UNIVERSITY OF CALIFORNIA 
 MEDICAL CENTER LIBRARY 
 SAN FRANCISCO 
 
 
 
 
 Gift of 
 LANE MEDICAL LIBRARY 
 
THE PHYSIOLOGY OF DIGESTION. 
 
MERCERS' COMPANY LECTURES 
 
 ON 
 
 RECENT ADVANCES 
 
 IN THE 
 
 PHYSIOLOGY OF DIGESTION 
 
 DELIVERED IN THE MICHAELMAS TEIIM, 1905, IN THE 
 
 PHYSIOLOGICAL DEPARTMENT OF UNIVERSITY 
 
 COLLEGE, LONDON. 
 
 BY 
 
 EBNEST H. [STABLING, M.D., F.E.S., 
 
 JODRELL PROFESSOR OF PHYSIOLOGY. 
 
 WITH TWELVE ILLUSTRATIONS. 
 
 LONDON: 
 
 AKCHIBALD CONSTABLE & CO. LTD., 
 
 16, JAMES STEEET, HAYMARKET. 
 
 1906. 
 
BRADBCRV, AGNEW, & CO. J.D., PRINTKRS, 
 LONDON AND TONBRIDGE. 
 
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 
 
 110155 
 
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. 
 
 EENEST H. STAELING. 
 
 PHYSIOLOGICAL LABORATORY, 
 
 UNIVERSITY COLLEGE, 
 
 March, 1906. 
 
CONTENTS. 
 
 LECTURE PAOK 
 
 I. THE FOOD-STUFFS AND THEIR CHANGES DURING DIGES- 
 TION THE MODE OF ACTION OF FERMENTS . . 1 
 
 II. THE MODE OF ACTION OF FERMENTS (continued} . . 20 
 
 III. SECRETION OF SALIVA 41 
 
 IV. DIGESTION IN THE STOMACH . . . . . . 62 
 
 V. PANCREATIC SECRETION 80 
 
 VI. CHANGES IN THE PANCREAS DURING SECRETION . . 94 
 
 VII. THE PROPERTIES OF THE PANCREATIC JUICE . . 102 
 
 VIII. THE BILE . . 112 
 
 IX. THE INTESTINAL JUICE 120 
 
 X. THE MOVEMENTS OF THE ALIMENTARY TRACT 129 
 
LIST OF ILLUSTRATIONS AND 
 DIAGRAMS. 
 
 PAGE 
 
 1. DIAGRAM SHOWING: (fl) TOTAL BLOOD FLOW THROUGH 
 
 SUBMAXILLARY GLAND, (b) TOTAL AMOUNT OF WATER 
 TRANSFERRED FROM BLOOD TO GLAND. (c) TOTAL 
 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 
 
 .">. 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 . . .05 
 
 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 
 
LIST OF ILLUSTRATIONS AND DIAGRAMS. 
 
 PAGE 
 
 SALIVARY AND PANCREATIC FISTULA, SMALL GLASS 
 PHIALS BEING ATTACHED TO EACH TO COLLECT THK 
 SECRETIONS 81 
 
 8. EFFECT OF INJECTION OF ACID INTO LOOP OF SMALL 
 INTESTINE AFTER DESTRUCTION OF I'J NKRVOUS 
 CONNECTIONS 87 
 
 1). EFFECT OF SECRETIN PREPARED BY THE " TION OF 
 DILUTE ACID ON INTESTINAL MUCOUS ^MBRANE 
 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 THEIR CHANGES DURING DIGESTION 
 THE MODE OF ACTION 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- 
 amino- 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. 
 
 (8) 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 of 
 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 0C. 
 
FOOD-STUFFS AND THEIR CHANGES DURING DIGESTION. 
 
 3 
 
 to 1C. 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 C0 2 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 com- 
 pelled 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, 
 
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 011 
 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 be 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 of 
 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 ; 
 
 (f) That contained as diamiiio-acids, or as bases such as 
 
FOOD-STUFFS AND THEIR CHANGES DURING DIGESTION. 
 
 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. 
 
 Moiiamino-N. 
 
 Crystallised serum albumin . . 
 
 6-5 
 
 34-4 
 
 60-2 
 
 Crystallised egg albumin 
 
 8-5 
 
 21-3 
 
 67'8 
 
 Crystallised edestin 
 
 10-2 
 
 38-1 
 
 55-0 
 
 Caseinogen of milk 
 
 10-4 
 
 28-9 
 
 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. 
 
