a determination of the amount of oxygen used up by the resting and by the secreting gland respectively. Experiments carried out with Dr. Barcroft have shown that the oxygen intake of the gland is approximately the same as that of the salivary gland, and that, as in the latter, the intake is increased two or three fold when the gland is made to secrete by the intravenous injection of secretin. These experiments were carried out in the following way:— =- In an anEesthetised dog the abdomen was opened, and the vein leading from the tail of the pancreas (which amounts to about one-sixth of the whole organ) was dissected out, and ligatures were so placed that a cannula might be rapidly inserted into the vein at a later stage of the opera- tion. A cannula was placed into the pancreatic duct and the abdomen closed. The dog's blood was then rendered uncoagulable (to prevent obstruction of the cannula by clotting) either by the injection of leech extract or by bleeding the animal several times, defibrinating, and returning the blood. The abdomen was then opened, and a cannula, placed in the pancreatic vein. The blood flowing from this was collected in measured vessels, (a) immediately ; (6) during active secretion excited by the injection of secretin. The total flow per minute was also measured. Corresponding samples of arterial blood were taken at the same time from the carotid artery. The gases from all these samples were collected by means of a mercurial pump and analysed, and the total gaseous changes of the gland were thus determined. When we investigate the histological changes in this- gland which accompany activity, we find many analogies with the corresponding changes in the salivary glands and stomach. The pancreas, however, presents certain peculiari- ties which merit particular attention. The normal pancreas, consists of a series of secretory tubules which branch out from small ducts, the latter leading into a few large ducts. The smalL DG THE PHYSIOLOGY OF DIGESTION. ducts are lined with a layer of narrow hyaline cells, the proto- plasm of which does not stain with either basic or acid dyes. At the point where a duct becomes continuous with a secreting tubule, we find outside these hyaline cells a layer of typical secreting cells. In cross section, therefore, such an alveolus shows two layers of cells, the continuation of the duct cells in the centre being known as the centro-acinar cells. Towards the end of the alveoli the centro-acinar cells disappear, leaving only the secreting cells. The latter in an ordinary resting gland, i.e., one taken from an animal which has not had food for twelve to twenty -four hours, show two well-marked zones. The outer zone consists of protoplasm with a strong affinity for basic dyes such as hsemotoxylin or toluidine blue. The inner zone, i.e., that turned towards the lumen, is made up of a mass of coarse granules, closely packed together, which stain intensely with acid dyes such as eosine. The nucleus, which is round and contains one or two well-marked acidophile nucleoli, is situated in the inner part of the protoplasm or basophile zone. If the gland has been secreting, the lumen of the alveoli contains a structureless material which, like the granules, stains deeply with eosine. If we study the" process of activity in the living gland of the rabbit, as was done by Kuhne and Sheridan Lea, we find that secretion, such as is pro- duced by the injection of pilocarpin, causes a diminution in the size of the cells and a discharge of the granules of the inner zone. We may conclude that here, as in the salivary glands,, the act of secretion involves some change in the granules and their discharge from the cell in the form of secretion. In the pancreas, as in the submaxillary gland, the process of dissimilation, which determines the formation of a secretion, is accompanied by a process of assimilation, i.e., the building up of fresh protoplasm from the surrounding lymph, and its continuous conversion into secretory granules. It is CHANGES IN THE PANCREAS DURING SECRETION. 97 evident that the occurrence of changes, such as I have described as the result of secretion, signifies a preponderance of the pro- cesses of dissimilation over those of assimilation, so that the whole cell gets smaller. This preponderance, however, is not a necessary feature of secretion. In the heart, for instance, the dissimilation which accompanies contraction is followed immediately or attended by an assimilation, which exactly balances the opposite process, so that the heart can continue to- contract throughout the whole of natural life- The same balancing of two processes may sometimes be observed in the pancreas. Thus in some cases we may excite a copious flow .of pancreatic juice by the injection of secretin. Provided that the preparation of secretin is free from any large amount of the depressor substances, with which it is usually contaminated, the injection may be repeated time after time without inter- fering in any way with the general condition of the animal. In such an animal, with a good blood pressure, a secretion may be produced continuously for as long as ten hours, and the pancreas at the end of this time may react as well to the injections as it did at the beginning of the experiment. If the animal be killed at the end of the experiment, the pancreas to the naked eye has the typical appearance of a resting gland. It is firm, opaque, and whitish. On microscopic examination the cells are found to possess the two zones which are distinc- tive of a resting gland. In this case one must conclude that the injection of this specific stimulating substance, secretin, has excited not only dissimilation but. also assimilation, that it has in fact stirred up the total activities of the living cells, so that there is a copious secretion without any loss of substance to the cells themselves. Usually the effect of repeated injections of secretin is to cause a gradual poisoning of the animal by the depressor substances, which are nearly always present in the decoction of intestinal mucous membrane, and P.D. H 98 THE PHYSIOLOGY OP DIGESTION. the consequent diminution of the circulation interferes with the process of assimilation more than with that of activity or dissimilation. A similar interference can be artificially brought about if the animal be bled while the injections of secretin are being administered. In such an experiment the amount of secretion produced by each injection becomes less and less, until finally the gland ceases to respond at all. If the animal be now killed, the gland presents a greyish pink appearance and is translucent and flabby. Sections made of such a gland, and stained with toluidine blue and eosine, show a diminution in the size of the cells and a diminution or entire disappearance of the red-staining granular zone. So far, then, the changes in the pancreas are exactly analogous to those in the salivary gland. Prolonged stimula- tion of the pancreatic cells, however, gives rise to changes to which we have no analogy in the other glands, changes which have been studied in detail by Dale. The pancreas has long been known to possess, in addition to the secretory alveoli and the ducts, certain structures, apparently separated from the secreting portions, which are called the ' islets of Langerhans.' These, which were first described by Langerhans in 1869, are roundish areas of tissue, varying in diameter between "1 and •24 mm., which consist of small polygonal cells with homo- geneous cell substance and round nuclei without nucleoli. These cells take up any stain with great difficulty, and in ordinary sections can be seen under the low power as unstained areas among the deeper staining alveoli. Most observers have regarded these structures as a tissue distinct from he secreting tissue and merely imbedded in the latter. Since the discovery by Minkowski that total extirpation of the pancreas gives rise to a fatal diabetes, this organ as a whole has been regarded as having two functions — (1) the secretion of a digestive fluid into the alimentary tract; (2) the secretion CHANGES IN THE PANCREAS DURING SECRETION. 99 into the surrounding lymph or blood stream of some substance which is a necessary condition for the utilisation of sugar in the body. It is evident that the secreting tubules are responsible for the production of the digestive secretion ; many physiologists have therefore regarded the islets as the organs for the production of the internal secretion. No evidence exists in support of this notion. A tissue of unknown origin has been accredited with the equally unknown anti-diabetic function of the pancreas. Certain Russian observers have, how- ever, suggested that these islets represent phases in the life history of the secreting alveoli, and that they are formed from the latter as the result of activity. This identity of origin of alveoli and islets receives support from the study of the structure of the pancreas in embryos. Laguesse describes the primitive buds, which in the sheep embryo form the pancreatic rudiment, as being of the nature of islets. These later become converted into secondary acini, which are again transformed into islets. The islets, after growth by continuous cell division, are yet again converted into a larger number of acini. Laguesse regards this process both as a method of growth and as representing an alternation between external and internal secreting (exocrine and endocrine) conditions of pancreatic tissue, and considers that the process may Continue to some extent throughout life. Dale's investigations confirm the views of the Eussian observers. The islets of Langerhans are not independent structures of separate origin, but are formed by certain definite changes in the arrangements and pro- perties of the cells of the ordinary secreting tissue. This change is gradually accelerate.d by exhaustion of the gland by means of secretin. As a result of such exhaustion there is, in the first place, a multiplication of the number of cell islets, and finally a conversion of the greater part of the secreting alveoli into islet tissue. Under such conditions the islets no h2 100 THE PHYSIOLOGY OF JHGESTION. longer form circumscribed spots scattered over the section but are spread diffusely throughout the whole gland. The changes are of such a kind as to assimilate all the £#•£? ■'.: :■#". ■.,; ■ ;-.V *.v f--?!,..^;*-' ::''■■■. retorii alve Pig. 10. — Formation of islet of Langerhams from secretory Portion of the pancreas of a toad in which active secretion had been excited by the injection of secretin. The islet of Langerhans, with its unstained hyaline cells, presents a marked contrast to the secretory alveoli, with their basophilc protoplasm and deeply- stained zymogen granules. The islet is, however, increasing in extent at the expense of ' the secreting tissue. The latter in many places is losing all its chromOr phile elements and undergoing conversion into islet tissue. In the middle of the islet is some of the secretory tissue where the change is not yet quite complete. (Drawn from a microphotograph of a specimen by H. H. Dale.) cells to those forming the epithelium of the ductules and the centro-acinar cells, thus bringing about a reversion to the embryonic type. Complete exhaustion thus causes, not CHANGES TN THE PANCREAS DURING SECRETION. 101 only an extrusion of the whole of the secretory granules, but also an emptying out and disappearance of the whole of the basophile protoplasm. It is worthy of note that the proportion of islet tissue to secreting tissue is increased, not only by prolonged activity, but also by the prolonged inactivity which occurs during starvation. In the latter case the gland, which is not required for digestion, is called upon to give up its stored material, whether granules or protoplasm, to serve as food for the working of those parts of the body whose continuous activity is a condition of the maintenance of life — such as the central nervous system, the brain, and the respiratory muscles. In this process of wasting, the same changes are brought about in the appearance of the cells as when the discharge of their constituents is required for the production of a juice for the purpose of digestion. Since the islets are in constant process of formation from alveoli as the result of activity, there must be a constant disappearance of islets and new formation of the alveoli to maintain the balance between the tissues. The embryological evidence brought forward by Laguesse, as well as Dale's experiments on the toad, show that pancreatic growth is a function of the islets, cell multiplication being observed only in the islets which are produced as a result of extreme activity. Whether the pancreatic tissue in its islet stage has special connections with the carbo- hydrate metabolism of the body, or whether the anti-diabetic functions of the gland are carried out by its alveolar cells, in addition to and at the same time as their ordinary secreting functions, we are not yet in a position to state. LECTUEE VII. THE PROPERTIES OF THE PANCREATIC JUICE. The pancreatic juice, -which is obtained after a meal from an animal with a permanent fistula, is similar in all respects to that obtained from one with a temporary fistula, as the result either of introduction of acid into the duodenum, or of the injection of secretin into the blood stream. It is a clear colour- less fluid, somewhat viscid, with a specific gravity of about 1030. It contains from 2 to 3"5 per cent, total solids, of which about 1 percent, consists of salts, the remainder of coagulable proteids. Among these proteids a certain proportion are precipitated on neutralisation. In a neutral solution about one-half the total proteids are coagulated between 55 and 60 degrees C, while the remainder are coagulated about 75 degrees C. The juice is always strongly alkaline; 10 cc. of juice for their com- n plete neutralisation require between 10 and 15 cc. of ^ acid It is worthy of note that the alkalinity of the juice corre- sponds almost exactly to the acidity of the gastric juice. Thus in one experiment, 70 cc. of pancreatic juice, obtained by injection of secretin, required for their complete neutralisa- tion 78 cc. of '4 per cent, hydrochloric acid. Each portion of chyme, which is ejected from the stomach into the duodenum, will continue to excite the production of secretin in the epithelial cells until, under the influence of the absorbed secretin, the pancreas has poured out an equal quantity of pancreatic juice, and the duodenal contents are THE PROPERTIES OP THE PANCREATIC JUICE. 103 thus neutralised. The pylorus will then open and allow a further portion of acid chyme to pass into the duodenum, to excite in the same way the secretion of a further equivalent portion of pancreatic juice. Since under normal conditions a secretion of bile occurs at the same time as the pancreatic secretion, and since bile has a certain power of neutralising the acid of the chyme, it is probable that under normal circum- stances the secretion of pancreatic juice will be rather smaller in amount than the chyme passing through the pylorus. The neutralising effects of these two juices is aided moreover by the secretion of an alkaline juice by the intestinal glands. The final result will be the production of a neutral fluid in the duodenum, and it is in this neutral fluid that the processes of intestinal digestion will go on. Pancreatic juice, obtained in either of the above-mentioned ways, contains ferments, which act as strong hydrolytic agents i on starches and fats. Starch is rapidly converted by the juice into dextrin and maltose, and the maltose is more slowly transformed into glucose.* The neutral fats are split up into fatty acids and glycerin. On proteids, juice obtained from a temporary fistula has very slight action. Boiled eggwhite or gelatin are not digested even after weeks of soaking in the fluid. Fresh fibrin and caseinogen are slowly digested. The juice may therefore be said to contain a weak proteolytic ferment, resembling that which can be extracted from almost any tissue of the body. A similar ferment can be obtained from extracts of the intestinal mucous membrane, and has been named by Cohnheim erepsin. Its chief function in this situation appears to be the further digestion of albumoses and peptones, and their conversion into amino-acids. It seems, therefore, that the pancreatic cells, produced as an outgrowth * The conversion into glucose takes place more rapidly in a slightly acid medium. from the mucous membrane of the intestine, have retained the power of producing this weak proteolytic ferment in common with the other cells clothing the inner surface of the gut. These properties of fresh pancreatic juice were described by Claude Bernard, who regarded the proteolytic functions of the juice as unimportant. Corvisart however, working, not with the juice as obtained from a cannula in the pancreatic duct, but with the juice as secreted into the duodenum, described as one of its essential properties an extremely energetic action on proteids. Most of the later re- searchers dealt chiefly with an extract of the pancreas itself. All of thesephysiologists, of whom Kuhne, Heidenhain, and Langley may be specially mentioned, found that the watery extract contained not only lipase and amylase, but also a substance which rapidly underwent conversion into an active proteolytic ferment. The latter was named trypsin, and its precursor in the gland trypsinogen. In the juice obtained from permanent fistulse, Pawlow found trypsin preformed, but showed later' that part, at any rate, of the trypsin was present, not in the form of ferment, but as its precursor trypsinogen. Chepowalnikow, working in Pawlow's laboratory,' found that the proteolytic activity of the juice was enormously in- creased by adding to it a drop of intestinal juice or of an extract of intestinal mucous membrane. He therefore con- cluded that the juice generally contained trypsinogen, which under -the influence of a ferment enter okinqse, contained in the succus entericus, was transformed into the active ferment trypsin. , Now it must be remembered that the juice obtained by Pawlow's method, before it is collected, has to trickle over ' the small portion of intestinal mucous membrane which is left in the abdominal wall surrounding the orifice of the duct. This mucous membrane can serve as a source of enterokinase, and Delezenne has found that, if a cannula be inserted through THE PROPERTIES OF THE PANCREATIC JUICE. 105 the papilla into the duct, so as to prevent the juice coming I in contact with the intestinal mucous membrane, the liquid j 30 obtained contains no trypsin at all, and is without effect on i coagulated proteid. We may say therefore that juice, as it is >,] secreted normally by the pancreas, contains no trypsin, but J a precursor of trypsin named trypsinogen. The trypsinogen can be converted into trypsin, only by the action of the ferment enterokinase furnished by the mucous membrane of I the gut. No other agent is able to effect this transformation. ! The spontaneous conversion of the trypsinogen, observed by the older workers to occur in extracts of the pancreatic gland, depends, not as they thought on the acidity or reaction of the gland, but on the accidental defiling of the tissue with intes- tinal contents in the process of extraction from the animal. If care be taken, in cutting the pancreas out of the dead body of an animal, to avoid any contamination of the gland with intestinal contents or mucous membrane, a watery or glycerin extract, though containing trypsinogen, will remain inactive j for months ; but at any time it can be activated by the I addition of a small amount of enterokinase. As I have said, the discoverers of enterokinase looked upon it as a ferment which converted trypsinogen into trypsin. Since, in this case, one ferment is formed by the action of another, Pawlow spoke of enterokinase as the " ferment of ferments." More lately a different view has been put forward of the mode of interaction between these two bodies, by D6l6zenne, and by Dastre and Stassano,* and this view has been accepted by such authorities as Metchnikow and Ehrlich. According to them, trypsin is not a single body, but is a j combination or association of two bodies, trypsinogen and j enterokinase. They have "thought that, just as two bodies, 1 called the amboceptor and the complement, are involved in the * Arnliivfis infcp.rnat. dfi PhvRinl.. Vol.. T.. t>. fifi. 19f)4. 106 THE PHYSIOLOGY OF DIGESTION. destruction of red blood corpuscles by foreign sera, so in tbe destruction of the proteid molecule by trypsin, the trypsinogen serves simply to anchor the active ferment, the kinase, on to the proteid molecule. In further support of this analogy with the phenomena of haemolysis, Del6zenne has stated that enterokinase can be obtained in large quantity front lymphatic glands, as well as from the leucocytes of the blood, and is therefore simply one of the cytases, the digestive ferments contained in the phagocytic cells of the body. Such an analogy between the methods employed in the defence of an animal against invasion by foreign cells, and that employed in normal nutrition, would be of far-reaching importance, and Bayliss and I have therefore reinvestigated the question. A decision between the two views is not difficult to arrive at. If trypsin be in all cases a combination of trypsinogen and enterokinase, there must always be a certain proportion between the quantities of the two substances present in any active juice, in order that it may exert its full powers. If on the other hand enterokinase acts simply as a ferment, it does not matter how small a quantity of enterokinase is added to the inactive juice containing trypsinogen, provided that a sufficient time is allowed for the ferment to work. We have found that, as a matter of fact, the smallest trace of entero- kinase is able, if it be given sufficient time, to activate any quantity of inactive juice. As we increase the amount of enterokinase added, we do not increase in any way the maximum digestive power of the juice. We simply hasten the process of activation. Moreover, if trypsin always owes its activity to an association of the two bodies, it must always | contain enterokinase, and therefore be able to activate I trypsinogen to which it may be added. This is not the case. Although certain preparations of trypsin contain traces of enterokinase and therefore exert a small activating effect, it is THE PROPERTIES OF THE PANCREATIC JUICE. 107 possible to procure specimens of trypsin which have not the slightest activating influence on fresh pancreatic juice. There is a further biological test which we can apply to decide the question. Normal serum resists the digestive action of trypsin in consequence of its content in a body — antitrypsin. This antitrypsin of serum has been regarded by Dastre as an antikinase. It is possible, however, to make antikinase by injecting an animal with successive doses of enterokinase. Such an antikinasic serum differs entirely from the normal antitryptic serum. Whereas normal serum, in most cases, has no influence on enterokinase but annuls the action of trypsin, an antikinasic serum, prepared by the subcutaneous injection of enterokinase, entirely paralyses the activating power of enterokinase on ' trypsinogen solutions, but has no influence on the digestive powers of a solution of trypsin. Finally it has been shown by Weinland, that intestinal worms owe their immunity from digestion to a substance which is present in their tissues and which has the property of preventing pan- creatic digestion. Weinland regards this body as an anti- trypsin, Dastre as an antikinase. It has been shown lately by Hamill that the antibody extracted from intestinal worms acts in all respects like the antitrypsin of normal serum. It has no effect on enterokinase, and its inhibitory influence is limited to fully formed trypsin. There are no grounds there- fore for the analogy which has been drawn between the interaction of these two bodies and the interaction of the two bodies which are involved in the solution of red blood corpuscles. Enterokinase is a ferment secreted by the intestinal epithelium and peculiar to this epithelium. We have found it impossible to extract any enterokinase from lymphatic glands or indeed from any tissues other than those of the intestine. There is no justification therefore for class- 108 THE PHYSIOLOGY OF DIGESTION. have been to confirm entirely the view of Pawlow, with regard to the action of this " ferment of ferments." Tnr: Qualitative Adaptation of the Pancreatio Juice. The mechanisms which we have studied in the last few lectures provide for a very extensive adjustment between the activity of the pancreas and the digestive needs of the animal. I Substances which are difficult of digestion will remain long in the stomach and will probably excite a greater flow of gastric juice. i The flow of pancreatic juice will be determined by the flow of J gastricjuice. Thegreatertheamountofacidchymeenteringthe duodenum the larger will be the amount of pancreatic secretion, "With a rapid flow we shall have a more watery juice, containing however the normal amount of sodium carbonate. The slower the flow the more concentrated in proteid and in trypsinogen shall we expect to find the juice. According to Pawlow, how- ever, the activity of this gland shows a marvellous qualitative adaptation to the nature of the food-stuffs. His pupil, Vasilieff, found that the pancreatic juice obtained from animals with permanent fistulas showed variations in the relative quantities 6i- the three ferments present, according to the nature of the food, the trypsin being formed in largest amount on a diet of meat, lipase on a diet of fat, and the amylase on a diet chiefly consisting of carbohydrates. There was thus a slow accom- modation of the pancreatic cells to the nature of the food which the animal receives. According to Walther the adaptation is still more rapid. If in the course of one day three meals, the first of milk, the second of bread, and the third of meat, be eaten in succession, at intervals of a few hours, the meat meal will give a juice containing the largest proportion of trypsin, while the meal of bread causes the secretion of a juice in which the THE PROPERTIES OF THE PANCREATIC JUICE. 109 ferment amylase is preponderant. The figures obtained by this observer are given in the following tables : Proteolytic Ferment. Amylolytic Ferment. Fat-splitting Ferment. Quantity of Juice. ' Diet. CO 3°§ H'S | 5 ho ffl s °-g * 1-5 03 do, "S.13 S bo m §1 Milk 600 co. . . 48 cc. 226 1085 9 432 903 4334 Bread 250 gms. . . 151 ce. 131 1978 106 1601 53 800 Meat 100 gms. . . 