 Histidin. 
 
 Tyrosh). 
 
 Oystin. 
 
 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 
 
 
 
 
 
 Egg albumin 
 
 
 
 
 
 
 
 1-5 
 
 0-29 
 
 Serum albumin 
 
 
 
 
 
 
 
 2-0 
 
 2-15 
 
 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 Physiologic," 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-stuff. 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. 
 
 Hydrated proteids and 
 certain coagulable 
 proteids such as 
 fibrin and caseinogen 
 
 Carbohydrates- 
 Starch 
 
 Ferment. 
 E rep sin 
 
 Maltose 
 Cane sugar 
 Milk sugar 
 
 Fats 
 
 Amylase of saliva . . 
 ,, of pancrea- 
 tic juice 
 Maltase 
 Invertase 
 Lac base 
 
 Lipase (steapsin) . . 
 
 Product of action. 
 Amino- acids, etc. 
 
 Dextrin and maltose. 
 
 Glucose. 
 
 Glucose and fructose. 
 
 Glucose and galactose. 
 
 Fatty 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 laevulose, 
 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 : 
 
 MONOAMINO-ACIDS 
 
 Glycine (aminoacetic acid) 
 Alanine (ammopropionic acid) 
 
 Serine or oxyalanine (oxyamiiiopropionic acid) 
 
 Amino valerianic acid 
 
 Leucine (aminoisobutylacetic acid) 
 
 Isoleucine (aminocaproic acid) 
 
 Aspartic acid 
 
 Glutamic acid . . . . . . . . 
 
 Phenylalanine 
 
 Tyrosine (oxyphenylalanine) 
 
 Proline (pyrrolidine carboxylic 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-ACIDS AND THEIR COMPOUNDS 
 
 Lysine (diaminocaproic acid) . . 
 Arginine -(guaiiidinaminovalerianic acid) 
 
 The 
 hexone bases.' 
 
 Histidine (a pyrimidine derivative) 
 Diaminotrioxydodecoic acid . . derived from a 12 carbon acid. 
 
 ( Sulphur - containing 
 Cystin (derived from aminothiolactic acid) . . j 
 
 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 process of hydra- 
 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 or catalysts. A 
 catalyse r 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 
 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. 13 
 
 specific as would appear when we confine our attention to the 
 food-stuffs themselves. Thus invertase not only breaks up cane 
 sugar, but also causes hydrolysis of rafrmose and gentianose. 
 Lactase, in addition to its action on lactose, or milk-sugar, has 
 the property of hydrolysing all the /2-galactosides. Emulsin 
 hydrolyses the /3-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 
 nil 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 catalyser s 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 THE PHYSIOLOGY OF 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, 1904), esp. pp. 245. 
 ct 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 Pt0 2 is formed and at once reduced by the hydrogen with 
 formation of water. 
 
 There is a certain amount of experimental evidence in favour of this 
 lypothesis. According to Engler and Wohler,* platinum black, which 
 las been exposed to oxygen, in virtue of the gas which it has occluded, 
 las the power of turning potassium iodide and starch blue. This power 
 not destroyed by heating to 260 in an atmosphere of C0 2 , or by wash- 
 ig with hot water. On exposure of the platinum black to hydrochloric 
 I, a certain amount is dissolved, and the substance loses its effect on 
 dum iodide. The amount dissolved corresponds with the amount 
 
 * Quoted by Mellor, loc. cit. t p. 269. 
 
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 OF 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 the gas will also be dissociated. Thus, if we stan 
 

 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 KG, 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 < = KG 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 
 
 4 = 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 
 
22 THE PHYSIOLOGY OF 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. Erode 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 CHI). 
 After the addition of the molybdic acid, the equation becomes 
 
 <f> = K (CH 2 2 -|- y. Cmoiybdic acid ) 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 FERMENTS. 23 
 
 the solution on polarised light, ifc is only necessary to put the 
 mixture of ferment and cane sugar into a polarimeter tube, 
 which is kept at a constant temperature by means of a water 
 jacket, and read off at intervals of a few minutes the change 
 in the rotatory power of the solution. From this change can 
 be easily calculated the percentage of cane sugar still present, 
 and therefore the total amount which has been converted into 
 fructose and glucose. 
 