144 eo. 106 1502 4-5 648 25 3800 It will be seen that, while their general statements as to trypsin and amylase are borne out by these figures, there is a very little difference between the lipase, secreted on a fatty diet such as milk, and that secreted on a proteid diet such as meat. Moreover, it must be remembered that the observations of these two physiologists were carried out before the discovery of enterokinase. The amount of trypsin they found in each specimen of juice therefore must have been purely accidental and dependent on the time at which they examined the proteolytic powers of the samples. Any postponement of the examination would give the small traces of enterokinase a longer time to act, and would increase the tryptic power of the juice. We have therefore only the results on amylase in support of the general statement as to the powers of adaptation presented by the pancreas. The subject is in need of further investigation. Pawlow's views seemed to receive weighty confirmation from the results of an experiment conducted by Weinland. Wein- land stated that, whereas the pancreas of an adult dog is free from lactase (the ferment which converts lactose into galactose and glucose), extracts made from the gland of an animal, taking milk or milk sugar with its diet, 11U THE PHYSIOLOGY OF DIGESTION. contained this ferment. Here then was a definite example of adaptation — the appearance in the gland and presumably in the juice, of a ferment, not previously present, as the result of a special form of diet. With the view of 1 determining the mechanism of this adaptation, Weinland's experiments were repeated by Bainbridge with the result that lactase was found in the pancreatic juice after feeding with lactose but was absent unless this substance were administered. A French observer, Bierry, having repeated these experiments with absolutely negative results, the whole subject has been reinvestigated by Plimmer. For the purpose of determin- ing the presence of lactase in the juice or extracts of the gland, 20 to 50 cc. of the extract or juice were allowed to digest for three days with a 5"0 per cent, solution of lactose, toluol being added to prevent bacterial changes. At the same time a control experiment was carried out, using the identical quantities, but after previously boiling the juice or pancreatic extract, to destroy any ferment that might be present. At the end of this time the proteids were removed by means of mercuric nitrate, the excess of mercury got rid of by sulphuretted hydrogen, and the amount of sugar determined in both fluids by means of Allihn's method. In this method, the copper oxide, produced by the reduction of Fehling's solution, is collected and weighed, so that no scope is left for error of judgment in determining the exact moment at which the reduction of Fehling's fluid is completed. In every case Plimmer found that the reduction power of the milk sugar, which had been treated with extracts of pancreas, or with pancreatic juice taken from animals fed for weeks on lactose, was identical with that of the control solution in which the. , j uice or extract had been previously boiled. We must conclude, therefore, that the pancreas has no power of altering its secretion in response to the presence of lactose in the gut. THE PKOPERTIES OF THE PANCREATIC JUICE. Ill Lactase is present as a normal constituent of the intestinal mucous membrane (at any rate in young-animals), so that there is no necessity for the development by the pancreas of the power of digesting this substance. The importance of Bierry's and Plimmer's results lies in the fact, that they disprove the one definite case, in which we thought we had a qualitative adaptation of the pancreatic secretion to the nature of the food. Popielski, a former pupil of Pawlow, has himself come to the conclusion that, in the process of secretion, the pancreas pours out the whole of its contained ferments or pro-ferments, and has denied altogether the power of adaptation wliich has been ascribed "to this gland. Pawlow regards the adaptation as deter- mined by a specific sensibility" of the mucous membrane of the duodenum to the different classes of food-stuffs and the consequent production of nerve impulses of varying qualities proceeding to the gland. We have already seen that the normal activity of the pancreas is called forth, not by nervous changes but by the chemical messenger, secretin. There is no evidence that, in the absence of this mechanism, stimulation of the mucous membrane of the intestine can evoke any pancreatic secretion, and it is therefore still more improbable that a qualitative adaptation of the juice to the type of food-stuff is determined by such a nervous mechanism. There are riddles enough in physiology without conjuring up a teleological adap- tation for which the experimental evidence is inadequate, the ' conception of its mechanism impossible, and which is not necessary for the well-being of the animal. LECTUEE VIII. THE BILE. The fact that the bile, the secretion of the liver, is in so many animals poured into the intestine by an orifice common • to it and the pancreatic juice, suggests that these two fluids co-operate in their actions on the ingested food-stuffs, and points to a direct use of the bile in the processes of digestion. In addition to this function, the bile must also be regarded as an excretion, representing as it does the channel by which the products of disintegration of haemoglobin— the red colouring matter of the blood — are got rid of from the organism. As an excretion the production of bile must be continuous, and related, not to the processes of digestion, but to the intensity of destruction of the red corpuscles. On the other hand bile, as a digestive fluid, is needed in the gut only during, the period that digestion is going on. The exigencies of the body, therefore, require a continuous excretion of bile by the liver, but a discontinuous entry of this fluid into the small intestine. This discontinuity in the entry of a continuous secretion into the. intestine is secured, in the majority of animals, by the existence of the gall bladder, a diverticulum from the bile ducts, in which all bile, secreted during the intervals between the periods of digestive activity, is stored up. In the horse,-where the gall bladder is absent, its place is taken to some extent by the great size of the bile ducts. Moreover, in such an animal the process of digestion is much more continuous in character than it is in carnivora. Since the bile accumulates in the gall THE BILE. 113 bladder during the whole time that digestion is not going on, md is only poured into the gut during digestion, we find on opening a fasting animal that the gall bladder is distended, svhereas in an animal some hours after a meal the gall bladder is practically empty. During the period that the bile secreted by the liver remains in the gall bladder, it undergoes certain changes, as is shown by comparison of the composition of bile obtained from the gall bladder with that obtained from a fistula of the bile iuct. Analyses of Bilb (Human). From a biliary fistula (Yeo and Heiroun). From the gall bladder (Hoppe-Soyler) in 100 parts. Mucin and pigments . . 0-148 Mucin . 1-29 Sodium taurocholate . . 0-055 Sodium taurocholate . . 0-87 Sodium glyoocholate . . 0-165 Sodium glycoeholate . . 303 Cholesterin •1 Soaps . 1-39 Lecithin . L 0-038 Cholesterin . 0-35 Fats •j Lecithin . 0-53 Inorganic salts . . 0-840 Fats .. .. . . . 0-73 Water . . ' . . . 98-7 During its stay in the bladder, the bile is concentrated by the loss of water and by the addition to it of mucin or nucleo- albumen, derived from the cells lining the bladder. Of the Dther constitutents of bile, the pigments must be regarded simply as waste products. They pass into the intestine and ire there converted by the processes of bacterial reduction into stercobilin, which is excreted for the most part with the Eseces, a small proportion being absorbed into the blood vessels and turned out in a more or less altered condition as the pigments of the urine. From the point of view of diges- tion, the important constituents of bile are the bile salts, with the lecithin and cholesterin held in solution by these salts. Before we enquire into the action of these essential digestive jonstituents, it will be interesting to determine the time 114 THE PHYSIOLOGY OF DIGESTION. relations of the secretion, as well as of the out-pouring of bile into the intestine, in connection with the processes of digestion. These time relations can be learnt from animals in whom the bile is conducted to the outside of the body by means of a permanent fistula. In order to determine the time relations of the flow of bile into" the intestine, Pawlow has devised the following operation : — In the dog, the abdomen is opened, and the common bile duct sought as it passes through the intestinal wall. The orifice of the duct, with a piece of the surrounding mucous membrane, is then cut out of the wall of the intestine, and the aperture thus made sutured. The excised portion of mucous membrane, with the opening of the duct, is then sewn on to the surface of the ' duodenum, and the loop of duodenum at this point is stitched into the abdominal wound. After healing, the natural orifice of the bile duct is thus made to open on the surface of the abdomen. In an animal treated in this way, the flow of bile from the fistula is found to run absolutely parallel to the pancreatic secretion. Although smaller in amount, it rises and falls with the latter. Thus a meal of meat produces a large flow of bile, a meal of carbohydrates only a small flow. Moreover, beginning almost immediately after taking food, it attains its maximum with the pancreatic juice in the third hour, and then rapidly declines. In the production of this flow of bile, two factors may be involved: (1) the emptying of the gall bladder ; (2) an increased secretion of the bile. In order to determine the relative impor- tance to be ascribed to each factor, we must compare the results obtained on an animal possessing a Pawlow fistula with those obtained on an animal provided with a fistulous opening into the gall bladder, the common bile duct in the latter having been ligatured to insure that the total secretion of THE BILE. 115 bile passes out by the fistula. In such animals we find, as we should expect, that the secretion of bile is a continuous process, but that, synchronously with the great outpouring of bile into the intestine during fie third hour after a meal, there is an increased secretion of this fluid. The passage, therefore, of the semi-digested food from the stomach into the duodenum causes, not only a slow contraction and empty- ing of the gall bladder, but also an increased secretion of/ bile by the liver. "What is the mechanism involved in the production of these two effects? The muscular wall of the gall bladder, as has been shown by Dale, is under the control of nerves derived both from the vagus and from the sympathetic, the former conveying motor and the latter inhibitory impulses. It is usual to suppose that the entry of acid chyme into the duodenum provokes reflexly the contrac ■ tion of the gall bladder, but the exact paths and steps in this reflex act have not yet been fully determined. The increased secretion of bile, which is produced by the passage of the acid chyme through the pylorus, can be also evoked by the intro- duction of acid, such as - 4 per cent. H.C1., into the duodenum, and occurs even after division of all connection between the liver and the central nervous system. Since the presence of bile is necessary for the full development of the activities of the pancreatic juice, and its secretion is initiated by the same sort of stimulus, i.e., acid applied to the mucous membrane of the gut, the question naturally arises whether the mechanism for the secretion of bile may not be identical with that for the secretion of pancreatic juice. In order to decide this point we must make a temporary biliary fistula, by inserting a cannula into the hepatic duct. A solution of secretin is then prepared from an animal's intestine. In making this solution, we must be careful to avoid any contamination by bile salts, which mav nnssihlv he adherent to the mucous mam limn fi nf the 116 THE PHYSIOLOGY OF DIGESTION. gut and would in themselves, on injection, evoke an increased secretion of bile. It is therefore better to extract the pounded mucous membrane with boiling absolute alcohol, until this fluid, evaporated into a small bulk, shows no trace of bile salts. The dried and powdered gut is then boiled with dilute acid. On injecting the solution of secretin so obtained into the animal's veins, an increased flow of bile is at once produced. In one experiment, for instance, we found that the injection into the veins of 5 cc. of a solution of secretin, prepared in this way, increased the secretion of bile by the liver from twenty-seven drops in fifteen minutes to fifty-four drops in fifteen minutes (Fig. 11).' The rate of secretion was therefore doubled. We must conclude from these experiments that the mechanism, by which the increased secretion of bile is pro- duced at the time when this fluid is required in the intestine, is identical with that for the secretion of pancreatic juice, and that in each case one and the same substance — secretin — is formed by the action of the acid on the cells of the mucous membrane, and that this secretin, on absorption into the blood stream, excites both the liver and pancreas to increased activity. THE DIGESTIVE FUNCTIONS OF THE BILE. Bile contains a weak amylolytic ferment. Its uses in digestion are dependent however, not on the presence of this ferment, but on the peculiar action of the bile salts on the fermentative powers of the pancreatic juice. It was shown long ago by Williams and Martin * that the amylolytic power of pancreatic extracts is doubled by the addition of bile or of bile salts. Pawlow has stated that the same holds good of the proteolytic power of this juice. Most important, however, is the part played by the bile in the digestion and absorption • Proc. Boy. Soc, Vol. XLV., p. 48 and Vol. XL VIII., p. 160, 1890. THE BILE. 117 of fats. The fat-splitting action of pancreatic juice is trebled by the addition of bile, whether boiled or unboiled. This quicken- ing action of the bile probably depends, like its function in the absorption of fats, on the peculiar physical properties of the bile salts, with those of the lecithin and cholesterin, which are held in solution. Not only does such a solution diminish the surface tension between watery and oily fluids, so promoting the closer approach by the lipase of the pancreatic juice to the fats on which it is to act, but it has also the MwYVAtywWW^^ Fig. 11. — Effect of injection of secretin on the flow of pancreatic juice and of bile. The lines from above downwards represent — (1) Blood pressure; (2) drops of pancreatic juice; (3) drops of bile; (4) signal marking moment of injection of secretin ; (5) time-marking 10" intervals. power of dissolving fatty acids and soaps, including even the insoluble calcium and magnesium soaps. It is probable that it aids also in holding in solution, and bringing in contact with the fat, the lipase of the pancreatic juice. It has been shown by Nicloux* that the lipase contained in oily seeds, such as those of the castor plant, is insoluble in water but soluble in fatty media. The dried ferment obtained from the pan- creas in many cases yields no lipase to water, but gives a strongly lipolytic solution when extracted with glycerin. The digestive function of bile therefore lies in its power of serving as a vehicle for the suspension and solution of the interacting * V. Proc. Boy. Soc, Series B, Vol. LXXVIL, p 454. 118 THE PHYSIOLOGY OF DIGESTION. fats, fatty acids, and fat-splitting ferment. This vehicular function plays an important part in the absorption of fats. These pass through the striated basilar membrane bounding the intestinal side of the epithelium, not, as has been formerly thought, in a fine state of suspension (an emulsion), but dissolved in the bile in the form of fatty acids or soaps and glycerin. On the arrival of these products of digestion in the epithelial cells, a process of resynthesis is set up. Droplets of neutral fat make their appearance in the cells, whence they are passed gradually into the central lacteal villus and so into the lymphatics of the mesentery and into the thoracic duct. The bile salts thus released from their function as carriers are absorbed by the blood circulating through the capillaries of the villi, and carried by the portal vein to the liver. Arrived here they are once more taken up by the liver cells and turned out into the bile. Owing to the fact of their ready excretion by the liver cells, bile salts are the most reliable cholalogues with which we are acquainted-. By this circulation of bile between liver and intestine, the synthetic work of the liver in the production of the bile salts is reduced to a minimum, and it has only to replace such of the bile salts as undergo destruc- tion in the alimentary canal, under the influence of micro- organisms, and are lost to the organism by passing out in the faeces as a gummy amorphous substance, known as dyslysin. Eurther investigation is still wanted as to the exact method in which secretin acts on the liver cells, and especially as to whether it actually excites in them the manufacture of fresh bile salts, or whether it simply hastens the excretion of such bile salts as have been formed by the spontaneous activity of the liver cells or have arrived at them after absorption- from the alimentary canal. Such questions can only be decided by studying the action of secretin on animals possessing a permanent biliary fistula. bile is greatest on a meat diet, it is somewhat less on a diet of fat, and is insignificant on a purely carbohydrate diet. That is to say, the secretion of bile is greatest on those diets, the digestion of which is attended by the passage of a large amount of acid chyme or of oil into the duodenum. We have seen earlier that oil is almost as efficacious as acid in promot- ing the production of secretin in the living duodenum, the production in this ease being probably determined by the formation of soap from the oil, and the direct action of the soap on the prosecretin in the epithelial cells of the gut. LECTUEE IX. THE INTESTINAL JUICE. We have seen that for 4he development of one of its most important properties, namely, that of proteolysis, the pan- creatic juice is dependent on the co-operation of the intestinal juice or succus entericus. Besides this activating power on the pancreatic juice, the intestinal juice has numerous other func* tions to discharge in the digestion of the food-stuffs. Before discussing its actions in detail, we may consider the conditions which determine its secretion. In spite of the great similarity which obtains between the microscopic structure of the wall of the gut at different levels from duodenum to ileo-colic valve, functionally there are many differences between the upper, middle, and lower portions of the gut. Speaking generally, we may say that, whereas the processes of secretion are best marked in the upper portions of the gut, the processes of absorption predominate in the lower sections, i.e., in the ileum. Much of the divergence in the statements, which have been made with regard to the factors determining secretion and absorption in the small intestine, is due to the failure to appreciate this great difference between the activity of the mucous membrane at various levels. The processes of secre- tion in the small intestine may be studied by isolating loops by means of ligatures, and determining the amount of secretion formed in these loops in the course of a few hours' experiment on an anaesthetised animal. Better results, however, may be obtained by establishing permanent fistulse. These fistulas are THE INTESTINAL JUICE. 121 of two kinds. Tbiry's original method of establishing a fistula consisted in cutting out a loop of intestine, and restoring the continuity of the* gut by suturing the two ends from which the loop had been severed. The upper end of the loop itself is closed and the lower end is sutured into the abdominal wound. For some purposes it is better to make a Thiry-Vella fistula. In this case the continuity of the gut is restored as in the simple Thiry fistula, but both ends of the excised loop are left open and brought into the abdominal wound. In such a fistula it is easy to introduce substances into the upper end and determine the flow of juice from the lower end, the constant emptying of the loop being provided for by the peristaltic contractions of its muscular coat. In animals with intestinal fistulse, a number of different con- ditions have been found to give rise to a flow of succus entericus, and so far no qualitative difference has been recorded between the upper and lower ends of the gut. A condition, which will cause a free flow of juice from a fistula high up in the intestine, will generally cause a scanty flow from a fistula made from the ileum. In all cases it is found that a flow of juice is pro- duced in consequence of a meal. If a dog with a fistula, which has been starved for twenty-four hours, be given a meal of meat, a flow of juice may begin within the next ten minutes. The flow remains very slight for about two hours and then suddenly increases in amount during the third hour, corresponding thus very nearly to the flow of pancreatic juice excited by the same means. In this postprandial secretion of juice it is not pro- bable that the nervous system takes any very large share, though its intervention in the secretion has not been excluded by direct experiment. There are certain facts which seem indeed to speak for an action of the central nervous system on the processes of intestinal secretion ; not in the direction of augmentation, but in the direction of inhibition of secretion. 122 TIIE PHYSIOLOGY OF DIGESTION. Thus it has been observed, on many occasions, that extirpa- tion of the nerve plexuses of the abdomen or section of the splanchnic nerves causes a condition of diarrhoea, which may last for two or three days. This condition might be deter- mined, either by an increased motor activity of the gut, or by removal of inhibitory impulses normally arriving at the intestinal glands. Such a view receives support from an experiment first performed by Moreau. The abdomen of a dog is opened under an anaesthetic, and three contiguous loops of 9mall intestine are separated by means of ligatures from the rest of the gut. The middle loop is then denervated by- destruction of all the nerve fibres lying on its blood vessels, as they course through the mesentery, care being taken not to injure the blood vessels themselves. The loops are then replaced in the abdomen and the animal left from four to sixteen hours. On killing the animal at the end of this time, it is often found that the middle loop, i.e., the denervated loop, is distended with fluid having all the properties of ordinary intestinal juice, whereas the other two loops are empty. A series of comparative experiments by Mendel * and by Falloise t have shown that the secretion begins about four hours after the operation, increases for about twelve hours, and then rapidly declines, so that at the end of two days all three loops will be found empty. This has often been inter- preted as due to the removal of inhibitory impulses passing from the central nervous system to the local secretory mechanism, and we have no direct evidence which can be adduced against such a view. It is possible, however, that the hyperaemia of the gut, which is produced by the processes of denervation, may be sufficient to account for the increased formation of intestinal juice, since the hyperaemia will tend to * Mendel, Pfliiger's Archiv., Vol. LXIIL, p. 425, 1896. t -Falloise, Archives internat. de Physiol., Vol. I., p. 261, 1904. THE INTESTINAL JUICE. 123 pass off as the vessels recover a local tone, just as we have seen happens with the increased secretion. It is not possible to explain the flow of intestinal juice, which follows a meal, by any assumption of nervous impulses transmitted through the local nerve plexuses of the gut, since these have been divided in the making of the fistula. If we exclude a nervous reflex action by the long paths, namely through the spinal cord and the sympathetic or vagus nerves, the flow which attends the passage of food into the first part of the duodenum must be excited by the formation of some chemical messenger. Ab to the existence of such a chemical messenger or hormone for the intestinal secretion, there can be no doubt, but the evidence as to its precise nature is at present conflicting. It is stated by Pawlow that the most effective stimulus to the flow of succus enlericus i3 the presence of pancreatic juice in the loop of gut. In the few experiments which I have made on a fistula from the middle of the small intestine, I have not observed such a marked stimulating effect of pancreatic juice on intestinal secretion as is described by Pawlow, but it is possible tbat the effect of the local introduction of pancreatic juice may vary with the location of the fistula. No evidence has yet been brought forward that injection of pancreatic juice into the blood stream. will, cause any flow of intestinal juice. Whatever, therefore, may be the local effects of this juice, it is doubtful whether we can regard it as the hormone, whose absorption from the duodenum determines the postprandial flow of juice in the isolated loop of gut. We have already seen that the simultaneous presence in the gut of the two juices, bile, and pancreatic juice, whose co- operation is necessary for the full manifestation of the actions of each, is ensured by the presence of one and the same chemical messenger for the arousing of both secretions. Since. 124 THE PHYSIOLOGY OF DIGESTION. the co-operation of suceus entericus is also necessary for the intestinal digestion, we might anticipate that the secretin, which excites both bile and pancreatic secretion, would also excite a secretion of suceus entericus. That this is true, at any rate for the upper segments of the gut, has been shown by Delezenne and Frouin. In procuring pancreatic juice by the intravenous injection of secretin, it is always found that the small intestine contains a considerable quantity of fluid, presumably intestinal juice. This might be regarded as a secretion excited by the escape of a small amount of pancreatic juice into the gut along the second pancreatic duct, which is generally left unligatured in this . experiment. The two French observers, however, have shown that in animals pro- vided with a permanent fistula involving the duodenum or upper part of the jejunum, intravenous injection of secretin always causes a secretion of intestinal juice. In the upper part of the gut, therefore, the simultaneous presence of the three juices necessary for complete duodenal digestion is ensured by one and the same mechanism, namely, by the simultaneous activity of the secretin, produced in the intestinal cells by the action of the acid chyme, on pancreas, liver, and intestinal glands. Recently a further chemical mechanism for the arousing of intestinal secretion has been described by Frouin. According to this observer, the flow of juice can be excited by intravenous injection of intestinal juice itself. Since this juice is alkaline, and does not produce any effect on the pancreas, it must be free from pancreatic secretin. It would seem, therefore, that the flow of juice in the upper part of the gut, excited by the pancreatic secretin, causes also a production of a different secretin or hormone, which can be absorbed from the lumen of the gut, travel by the blood" stream to other segments of the .small intestine, and there excite a secretion in preparation THE INTESTINAL JUICE. 