 The question of the velocity of reaction becomes more 
 complex when we deal with the proteolytic ferments, owing to 
 the immense variety of products which result from the breaking 
 down of a proteid and its disintegration in successive stages, 
 albumoses being first formed, then peptones, and finally 
 amino-acids. The matter is still further complicated by the 
 fact that these stages are not adhered to rigidly, a certain 
 amount of amino-acids being formed at the very beginning 
 of the reaction. In any investigation, however, of the action 
 of proteolytic ferments such as pepsin or trypsin, we may 
 take any given alteration of proteid and observe the velocity 
 with which it occurs. Thus, if we are studying the action of 
 trypsin on caseinogen, we can take samples at five-minute 
 intervals and run them into some substance such as trichlor- 
 acetic acid, which will precipitate all the unchanged proteid, 
 i.e., caseinogen, but will leave in solution the products of 
 hydration of the proteid. From the amount of nitrogen in 
 the filtrate from the precipitate can be determined the total 
 amount of proteid which has undergone hydration in the 
 sample under observation. Or we may take measured por- 
 tions at intervals, and judge of the amount of albumoses and 
 peptones present by the intensity of the biuret reaction which 
 can be obtained in each sample. This method, however, 
 suffers from the drawback that the albumoses and peptones, 
 at any rate in the action of trypsin, are formed merely as a 
 
24 THE PHYSIOLOGY OF DIGESTION. 
 
 stage in the process, and the intensity of the reaction will first 
 rise to a maximum and then gradually disappear. 
 
 In the process of proteolysis there is a breaking down of the 
 complex colloid molecules into a large number of simpler 
 molecules. The colloidal proteid molecule has very small 
 conducting power for electricity. The products of its disinte- 
 gration, namely, albumoses and amino-acids, belong to a class 
 of bodies known as the amphoteric electrolytes, which have a 
 conducting power, small in itself, but large compared with 
 that of the original proteid molecule. Moreover, in the 
 process of disintegration, the salts which are absorbed by the 
 colloidal molecule, and therefore not free to exercise their con- 
 ducting power, are set free. These two factors together, the 
 production of smaller molecules and the setting free of saline 
 electrolytes, account for the rapid rise in the conductivity of 
 a proteid solution when it is subjected to hydrolysis. The 
 change in conductivity can be used as a means of judging the 
 rate of proteolysis. This method presents the great advantage 
 that a continuous series of readings can be taken without 
 removing the solution from the bath, and without altering in 
 any way the chemical conditions of the solution. These obser- 
 vations may, moreover, be quickly carried out, so allowing 
 a large number of comparative experiments under different 
 conditions to be made. This method has therefore been 
 employed by Bayliss in an investigation of the conditions 
 which determine the velocity of action of trypsin on solutions 
 of caseinogen. 
 
 We may consider first those experiments in which the 
 amount of trypsin was small compared to the amount of 
 substrate (caseinogen). In this case it was found that the 
 velocity of reaction was independent of the concentration of 
 the caseinogen solution, and was a direct linear function 
 of the amount of ferment present. This is shown by the 
 
THE MODE OF ACTION OF FERMENTS. 
 
 25 
 
 experimental results in the following table, where is given 
 the effect of altering the concentration of the ferment on the 
 time taken for the hydrolysis to proceed to a certain point. 
 The point chosen was the time taken for the conductivity 
 to increase to 350 gemmhos (the reciprocal of the unit of 
 resistance, megohm). 
 
 RELATION TO CONCENTRATION OE TRYPSIN. 
 
 Trypsin. Time of equal change. 
 
 40 3 
 
 20 6-5 
 
 10 
 4 
 2 
 1 
 
 10 
 
 40 
 
 75 
 
 150 
 
 It will be seen that the time taken for this change is inversely 
 proportional to the concentration of the ferment. 
 
 The same result has been observed in the case of other 
 ferments. Thus the table below shows the results obtained 
 by E. F. Armstrong* on the hydrolysis of lactose by small 
 quantities of lactase. 
 
 PROPORTIONS HYDROLYSED IN 100 cc. OF A 5 PER CENT. 
 SOLUTION OF LACTOSE. 
 
 Solutions containing 
 
 1*5 hours. 
 
 20 hours. 
 
 45 hours. 
 
 1 cc. lactase 
 
 0-15 
 
 2-2 
 
 3-9 
 
 10 cc. 
 
 1-6 
 
 23-3 
 
 38-6 
 
 20 cc. 
 