125 for the oncoming food. Further experiments are, however, necessary on this point. Besides this sensitiveness to chemical stimulation, the glands of the small intestine can he excited by direct mechani- cal stimulation of the mucous membrane. The easiest method of exciting a flow of intestinal juice from a permanent fistula is to introduce into the intestine a rubber tube. The presence of the solid object in the gut causes a secretion, and within a few minutes drops of juice can be obtained from the free end of the tube. The object of such a sensibility to mechani- cal stimuli is obvious ; it is of the highest importance that the onward passage of any solid object, especially if it be indiges- tible, shall be aided by the further secretion of juice in the portions of gut which are immediately stimulated. This mechanical stimulation probably acts on the tubular glands of the intestine through the intermediation of the local nervous system, the plexus of Meissner. It is stated by Pawlow that a juice obtained by mechanical stimulation differs from that produced by the introduction of pancreatic juice into the loop, in containing little or no enterokinase. Apparently the pan- creatic juice excites the secretion of the substance which is necessary for its own activation. CHARACTERS OF INTESTINAL JUICE. The intestinal juice obtained from a permanent fistula has a specific gravity of about 1010. It is generally turbid from the presence in it of migrated leucocytes and disintegrated epithelial cells. It contains about 1*5 per cent, total solids, of which *8 per cent, are inorganic and consist chiefly of sodium carbonate and sodium chloride. It is markedly alkaline in reaction, but less so than the pancreatic juice. The organic matter, besides a small amount of serum albumen and serum globulin, includes a number of ferments, all of 126 THE PHYSIOLOGY OF DIGESTION. which are adapted to complete the processes of digestion of the food-stuffs commenced in the stomach and duodenum. Of these ferments two are concerned in proteolysis. Entero- kinase we have already studied in detail. Possessing no action itself on proteids, it is a necessary condition for the development of the full pro'eolytic powers of the pancreatic juice. In addition to this ferment another ferment has been described by Cohnheim under the name ' erepsin.' Erepsin or some similar ferment is present in the fresh pancreatic juice and in almost all tissues of the body. It is distin- guished by the fact that, although it has no power of digest- ing coagulated proteid or gelatin, and only slowly dissolves caseinogen and fibrin, it has a rapid hydrolytic effect on the first products of proteolysis, converting albumoses and pep- tones into amino- and diamino-acids — their ultimate cleavage products. The other ferments of the intestinal juice are all connected with the digestion of carbohydrates. In all mammals the intestinal juice is found to contain invertase, which trans- forms cane sugar into glucose and laevulose or fructose, and maltase which converts maltose into glucose. In young mammals, as well as in those in whom the milk diet is con- tinued throughout life, the intestinal mucous membrane also contains lactase, i.e., a ferment converting milk sugar into galactose and glucose. Such a ferment can be extracted from the mucous membrane of all young animals, but may be very slight or even absent in the intestines of older animals, when it is no longer needed for the ordinary processes of nutrition. By means of these three ferments, coming as they do after the digestion of the starches by the amylase of the saliva and pan- creatic juice, it is provided that all the carbohydrate food of the animal is transformed into a hexose, in which form alone ■carbohydrate can be taken up and assimilated by the cells of THE INTESTINAL JUICE. 127 the body. If a disaccharide, such as cane sugar or lactose, be injected into the circulation, it is excreted unchanged in the urine. On the other hand the injection of moderate quantities of the hexoses, glucose, fructose, or galactose into the circula- tion does not lead to the appearance of the sugars in the urine, but causes an increased formation of glycogen by the liver. The seat of origin of these various ferments has been the subject of special investigation by Falloise.* Bayliss and I had already shown that secretin can be obtained from the whole thickness of the mucous membrane, and is probably therefore contained in the form of prosecretin in the epithelial cells covering the villi as well as in those lining the follicles of Lieberkuhn. On the other hand a superficial scraping of the mucous membrane, which removes only the epithelial cells covering the villi with the adherent mucus and intestinal secre- tion, gives a much more active solution of enterokinase than the deeper scraping of mucous membrane. This result is confirmed by Falloise, who therefore places the seat of pro- duction of enterokinase in the cells covering the intestinal villi. The most active solutions of enterokinase are, however, to be obtained from the fluid found in the cavity of the intestine after the injection of secretin. We are therefore inclined to believe that enterokinase is not present as such in the epithelial cells, but is first produced in the process of secretion and formation of the intestinal juice. The other ferments, namely erepsin, maltase, invertase, and lactase, pro- bably pre-exist as such in the epithelial cells, especially in those lining the tubular glands of the gut, since pounded mucous membrane in water yields a solution of these ferments which is generally more powerful in its action than the succus entericus itself. So great is the difference, in fact, that many physiologists have suggested that the chief action of these * Archives internat. de Physiol., Vol. II., p. 299, 1905. 128 THE PHYSIOLOGY OF DIGESTION. ferments occurs, not in the lumen of the gut, but in the pass- age of the food-stuffs through the epithelial cells of the sma-11 intestine on their way to the blood vessels. As the result of all these changes, the three classes of food- stuffs are reduced to a soluble condition, and in solution are taken up by the cells lining the intestine. In the case of the fats, the greater part are at once resynthesised into insoluble neutral fats in the cells themselves, and passed on in this form by the lacteals and lymphatic system into the blood stream. So far as experimental evidence goes, the sugars and disintegra- tion products of the proteids pass directly into the blood stream, by which they are conveyed to the liver and other organs of the body, where they are either stored up or utilised in furnishing the energy required for the discharge of the bodily functions. Only to a small extent are they required for the building up of the tissues in replacement of loss by injury or local old age and death. The main function of the alimen- tary tract is, therefore, the presentation to the tissues of the body of the food-stuffs in a form in which they are directly assimilable. LEGTUEE X. THE MOVEMENTS OP THE ALIMENTARY TEAOT. An essential part in the digestive act is played by the con- tinual movements, by means of which the food is intimately mixed with the digestive juices and gradually passed on from one segment of the canal to the next. By these movements the organism provides for: (1) the preparation of the food for digestion by reducing it to a condition of fine sub-division by means of the movements of mastication ; (2) the intimate mixing of the food with the digestive juices, so as to allow of these coming in contact with every particle ; (3) the propul- sion of the food from one cavity of the canal to the next so soon as the processes of digestion in the first cavity have been completed ; and (4) finally the rejection and expulsion from the body of the undigestible portions of the food-stuffs, mixed with the products of excretion of the wall of the alimentary canal itself. Although the researches on the movements of the alimentary canal date from the very beginning of physiology, it is only within the last ten yearB that the enormous mass of facts and observations, which have been made, have been reduced to an orderly whole, so that we may form a conception of the course of events concerned in the movements of the food, from the time that it enters the mouth to the rejection of the undigested portions in the faeces. In the case of the secretory mechanism we have seen that, whereas the first parts of the alimentary canal are under the direct control of the central P.D. k 30 THE PHYSIOLOGY OF DIGESTION. ervous system, this control gets less and less with the onward rogress of the food ; and that, in the duodenum and small ltestine, the mechanism for evoking the secretion of the igestive juices, at the exact time and place where they are squired, is local or chemical, and occurs in 1 the entire absence f any connection with the central nervous system. In the ame way the motor reactions, which affect the beginning of the anal, are subject to the central nervous system. This direct ontrol is also manifested in the reactions of the lowest por- xras of the gut, which are concerned in the act of defaecation. 'he middle of the alimentary canal however, although apable of being affected by the central nervous system through le splanchnic and vagus nerves, depends for the greater part E its activity on a nervous mechanism situated in the wall of le gut itself. The mechanism is apparently in all cases ervous, and we have, at present, no evidence of motor tactions being evoked by the circulation in the blood of tiemical substances or hormones.* There must naturally e a wide variation in the details of the motor reactions of the Limentary canal, according to the nature of the food-stuffs tiiefly made use of by the animal ; and we find great ifferences in this respect, as in the anatomy of the canal, etween a carnivorous animal such as the dog and a herbi- orous animal such as the rabbit. In the following account I ball deal chiefly with those facts which, though determined by speriments on animals of both classes, can be directly pplied to the movements of the alimentary tract in man. After the food has been reduced by movements of the jaw, " Apart, that is to say, from any co-operation on the part of nervous iructures. Adrenalin, the hormone manufactured by the suprarenal adies, seems to be necessary for the normal display of the functions of ie sympathetic system, and its motor or inhibitory effects on the gut are roduced through this system. THE MOVEMEKTS OF THE ALIMENTARY TEACT. 131 cheeks, and tongue to a state of fine pulp, it is collected by movements of the tongue into a bolus. This bolus is then rapidly thrust by movements of the tongue muscles back into the upper part of the oesophagus, its passage over the region of the pharynx common to the purposes of alimentation and respiration being effected rapidly, so as to interfere as little as possible with the respiratory movements. The oesophagus is ' a muscular tube lined internally with mucous membrane, which is constantly moistened with mucus secreted by numerous glands. The muscular coat consists of two layers, longitudinal fibres externally and circular fibres internally. In the upper part of the oesophagus both these layers are composed of voluntary striated muscle. In the lower third of the oesophagus the muscle is entirely of the unstriated variety, and in the middle part there is a gradual transition between these two types. The food, on arriving at the upper part of the tube, is passed rapidly down to the lower end and through the cardiac orifice into the stomach by means of a peristaltic contraction. As this form of contraction plays a great part in the onward movement of food in all the tubular portions of the alimentary canal, it may be well to define here more explicitly what we mean by the term ' peristalsis.' A peristaltic contraction is a co-ordinated act, comparable in many respects with the co- ordinated movement of extension or flexion which occurs in a limb as a result of an appropriate sensory stimulus. Each such co-ordinated movement involves, as has been so ably demonstrated by Sherrington, two opposed processes — excita- tion and inhibition. If, for instance, the leg be flexed in response to a painful stimulus applied to the sole of the foot, this flexion includes contraction of the flexor muscles and inhibi- tion of the extensor muscles. If the flexor muscles be divided, it is still possible to show that the extensor muscles undergo 32 THR PHYSIOLOGY OF DIGESTION. lengthening as the result of the application of the stimulus, n the same way a movement of extension of the leg, in esponse to a particular tactile stimulus applied to the ball of he foot, can be properly carried out only by a two-fold disc- harge causing inhibition of the flexor muscles, and contraction if the extensor muscles. The uncoordinated spasms which listinguish strychnine poisoning are due to the abolition of he inhibitory part of each reflex and its conversion into a :ontractile reaction, so that antagonistic muscles are set into ontraction by one and the same sensory stimulus. The mysiological purpose of a peristaltic contraction is the pro- vision of a solid or semi-solid object along a tube. A simple sontraction of the tube, even if propagated along its walls, vould probably pass over the object, squeezing it in its course rat not effecting an onward movement. In order that the )bject or bolus may be moved from one end of the tube to the )ther, it is necessary that a process of contraction of the nuscle behind it should be accompanied with a process of relaxation of the muscular walls of the tube in front of it. This is the distinguishing feature of a peristaltic contraction — i process of contraction behind the object, and a process of nhibition and relaxation in front of the object. Such a. louble process can be effected only by a co-ordinating centre, [n the case of the oesophagus this co-ordinating . centre is situated in the medulla, and the orderly progression of the peristaltic wave of inhibition phis contraction along the walls- oi the tube is dependent on the integrity of the branches of the vagus nerve, by which the medullary centre is united to the gullet. Division of these nerves destroys the power of swallow- ing. If food be thrust by the movements of the tongue into the upper part of the oesophagus, this latter may become filled up with food. The food cannot pass into the stomach on account of the absence of ^the one definite factor in the peristaltic; TIIE MOVEMENTS OF THE ALIMENTARY TRACT. 133 contraction, namely the inhibition in front of the bolus, an inhibition which involves also the cardiac sphincter of the stomach. It seems that, under normal conditions, a stimulus applied to the root of the tongue or back of the pharynx and travelling by the superior laryngeal nerves to the vagus centre in the medulla, causes a fusillade discharge from the centre along the successive fibres of the vagus, an inhibitory discharge preceding in each case the motor discharge. In man the peristaltic wave takes about five to six seconds to pass from the level of the glottis to the stomach, the passage being rapid in the upper third, in the region of the striated muscle, and gradually becoming slower as the striated muscle gives place to involuntary muscle. "When a series of swallowing movements are carried out, the lower end of the - oesophagus remains in a state of inhibition, and we have simply a series of annular constrictions passing down the oesophagus behind each food bolus. The arrival of each bolus in the stomach can be detected by auscultating the back of a patient over the region of the cardiac orifice. A gurgling sound is heard each time the food passes into the stomach. - MOVEMENTS OF THE STOMACH. When a meal is taken the inhibition, which precedes the passage of each bolus, spreads to the whole stomach wall, so that any movements, which have been present before the meal, come to an end, and the stomach is in a relaxed and passive condition ready to receive the food passing to it from the mouth. The food passes into the large fundus of the stomach and accumulates there to form one mass. The stomach remains passive for some time after the beginning of a meal , and it is not until twenty to thirty minutes later that the first movements make their appearance. Secretion of gastric juice commences even while the food is in the mouth. 34 THE PHYSIOLOGY OF DIGESTION. 'h'e'acid juice cannot, however, penetrate the great mass of jod which is lying in the fundus, and in the interior of this lass salivary digestion can go on from thirty minutes to one nd a half hours after the food has been swallowed. A very onsiderable portion therefore of the salivary digestion occurs a the stomach itself. For the understanding of the sub- equent movements of the gastric wall, it is important to emember its functional division into two parts, namely, undus and pyloric end or antrum. Although the dead tomach appears to form one sac, observation of a stomach, ecently removed from the living animal and placed in warm lalt solution, shows distinctly this division into two parts, lamely, a tubular part at the pyloric end and a bag-like >ortion, forming four-fifths of the stomach, at the cardiac end. The division between the two is marked by what has been jailed, the ' transverse band ' of the stomach, a region where .here is almost always contraction of the circular muscle ibres. So marked is this in the living stomach that one ivould expect on dissection to find evidence of sphincter-like ihickenings at this point. It is, however, a physiological and lot an anatomical condition. The movements of the stomach can be best studied by Gannon's method, that is, by direct observation of the move- ments in a living un anaesthetised animal, by means of the Etontgen rays. In order to make the shape of the stomach risible, the food — bread and milk — is mixed with a quantity 3f bismuth subnitrate. The presence of this salt does not interfere with the processes of digestion, but renders the gastric contents opaque to the Eontgen rays. On examining by this means the stomach of a cat, which has just taken a meal, the whole of the food is seen to be lying in the fundus, tt is marked off by a strong constriction of the transverse band from the antrum. In about twenty to thirty minutes, THE MOVEMENTS OF THE ALIMENTARY TRACT. ISO faint waves of contraction begin a little to the cardiac side of the transverse band and travel slowly towards the pylorus. These waves succeed one another, so that the pyloric part of the stomach may present a series of constrictions. The effect of these waves is to force the food, which has been digested by the gastric juice and detached from the surface of the mass of food in the fundus, towards the pylorus. The pylorus remaining closed, the food cannot escape, and there- fore is squeezed back, forming an axial reflux stream towards the cardiac end. These contractions last throughout the whole period of gastric digestion and become more marked as digestion proceeds. Their effect is to bring the whole of the food in close contact with every particle of pyloric mucous membrane, and to cause a thorough mixture of food and gastric juice. At varying periods after- a meal, according to the nature of the food taken, the arrival of one of these waves of contraction at the pylorus causes a relaxation of its orifice, and a few cubic centimetres of gastric contents are squirted into the first part of the duodenum. While these movements of the pyloric mill are going on, the cardiac portion of the stomach is exercising a steady pressure on its contents, in consequence of a tonic contraction of its muscular wall, so that each successive portion of the food mass, which is loosened by the digestive action of the gastric juice, is forced on into the pyloric mill. As digestion proceeds, the opening of the pylorus becomes more frequent. The stomach empties itself more and more, until finally the whole of the viscus has the shape of a curved tube. At the very end of digestion, the pylorus may open to allow the passage even of undigested morsels of food. These movements of the two portions of the stomach may be observed also on anaesthetised animals, and even on a stomach which has been excised and placed in warm Bait 136 THE PHYSIOLOGY OF DIGESTION. solution. They must therefore have their origin in the walls of the stomach itself. Although the co-ordination between the two parts of the stomach, between the tonic contraction of the fundus and the rhythmic contractions of the antrum, may be carried out by the local nervous system — Auerbach's plexus — situated between the layers of the muscular coat, it is pro- bable that the advancing waves of contraction observed in the antrum are myogenic, i.e., directly originated in and deter- mined by the muscle fibres themselves. Although we have no direct evidence that these movements persist after throwing the local nervous system out of action, it is evident that they do not partake of the nature of a true peristalsis, since they are not preceded by a wave of relaxation. The opening of the pylorus, on the other hand, which occurs at increasingly frequent intervals at the end of a wave, must be ascribed to a nervous mechanism. The local mechanism probably plays the greater part in this act of relaxation, though there is no doubt that the normal emptying of the stomach is also largely dependent on the integrity of the connection of this viscus with the central nervous system. If both vagus nerves be divided in a dog, below the point at which they give off their branches to the lungs and heart, it is found that a large amount of food remains in the stomach in an undigested condition. The secretion of gastric juice is deficient, the movements of the stomach are also deficient, and the opening of the pylorus is not easily carried out. Such dogs, therefore, tend to die of saprsemia, being poisoned by the absorption of products of putrefaction from the gastric contents. Pawlow has shown that animals can be kept alive for months after division of both vagi, if a gastric fistula be made, the animals be carefully fed. and care be taken to wash out adherent non- digested portions of food from the stomach. The opening of the pylorus depends not only on intragastric THE MOVEMENTS OF TIIE ALIMENTARY TRACT. 137 events but also on the condition of the duodenum. It has been shown by Serdjukow* that the pylorus remains firmly closed so long as the contents of the duodenum are acid. If alkaline fluid be introduced into the stomach, this is rapidly passed into the duodenum. If, however, some acid be intro- duced at the same time into the duodenum by means of a duodenal fistula, the pylorus remains firmly closed, and no fluid passes into the duodenum until the acid, which' was placed there, has been neutralised by the secretion of pan- creatic juice and succus entericus. We have therefore, in the walls of the alimentary canal, a local nervous mechanism for the movements of the pyloric sphincter. This may be played upon by impulses starting either in the stomach or in the duodenum, probably by the contact of acid with the mucous membrane. Increasing acidity on the side of the stonxach causes relaxation of the orifice, whereas acidity on the duodenal side.eauses contraction of the pyloric sphincter. The exact parts played in this mechanism by the local system and by the central nervous system respectively have not yet been thoroughly made out. MOVEMENTS OF THE INTESTINES. The movements of the intestines can be investigated either by observation of the exposed gut, or by the shadow method introduced by Cannon, in which the nature of the movements is judged from the shadows of food containing bismuth which are thrown on a sensitive screen by means of the Eontgen rays. These movements have been the subject of experimental investigation for many years, but with very varying results. The great discrepancy, which obtained between the statements of earlier observers, is due to the fact that they failed to exclude * Quoted by Pawlow, loo. cit., p. 161. 138 THE PHYSIOLOGY OP DIGESTION. the many disturbing impulses which can play on any segment of the gut, either reflexly through the central nervous system, or from other parts of the alimentary canal itself through the local nervous system. In order to observe the normal move- ments of the gut, it is necessary to exclude the disturbing influences due to reflexes through the central nervous system, either by extirpation of the whole of the nerve plexuses in the abdomen, or by division of the splanchnic nerves, or by destruction of the lower part of the spinal cord from about the middle dorsal region. If the abdomen of an animal, which has been treated in this way, be opened in a bath of warm normal salt solution, so as to exclude the disturbing influence of drying and cooling of the gut, the small intestine will be seen to present two kinds of movements. In the first place, all the coils of gut undergo swaying movements from side to side — the so-called pendular movements. Careful observation of any coil will show that these movements are attended with slight waves of contraction passing rapidly over the surface. If a rubber balloon, filled with air and connected with a tam- bour, be inserted into any part of the gut, it will show the existence of rhythmic contractions of the circular muscle repeated from twelve to thirteen times per minute. By means of a special piece of apparatus (the ' enterograph '), it is possible without opening the gut to record the movements of either circular or longitudinal muscular coatis ; and it is then found that both coats present rhythmic contractions at the same rate, the two coats at any point contracting synchronously. "When the contractions are recorded by means of a balloon, the constriction which accompanies each contraction is seen to be most marked at the middle of the balloon, i.e., at the point of greatest tension, and the amplitude of the contrac- tions is augmented by increasing the tension on the walls of the gut. These movements are unaffected by the direct THE MOVEMENTS OP THE ALIMENTARY TEACT. 139 application of drugs such as nicotine or cocaine, which we might expect to paralyse any local nervous structures in the wall of the gut. Bayliss and I therefore concluded that these rhythmic contractions were myogenic,* that they were pro- pagated from muscle fibre to muscle fibre, and that they coursed down the gut at the rate of about 5 cm. per second. Since, however, they may -apparently arise at any portion of the gut which is subject to any special tension, it is not easy to be certain that a contraction recorded at any point is really propagated from a point two or three inches higher up. We suggested that the action of these contractions was to cause a thorough mixing of the contents of the gut with the digestive fluids. The exact value of these movements for the digestive pro- cesses is shown very clearly when they are observed by Cannon's method, t On examining under the Bontgen rays the intestines of a cat, which has taken a large meal of bread/ and nilk mixed with bismuth some hours previously, a length of gut may be seen, in which the food contents form a con- tinuous column. Suddenly movements occur in this column, which is split into a number of equal segments. Within a few seconds each of these segments is halved, the correspond- ing halves of adjacent segments uniting. Again contractions * Magnus has shown that it is possible to pull off strips of the longi- tudinal (outer) coat of muscle fibres from the small intestine. Such strips, if they contain Auerbach's plexus, will contract rhythmically if kept in warm oxygenated Einger's fluid. If, however, the plexus has been left behind in stripping off the muscle, no rhythmic contractions are to be observed, although contraction can still be excited by artificial stimulation. Magnus concludes that even the rhythmic ' pendular ' con- tractions depend for their occurrence on the integrity of the connection between local ganglionic centres and muscle fibres, and cannot therefore be strictly regarded as myogenic (Pfliiger's ArcMv., OH., p. 349, 1904). t Cannon, Amer. Journ. of Physiol., Vol. VI. p. 251, 1901. 