 3'2 
 
 45-8 
 
 
 
 Here again the amount of change is proportional to the 
 amount of ferment present. The same observer has found 
 that, if the amount of substrate is veiy large compared to the 
 ferment, increasing the concentration of the substrate does 
 
 "Studies on Enzyme Action." Proc. Koy. Soc. Vol. LXXIII. pp. 500 et seq. 
 
26 
 
 THE PHYSIOLOGY OF DIGESTION. 
 
 not increase the amount hydrolysed, i.e., a given quantity of 
 ferment is able to change only a certain amount of sugar in 
 a given time, whatever may be the concentration of the latter. 
 This is shown in the following table (Armstrong) : 
 
 AMOUNT OF SUGAR (LACTOSE) HYDROLYSED. 
 
 
 24 hours. 
 
 46 hours. 
 
 
 
 
 
 Proportion. 
 
 Weight. 
 
 Proportion. 
 
 Weight. 
 
 10 per cent, lactose 
 
 14-2 
 
 1-42 
 
 22-2 
 
 2-22 
 
 20 
 
 7'0 
 
 1-40 
 
 10-9 
 
 2-18 
 
 30 
 
 4-8 
 
 1-44 
 
 7-7 
 
 2-21 
 
 Moreover, if we take only the earlier stages of the ferment 
 action, it is found that, with small proportions of ferment, 
 equal amounts of substrate are changed in successive intervals 
 of time until about 10 per cent, has been hydrolysed. This 
 is shown in the following table : 
 
 2 PER CENT. LACTOSE WITH LACTASE. 
 
 Time. Amount hydrolysed. 
 
 hour . . . . 3'2 
 
 | ..6-4 
 
 1 9-6 
 
 2 hours 
 3 
 
 16-4 
 20-8 
 
 Quite a different result is observed when the amount of 
 ferment is large relatively to the amount of substrate. 
 
 EFFECT OF CONCENTRATION OF SUBSTRATE (BAYLISS). 
 
 Caseinogen, per cent. Change in 20 minutes. 
 
 4 . . . . . . . . . . . . 385 gemmhos. 
 
 3-2 395 
 
 2 .... 200 
 
 8 ..110 
 
 4 10 
 
THE MODE OF ACTION OF FERMENTS. 27 
 
 Thus, in the experiment of Bayliss represented here, it 
 will be noticed that, with 2 cc. of the 2 per cent, solution 
 of trypsin, the amount of change in twenty minutes was 
 approximately equal in a 3 per cent, solution and in a 4 per 
 cent, solution of caseinogen. On diminishing the amount 
 of caseinogen so that it was 2, '8, and *4, he found, however, 
 a rapidly lessening amount of change with the diminishing 
 concentration of the caseinogen. This, of course, is what 
 one would expect either in a unimolecular or bimolecular re- 
 action ; but if a series of observations are made at intervals 
 of ten minutes -on a mixture containing caseinogen and a 
 proportionately large amount of ferment, it will be seen that 
 there is a rapid diminution of the rate of change from the 
 very beginning. This is shown in the table below, in which 
 the velocity constant K has been calculated from a series of 
 observations. 
 
 VELOCITY OF TRYPSIN EEACTION. 
 
 6 cc. 8 per cent, caseinogen + 2 cc. AmHO + 2 cc. 2 per cent. 
 
 trypsin at 39 C. 
 
 1st 10 minutes . . . . K = 0'0079 
 
 2nd . . . . 0-0046 
 
 3rd . . . . -0032 
 
 4th . . . . -0022 
 
 5th .. .. -0016 
 
 7th .. .. -0009 
 
 Etc. Etc. 
 
 Whereas in an ordinary chemical reaction, such as those 
 mentioned at the beginning of this chapter, K remains con- 
 stant throughout the reaction, here we see a rapid diminution 
 in this factor. 
 
 How are we to account for the results obtained with small 
 ^and large quantities of ferment respectively ? The experi- 
 ments made on small quantities of ferment can only be 
 interpreted by assuming that the first stage in the reaction 
 