140 TIIE PHYSIOLOGY OF DIGESTION. recur in the original positions, dividing the newly-formed segments of contents and re-forming the segments in the same position as they had at first (Fig. 12). If the con- traction is a continuous propagated wave, it is evidently reinforced at regular intervals down the gut, so as to divide the column of food into a number of spherical or oval segments. In this way the points of greatest tension immediately become the points which are midway between the spots where the 1'IG. 12. Diagram (from Cannon) showing the appearance of a length of gut filled with food contents. Each of the portions, into which the contents are divided, are segmented by subsequent contractions at two points (shown by dotted lines) and then return to their' first condition. The arrows indicate the rela- tion of the pieces to the portions they subsequently form. first contractions were most pronounced. The second con- tractions, therefore, start at these points of greatest tension, and divide the first formed segments into two parts, which join with the corresponding halves of the neighbouring segments. In this way every particle of food is brought successively into intimate contact with the intestinal wall. These movements have not a translalory effect, and a column of food divided up in this way may remain at the same level in the gut for a considerable time. The onward progress of the food is caused by a true peri- staltic contraction, i.e., one which involves contraction of the THE MOVEMENTS OP THE ALIMENTARY TI1ACT. 141 gut above the food mass and relaxation of the gut below. If a balloon be inserted in the lumen of the exposed gut, it will be found that pinching the gut above the balloon causes an immediate relaxation of the muscular wall in the neighbour- hood of the balloon. This inhibitory influence of the local stimulus may extend as much as two feet down the intestine towards the ileo-caecal valve. On the other hand, pinching Fig. 13. Bhythmic contractions of the wall of the small intestine (dog) recorded by inserting a rubber balloon into the lumen of the gut, and connecting it by a tube with a piston recorder. At the signal (1), the intestine was gently pinched one inch above the balloon. The effect was immediate and lasting inhibition. At (2) and (3) the intestine was. pinched half an inch below the balloon with the result of causing in each case increased contractions at the level of the balloon. (Bayliss and Starling.) the gut half an inch below the situation of the balloon causes, a strong continued contraction to occur at the balloon itself (Fig. 13). We see, therefore, that stimulation at any portion of the gut causes contraction above the point of stimulus and relaxation below the point of stimulus (the ' law of the in- testines ')• The same effect is produced by introduction of a bolus of food, especially if it be large or have a direct irritat- ing effect on the wall of the gut. In this case the contraction above and the inhibition below cause an onward movement 142 THE PHYSIOLOGY OF DIGESTION. of the bolus, which travels slowly down the whole length of the gut until it passes through the ileo-csecal opening into the large intestine. The peristaltic contraction involves, as I have mentioned before, the co-operation of a nervous system. Whereas in the oesophagus it was the central nervous system which was involved, the peristaltic contractions in the small intestine occur after severance of all connection with the brain and spinal cord. On the other hand, it is absolutely abolished by painting the intestine with nicotine or with cocaine. It must therefore be ascribed to the local nervous system con- tained in Auerbach's plexus, which we can regard as a lowly organised nervous system with practically one reaction, namely, that which we have formulated above as the ' law of the intestines.' An anti-peristalsis is never observed In the small intestine. Mall * has shown that, if a short length of gut be cut out and re-inserted in the opposite direction, a species of partial obstruction results, in consequence of the fact that the peristaltic waves, started above the point of operation, cannot travel downwards over the reversed length of gut. The intestine above this point therefore becomes dilated. If, however, tho reactions of the local nervous system be paralysed or inhibited, a reflux of intestinal contents is quite possible, since the contractions excited at any spot by local stimula- tion of the muscle have the effect of driving the food either upwards or downwards; the direction of movement of the food will be that of least resistance. The movements of the small intestine are also subject to the central nervous system. Stimulation of the vagus has the effect of producing an initial inhibition' of the whole small intestine, followed by increased irritability and increased con- tractions. On the other hand, stimulation of the splanchnic * Johns Hopkins Hospital Beports, Vol. I. p. 87, 1896. THE MOVEMENTS OF THE ALIMENTARY TEACT. 143 nerves causes complete relaxation of both coats of the small gut. It seems that the splanchnics normally exercise a tonic inhibitory influence on the intestinal movements, which can be increased by all manner of peripheral stimuli. On this account it is often impossible to obtain any movements in the exposed intestine, so long as these remain in connection •with the central nervous system through the .splanchnic nerves. The relaxed condition of the gut, which obtains in many abdominal affections, is probably also reflex in origin, and is due to reflex inhibition through the splanchnic nerves. As a. result of the two sets of movements described above, the food is thoroughly mixed with the digestive juices, and the greater part of the products of digestion are brought into con- tact with the intestinal wall and absorbed. What is left — a proportion varying in different' animals according to the nature of the food — is passed on by occasional peristaltic con- tractions through the lower end of the ileum into the colon, or large intestine. The lowest two centimetres of the ileum present a distinct thickening of its circular muscular coat forming the ileo-colic sphincter. This sphincter relaxes in front of a peristaltic wave and so allows the passage of food into the colon. On the other hand, it contracts as a rule against any regurgitation which might be caused by contrac- tions in the colon. Although thus falling into line with the rest of the muscular coat, as concerns its reaction to stimuli arising in the gut above or below, it presents a marked con- trast to the rest of the gut in its relation to the central nervous system. It is apparently unaffected by stimulation of the vagus. Stimulation of the splanchnic however, which causes complete relaxation of the lower part of the ileum with the rest of the small intestine, produces a strong contraction of the muscle fibres forming the ileo-colic sphincter. 114 THE PHYSIOLOGY OF DIGESTION. MOVEMENTS OP THE LARGE INTESTINE. By means of the occasional peristaltic contractions, accom- panied by relaxation of the ileo-colic sphincter, the contents of the small intestine are gradually transferred into the large. In man, these contents are considerable in bulk, are semi- fluid, and probably fill the ascending as well as the transverse colon. The large intestine is supplied with nerves from the central nervous system. These run partly in the sympathetic system along the colonic and inferior mesenteric nerves, partly in the pelvic visceral nerves or nervi erigentes, which come off from the sacral cord and pass direct to the pelvic viscera. In addition -it possesses a local nervous system, presenting the same structure as that found, in the small intestine. The movements of the large intestine differ considerably in various animals, as has been shown by Elliott, according to the nature of the food and the part played by this portion of the gut in the processes of absorption. In the dog the process of absorption is almost complete at the ileo-colic valve, whereas in the herbivora a very large part of the processes of digestion and absorption occurs in the colon and caecum. Man takes an intermediate position as regards his large intestine between these two groups of animals. Bayliss and I, working on dogs, were able to demonstrate a local reaction in the large gut similar to that we had described in the small. Elliott* has shown however that, if one considers a number of different animals, one must divide the large intestine into four parts, according to their functions, viz., the caecum, and the proximal, intermediate and distal portions of the colon. Of these the * Elliott and Barclay. Smith, Joum. of Physiol. Vol. XXXI p 272 1904. ' *' THE MOVEMENTS OF THE ALIMENTARY TRACT. 145 dog possesses practically only the distal colon. We may take Elliott's account of the movements as they probably occur in man. They agree very closely with those observed by Cannon under normal circumstances in the cat, by means of the Bontgen rays. The food as it passes from the ileum first fills up the proximal colon. The effect of this distension is to cause a contraction of the muscular wall at the junction between the ascending and transverse colon. This contrac- tion travels slowly over the tube in a backward direction towards the caecum, and is quickly succeeded by another, so that the colon may present at the same time several of these advancing waves. These waves are spoken of as anti-peri- staltic ; but, as they do not involve also an advancing wave of inhibition, they must not be regarded as representing the exact antithesis of a peristaltic wave, as we have defined it. The effect of these waves is to force the food up into the caecum, regurgitation into the ileum being prevented partly by the obliquity of the opening, partly by the tonic contraction of the ileo-colic sphincter. As the whole of the contents cannot escape into the caecum, a certain portion will slip back in the axis of the tube, so that these movements have the same effect as the similar contractions in the pyloric end of the stomach, causing a thorough churning up of the contents and its close contact with the intestinal wall. The movements are rendered still more effective by the sacculation of the walls of this part of the large intestine. The distension of the caecum caused by this anti-peristalsis excites occasionally a true co-ordinated peristaltic wave, which, starting in the caecum, drives the food down the intestine into the transverse part. These waves die away before they reach the end of the colon, and the food is driven back again by waves of anti-peristalsis. Occasionally more food escapes through the ileo-colic sphincter from the ileum, so that the whole ascending and transverse colon P.D. L 146 THE PHYSIOLOGY OF DIGESTION. may be> filled with the mass undergoing a constant knead- ing and mixing process. The result of this process is the absorption of the greater, part of the water of the intestinal contents, as well as of any nutrient material, and the drier part of the intestinal mass collects towards the splenic flexure, where it may be separated by transverse waves of constriction from the more fluid parts which are being driven to and fro in the proximal and intermediate portions. By means of occasional peristaltic waves these hard masses are driven into the distal part of the colon. The distal colon must be regarded as a place for the storage of the faeces, and as the - organ of def aecation. In the transverse colon, in the descending and ileo-colon, the anti-peristaltic movements and consequent churning of the contents are probably slight. These therefore represent the intermediate colon with propulsive peristalsis as its chief activity. The descending colon is never distended, and Elliott therefore regarded it as a transferring segment of exaggerated irritability. The storage of the waste matter takes place chiefly in the sigmoid flexure. This with the rectum represents the distal portion of the colon. The distinguishing feature of the distal colon is its complete subordination to the spinal centres. It probably remains inactive until an increasing distension excites reflexly through the pelvic visceral nerves a complete evacuation of this portion of the gut. Stimulation of these nerves in an animal, such as the cat, produces a rapid shortening of the distal part of the colon, due to contraction of the recto-coccygeus and longi- tudinal fibres of the gut, followed after some seconds by a contraction of the circular coat. This originates at the lower limit of the area of anti-peristalsis, i.e., probably at the upper end of the sigmoid flexure, and spreading rapidly downwards, empties the whole of this segment of the gut. In man the emptying of the rectum itself is, of course, largely assisted THE MOVEMENTS OF THE ALIMENTARY TRACT. 147 by the contractions of the voluntary muscles of the abdominal walls and pelvic floor. We see, then, that the whole of the movements of the alimentary canal are completely adapted to effect the digestion and absorption of the food-stuffs. At the upper and lower ends of the canal, these movements are under the direct control of the central nervous system, since they have to be guided in accordance with the requirements of the animal's environment. In the middle parts of the gut, where the processes of digestion and absorption must go on without reference to the external conditions or activities of the animal, the movements are chiefly determined by local mechanisms. Even here, however, they can be completely abolished, through the spinal cord and sympathetic system, in cases where injury of the abdominal cavity may render the' local activities dangerous for the animal. The complete paralysis of the gut, which has been observed in cases of gun-shot wound of the abdomen, is probably protective in function and determined by splanchnic stimulation. The motor activities of the alimentary canal present an ordered march of events as suited to the needs of the organism as are those which we have studied in dealing with the secre- tion of the digestive fluids. They differ from these in being more rapidly adaptable, and are therefore determined entirely by nervous mechanisms. So far as we know, chemical mechanisms play no part in the muscular activities of any part of the alimentary canal. APPENDIX. LIST OF PAPEKS, Bearing on the Subjects treated of in the preceding Lectures, which have been published, since 1899 by Workers in the Physiological Department, University College. LECTUEE I. (1) " Some Eesearchcs on the Autolytic Degradation of Tissues." Pt. I. By Janet E. Lane-Claypon, B.Sc, and S. B. Schryver, D.Sc. {Journ. of Physiol, Vol. XXXI., 1904.) (2) "Besearches on the Autolytic Degradation of Tissues." By S. B. Schryver. Pt. II. {Journ. of Physiol, Vol. XXXII., .;■ 1905.) LECTU-EE II. (3) " The Kinetics of Tryptic Action." By W. M. Bayliss, P.E.S. {Archives des Sciences Biol., Vol. XL, Suplt. St. Petersburg, , .1904) (4) "The Effect of Electrolytes on Adsorption." By W. M. Bayliss. {Biochemical Journal, Vol. I., 1906.) (5) " The Separation of Phosphorus from Caseinogen by the Action of Enzymes and Alkali." By E. H. Aders Plimmer, -:. D.Sc, and W. M. Bayliss, E.E.S. {Journ. of Physiol, Vol. XXXIIL, p. 439, 1906.) L * 150 APPENDIX. LECTDEE III. (6) "On the Changes in Volume of the Submaxillary Gland during Activity." By J. Le M. Bunch, D.Sc, M.D. (Journ. of Physiol, Vol. XXVI., 1900.) (7) " Observations on the Lymph Plow from the Submaxillary Gland of^the Dog." By P. A. Bainbridge, B.A., B.Sc. (Journ. of Physiol, Vol. XXVI., 1900.) LECTUEE V. (8) " On the Causation of the so-called ' Peripheral Eeflex Secre- tion' of the Pancreas." (Preliminary communication.) By W. M. Bayliss and E. H. Starling. (Proc. Boy. Soc, January 23, 1902.) (9) " The Mechanism of Pancreatic Secretion." By W. M. Bayliss and E. H. Starling. (Journ. of Physiol, Vol. XXVIII., 1902.) (10) " On the Uniformity of the Pancreatic Mechanism in Verte- brata." By W. M. Bayliss and E. H. Starling; (Journ. of ■ Physiol, Vol. XXIX., 1903.) (11) " On some Pathological Aspects of Becent Work on the Pancreas." By E. H. Starling. (Trans, of Path. Soc. of London, Vol. LIV., 1903.) (12) Croonian Lecture (Eoyal Society) on "The Chemical Eegu- lation of the Secretory Process." By W. M. Bayliss and E. H. Starling. (Proc. Boy. Soc, Vol. LXXIIL, 1904.) LECTUEE VI. (13) "The 'Islets of Langerhans' in' the Pancreas." By H. H. Dale, B.Ch. (Proc. Boy. Soc, Vol. LXXIIL, 1904, and Phil. Trans. Boy. Soc, Series B, Vol. CXCVIL, 1904.) (14) " The Oxygen Exchange of the Pancreas." By J. Barcroft ' and E. H. Starling. (Journ. of Physiol, Vol. XXXI., 1904.) (15) "The Lymph Plow from the Pancreas." By P. A. Bain- bridge, M.D. (Journ. of Physiol, Vol. XXXII. , 1904.) APPENDIX. 151 LECTUEE VII. (16) "On the Composition of the Pancreatic Juice." By L. A. E. de Zilwa, M.B. (Journ. of Physiol., Vol. XXXI., 1904.) (17) "The Proteolytic Activities of the Pancreatic Juice." By W. M. Bayliss and E. H. Starling. {Journ. of Physiol., Vol. XXX., 1903.) (18) " On the Eelation of Enterokinase to Trypsin." By W. M. Bayliss and E. H. Starling. (Journ. of Physiol, Vol. XXXII., 1905.) (19) " On the Adaptation of the Pancreas to Different Eood-stuffs." (Preliminary communication.) By P. A. Bainbridge. (Proo. Boy. Soc, Vol. LXXIL, 1903.) (20) " On the Adaptation of the Pancreas." By P. A. Bainbridge. (Journ. of Physiol, Vol. XXXI, 1904.) (21) " On the Alleged Adaptation of the Pancreas to Lactose." By E. H. Aders Plimmer, D.Sc. (Journ. of Physiol, Vol. XXXIV.', 1906.) (22) " On the Identity of Trypsinogen and Enterokinase respec- tively in Vertebrates." By J. Molyneux Hamill, M.A., M.B. " (Journ. of Physiol, Vol. XXXIII., 1906.) (23) " On the Mechanism of Protection of Intestinal Worms, and its Bearing on the Eelation of Enterokinase to Trypsin." By J. M. Hamill. (Journ. of Physiol, Vol. XXXIII., 1906.) LECTUEE VIII. (24) Ppr "Action of Secretin on Bile" v. Paper No. (9), in Journ. of Physiol, Vol. XXVIIL, 1902. (25) " The Contractile Mechanism of the Gall Bladder and its Extrinsic. Nervous Control." By P. A. Bainbridge and H. H. Dale. (Journ. of Physiol, Vol. XXXIII.", 1905.) (26) " A Note on Hiifner's Method of Preparing Pure Glycocholic Acid." By W. A. Osborne. (Proc. Physiol. Soc, 1900.) (27) "On the Pormation of Lymph by the Liver." By P. A. Bainbridge (Journ. of Physiol, Vol. XXVIIL, 1902.) 152 APPENDIX. LECTUEE IX. (28) "The Presence of Lactose in Animals." By B. H. Aders Plimmer. (Proc. Physiol. Soc., 1906.) (29) Croonian Lectures given at the Eoyal College of Physicians, London, " On the Chemical Correlation of the Functions of the Body." By E. H. Starling. (Published in Lancet, August, 1905.) LECTUEE X. (30) " The Movements and Innervation of the Small Intestine." Pt. T. By "W. M. Bayliss and E. H. Starling. (Joum. of Physiol., Vol. XXIV., 1899.) (31) Idem. Pts. II. and III. (Joum. of Physiol, Vol. XXVI.; 1901.) (32) " The Movements and Innervation of the Large Intestine." By W. M. Bayliss and E. H. Starling. (Joum. of Physiol., Vol. XXVI., 1901.) (33) "On the Movements and Innervation of the Stomach." By W. Page May, M.D. (Brit. Med. Joum., Sept. 13, 1902,) (34) " The Innervation of the Sphincters and Musculature of the Stomach." By W. Page May. (Joum. of Physiol., Vol. XXXL, 1904.) INDEX. Active mass, 28. Adaptation of pancreas, 108. of stomach to food, 77. Adrenalin, 91, 130. Adsorption, 15. of dyes, 38. of toxins by antitoxins, 38. Agglutination of bacilli, 36. Alimentary tract, movements of, 129 —147. Amide-nitrogen, 6. Amino-acids, 6, 9. Amylase, 9, 104. of saliva, 42. Antikinase, 107. Antilysin, 34. Antiperistalsis in colon, 145. Antitoxin, 34. Antitrypsin, 107. Armstrong, experiments on lactase, 25. A rrhenius, on toxins and antitoxins 37. itropin, effect on salivary secretion, 48. Auerbach's plexus, function of, 142. Bainbridge, on lactase, 110. on lymph flow from sali- vary glands, 51. Barcroft, on gaseous exchanges of pancreas, 95. — — - on salivary glands, 50. Bayliss, on intestinal ferments, 127. on movements of intestines, 139, 144. on action of trypsin, 24. Bernard, on pancreatic fistula, 81. Bile, 112—119. — — analyses of, 113. digestive functions of, 116. — *- pigments, 113. salts, function of, 117. Biliary fistula, 114. Bredig, on preparation of sols, 39. Bunch, on salivary glands, 52. Calorie, definition of, 2. Cannon, on movements of intestines, 137. on movements of stomach, 134. Carbohydrates, 2. digestion of, 9. Caseinogen, digestion of, 24. Catalysers (catalysts), 11. specificity of, 13. Catalytic action of sols, 40. Chemical correlation, 88. Chorda tympani, 44. Colloidal solutions, 1 5. Colon, movements cf, 144. Craw, on interaction of toxins and antitoxins, 36. Dakin, on lipase, 32. Dale, on gall-bladder, 115. on islets of Langerhans, 9S. Dastre, on enterokinase, 105. Defaecation, 146. Deglutition, 131. De Graaf, on pancreatic fistula, 80. 154 INDEX. Delezenne, on enterokinase, 105. Diabetes, relation to pancreas, 98. Diamino-acids, 6, 10. Diastase, velocity of reaction, 22. Diet, 2. Digestion in the stomach, 62—79. Edkins, on gastric secretion, 74. Ehrlich's theory of hemolysins, 34. Elliott, on movements of large intes- tine, 144. Emulsin, 31. Energy of food-stufls, 3. of salivary secretion, 49, 58. Enterokinase, 104. origin of, 107. Equation of reaction, 21. Erepsin, 9, 103, 126. Falloise, on intestinal ferments, 127. on intestinal secretion, 122. Fats, absorption of, 118. composition of, 2. digestion of, 9, 116. Ferments, action of, 8, 14. autodestruction of, 28. chemical composition of, 33. colloidal nature of, 33. combination with substrate, 31, 39. effect of bile on, 116. effects of concentration of, 24. mode of action of, 10 — 40. optical activity of, 32. — — retarding effect of end-pro- ducts, 30. reverse action of, 30. specificity of, 12, 31. of alimentary canal, 8. of intestinal juice, 126. of pancreatic juice, 103. Fleig, on secretin, 92. Food-stuffs, absorption of, 128. changes during digestion, 1—10. classification of, 2. Food-stuffs, digestion of, 8. effect on biliary secretion, 119. heat value of, 2. Gall-bladder, movements of, 115. Gaseous exchanges of pancreas, 95. of salivary glands, 58. Gastric fistula, 64. juice, properties of, 67. secretion of, 62, 66. • secretion, chemical mechanism of, 74. ■ • effect of quality of food on, 76. nervous mechanism of, 69. Glands, changes during secretion, 54. of stomach, 62. Glucose, oxidation of, 16. Glucosides, action of ferments on, 31. Granules of pancreas, 97. of salivary glands, 56. Hsemolysins, 34. Hamill. on antitrypsin, 107. Haptophore, 35. Heat production in salivary glands, 59. Hormone, gastric, 75, Hormones, chemical nature of, 91. definition of, 90. for intestinal secretion, 124. Hydrochloric acid, secretion by stomach, 64. Hydrogen peroxide, catalysis of, 11. Hydrolysis of food-stuffs, 10. Ileocolic sphincter, 143. Indigo, effect on glucose, 16. Inhibition, 131. in intestine, 141. Intermediate products, 16. Intestinal fistula, 121. . juice, 120—128. INDEX. 155 Intestinal juice, characters of, 125. Intestine, distribution of prosecretin in, 88. law of, 141. local reflexes of, 125. movements of, 137 — 143.- large, movements of, 144 — 147. Invertase, 9, 12, 126. ■ chemical composition of, 33. velocity of reaction, 22. Islets of Langerhans, 98. ■ formation during activity, 100. Lactase, 9, 12, 25, 110, 126. Laguesse, on islets of Langerhans, 101. Langley, on secretory nerves, 46. Lipase, 9, 32, 104. solution of, 117. ■ Ludwig, on salivary glands, 48. Lymph flow from salivary glands, 51. production in salivary glands, 60. Lysin, 34. Magnus, on intestinal movements, 139. Mall, on reversal of gut, 142. Maltase, 9, 12, 126. Mammary glands, growth of, 91. Mandelic acid, 32. Mendel, on intestinal secretion, 122. Molybdic acid, catalytic action of, 18. Moreau, on intestinal secretion, 122. Movements of alimentary tract, 129 — 147. Nervi erigentes, effect on colon, .144. Nervous mechanism of intestinal secre- tion, 122. Nitrogen, condition in proteid mole- cule, 6. Nitrogenous derivatives of proteids, 9. (Esophagus, movements of, 131. Optimum temperature of ferment action, 13. Osborne, on invertase, 33. Osmotic pressure of saliva, 47. Oxygen carrier, 17. requirements glands, 58. Oxyntic cells, 63. of salivary Pancreas, changes during secretion, 94—101. histology of, 96. normal stimulation of, 92. Pancreatic fistula, 80. juice, alkalinity of, 102. '- properties of, 102— 111. qualitative adapta- tion of, 108. time relations ' of secretion of, 83. secretion, 80 — 93. chemical mecha- nism of, 86. Parietal cells, 63. Pawlow, on adaptation of pancreas, 108. on biliary fistula, 114. on division of vagi, 136. on enterokinase, 105. on gastric fistula, 64. on intestinal secretion, 123. on pancreatic fistula, 81. on secretion of saliva, 43. Pendular movements, 138. Pepsin, 8. — — secretion of, 64. separation of, 68. Peptic cells, 63. Peptogenic substances, 73. Peristalsis, definition of, 131. of small intestine, 140. of large intestine, 145. Platinum, catalytic effect of, 11. nature of catalytic action of, 17. Plimmer, on lactase, 110. Popielski, on gastric juice, 76. on pancreatic secretion, 85. Prosecretin, 88. Proteid, significance as food-stuff, 3. Proteids, 2. constitution of, 6. 156 INDEX. Proteids, digestion o£, 9. effect of gastric juice on, 67. effect on excretion, 3. Proteolysis, change of conductivity during, 24. Proteolytic ferments, velocity of re- action, 23. Protoplasm, building up of, 6. Psychical secretion of gastric juice, 69. ' Ptyalin, 42. Pylorus, movements of, 137. Eeaction, modes of studying velocity of, 22. ■ velocity of, 11, 20. Reactions, bimolecular, 21. monomolecular, 21, reversible, 29. Reflex secretion of pancreatic juice, 84. Rennin, 36. Revertose, 30. Saliva, composition of, 41. functions of, 42. molecular concentration of, 47. — — secretion of, 41 — 61. Salivary glands, changes during secre- tion, 53. nerves of, 44. Sapocrinin, 92. Secretin, effect on bile, 115. intestinal secretion, 123. structure of pan- creas, 97. gastric, 75. ■ pancreatic, 87. Secretion of intestinal juice, 121. • of saliva, 41 — 61. mechanism of, 45, 59. pancreatic, 80 — 93. psychical, of saliva, 43. Secreto-motor nerves, 46. Secretory nerves to pancreas, 84. to stomach, 70. pressure, 48. -. of pancreas, 94. Serdjukow, on contraction of pylorus, 137. Sol, 40._ ' Splanchnic nerve, effects on intestinal movements, 143. Steapsin, 9. Stomach, digestion in, 62—79. - movements of, 79, 133—137. mucous membrane of j 62. Substrate, 19. combination with ferments, 31. effect of concentration of, 26. Succus entericus, 120 — 128. Sugars, assimilation of, 127. Surface, effects of, 15. Sympathetic saliva, 45. Temperature, effect on ferment action, 14- Toxin, neutralisation of, 36. Toxins, 34. Toxoids, 35. \^ Toxones, 37. Toxophore, 35. Transverse band, 134. Trophic nerves of salivary glands, 46. Trypsin, 8, 104. • — — modification by heat, 35: reaction, velocity of, 27. velocity of action, 23. Trypsinogen, 104. relation to enterokiuase, 105. Vagus, effect on gastric secretion, 70. intestinal movements, 142. oesophagus, 132 — — gastric movements, 136; Telocity constant, 21. . Weinland, on antitrypsin, 107. — — on lactase, 109. Wertheimer, on pancreatic secretion. 85. Zymoids, 35. BRADBURY, AONEW, & CO. LD., PRINTERS, LONDON AND TONBRIDQE.