28 THE PHYSIOLOGY OF DIGESTION. 
 
 is a combination of ferment with substrate. It is only this 
 compound which represents the act ire mass of the molecules, 
 i.e., the molecules of substrate which are undergoing change. 
 This compound, as soon as it is formed, takes up water and 
 breaks down, setting free the hydrolysed substrate and the 
 ferment, which is at once ready to combine with a further 
 portion of the substrate. In such a case the velocity of 
 reaction must be directly proportional to the amount of fer- 
 ment, and the same absolute quantity of substance will con- 
 tinue to be changed in succeeding units of time. Supposing, 
 for instance, we had at the bottom of a hill a load of bricks 
 which had to be transferred to the top, and five men to effect 
 the transference. The rate of transference would be directly 
 proportional to the number of men employed ; we could 
 double the rate by doubling the men. Moreover, the number 
 of bricks carried in each unit of time would be the same. 
 Five men would carry as many bricks in the second ten 
 minutes as they would in the first, and so on. On the other 
 hand, the velocity with which the transference was effected 
 would be independent of the number, that is, the concentra- 
 tion of the bricks at the bottom of the hill. The active mass 
 of bricks could be regarded as that number carried at any 
 moment by the transferring factor, namely, the men. The 
 equation of change would be < = K C, where C is the con- 
 centration of the ferment. This concentration is always 
 being renewed, and kept constant by the breaking down of 
 the intermediate product, so that the rate of change would be 
 continuous throughout the experiment. 
 
 The condition of things which obtains when the amount of 
 ferment is largely increased is more difficult to interpret. 
 The rapid diminution in the velocity of change may be caused, 
 in part at least, by the autodestruction of the ferment. All 
 these ferments are unstable bodies, and tend to undergo 
 
THE MODE OF ACTION OF FERMENTS. 21* 
 
 disintegration in watery solutions. That this is not the 
 most important factor, however, is shown by the fact that, 
 when the action of trypsin on caseinogen has apparently come 
 to an end, it may be renewed by further dilution of the 
 mixture or by removal of the end products of the action by 
 dialysis. It is evident that, in this retardation of the later 
 stages of ferment action, the end products are concerned in 
 some way or other, and the retardation can be augmented by 
 adding to the digesting mixture the boiled end products of a 
 previous digestion. The retarding effect of the end products 
 resembles in many ways that observed in a whole series of 
 reactions which are known as reversible. As an example of 
 such a reaction we may take the case of methyl acetate and 
 water. When methyl acetate is mixed with water it undergoes 
 decomposition with the formation of methyl alcohol and acetic 
 acid. On the other hand, if acetic acid be mixed with alcohol, 
 an interaction takes place with the formation of methyl acetate 
 and water. These changes are represented by the equation 
 Me C 2 H 3 2 + HOH ^ Me OH + HC 2 H 3 2 . Each of these 
 changes has a certain velocity constant, and, since they are in 
 opposite directions, there must be some equilibrium point 
 where no change will occur, and where there will be a certain 
 definite amount of all four substances present in the mixture, 
 namely, water, alcohol, ester, and acid. This equilibrium 
 point can be altered by altering the amount of any of the four 
 substances. Thus the interaction of methyl acetate and water 
 can be diminished to any desired extent by adding to the 
 mixture the products of the interaction, namely, methyl 
 alcohol and acetic acid. 
 
 The question at once arises whether we have in the action 
 of ferments a similar reversible phenomenon. There is 
 evidence that some of the ferment actions are reversible. 
 Thus nialtase acts on maltose with the formation of two 
 
30 THE PHYSIOLOGY OF DIGESTION. 
 
 molecules of dextrose. If, however, the maltase be added to a 
 concentrated solution of dextrose, we get a reverse effect, with 
 the production of a disaccharide which has been designated 
 as isomaltose or revertose. The addition of the proteolytic 
 ferment, pepsin, to a strong solution of albumose and peptone 
 causes the appearance of a precipitate, which has been called 
 plastein, and is probably due to a reaggregation of the albu- 
 mose and peptone molecules which had been separated by 
 the process of hydrolysis. It is possible that to this reverse 
 action is due a certain amount of the retardation observed 
 in the action of trypsin on coagulable proteid. It is pro- 
 bable, however, that another factor is involved and is the 
 more important of the two, namely, the combination of the 
 ferment itself with the end products, and the consequent 
 removal of the ferment from the sphere of action. Several 
 facts speak for such a mode of explanation. Thus the action 
 of lactase on milk sugar is not retarded by both its end 
 products, namely, glucose and galactose, but only by galactose. 
 In the same way the action of invertase on cane sugar is 
 retarded by the end product fructose, but not at all by the 
 other end product, glucose. The effect of trypsin on proteids 
 is retarded not only by the end products of its own reaction, 
 but also by the addition of various end products derived 
 from the action of proteolytic ferments on other proteids. 
 
 So far, therefore, a study of the velocity of ferment actions 
 would lead us to suspect that the ferment combines in the 
 first place with the substrate, and that this combination is 
 .a necessary step in the alteration of the substrate. In the 
 second place, the ferment is taken up to a certain extent by 
 some or all of the end products, and this combination acts in 
 opposition to the first combination, tending to remove the 
 ferment from the sphere of action, and therefore to retard the 
 whole reaction. Other facts can be adduced in favour of these 
 
THE MODE OF ACTION OF FERMENTS. 31 
 
 conclusions. Thus it has been shown that invertase ferment, 
 which is destroyed when heated in watery solution at a 
 temperature of 60 C., can, if a large excess of its substrate, 
 cane sugar, be present, be heated 25 higher without under- 
 going destruction. The same protective effect is observed in 
 the case of trypsin. Trypsin in watery or weakly alkaline solu- 
 tions undergoes rapid decomposition. At 37 C. it may lose 
 50 per cent, of its proteolytic power within half an hour.* If, 
 on the other hand, trypsin be mixed with a proteid such as 
 egg-albumin or caseinogen, or with the producis of its own 
 action, namely albumoses and peptones, it can be kept many 
 hours without undergoing any considerable loss of power. 
 
 Another fact, which tells in favour of some form of 
 combination between ferment and substrate, is the specificity 
 of the ferment; i.e., each ferment will act only on a class 
 of bodies grouped together by their chemical composition, 
 and especially by the stereochemical configuration of their 
 molecules. In the table on next page is drawn up a list 
 of four ferments, with the substances with which they can 
 combine.! 
 
 In this list it will be seen that, whereas maltase splits up all 
 the a-glucosides, it has no power on the /?-glucosides ; that is 
 to say, maltase will fit into a molecule of a certain configura- 
 tion, but is powerless to affect a molecule which differs only 
 from the first in its stereochemical structure. On the other 
 hand, emulsin, which breaks up /?-glucosides, has no influence 
 on a-glucosides. 
 
 This specific affinity of the ferments for optically active 
 groups of bodies suggests that the ferment itself may be 
 optically active. We cannot of course isolate the ferment and 
 
 * Cp. Vernon, Journ. of Physiol. Vol. XXVIII. p. 448, 1902. 
 t E. F. Armstrong, loc. cit. p. 520. 
 
32 
 
 THE PHYSIOLOGY OF DIGESTION. 
 
 determine its optical behaviour, but that it is optically active 
 is rendered probable both by these results and by certain 
 results obtained by Dakin * on lipase, the fat-splitting ferment. 
 Dakin carried out his experiments on the esters of mandelic 
 acid. Mandelic acid is optically inactive, but this optically 
 inactive modification consists of a mixture of equal parts of 
 dextro-rotatory and Isevo-rotatory mandelic acid. The esters 
 
 Enzyme. 
 
 Corresponding hydrolyte. 
 
 Effect of hexose on rate of change. 
 
 Glucose. 
 
 Galactose. 
 
 Fructose. 
 
 Lactase. 
 
 - galactosides, milk 
 sugar ; 0-alkylgalac- 
 tosides. 
 
 No 
 influence. 
 
 Retards. 
 
 No 
 influence. 
 
 Emulsin. 
 
 -glucosides (most 
 natural glucosides) ; 
 8-galactosides. 
 
 Eetards 
 consider- 
 ably. 
 
 Retards 
 slightly. 
 
 No 
 
 influence. 
 
 Maltase. 
 
 a- glucosides, maltose, 
 and a-alkylglucosides; 
 a- galactosides (i.e., 
 o-alkylgalactosides). 
 
 Eetards 
 consider- 
 ably. 
 
 Retards 
 slightly. 
 
 No 
 
 influence. 
 
 Invertase. 
 
 Fructosides; cane 
 sugar; raffinose; 
 gentianose. 
 
 No 
 
 influence. 
 
 
 Retards. 
 
 prepared from the optically inactive acids are themselves 
 optically inactive. Dakin found that, when an optically 
 inactive mandelic ester was acted upon by a lipase prepared 
 from the liver, the final results of the action were also inactive ; 
 but if the reaction were interrupted at the half-way point, the 
 mandelic acid which had been liberated was dextro-rotatory, 
 while the remainder of the ester was laevo-rotatory. Thus 
 the rate of hydrolysis of the dextro-component of the ester 
 is greater than that of the laevo- component, a result which 
 
 * Dakin, Journ. of Physiol Vol. XXXII. p. 199, 1905. 
 
THE MODE OF ACTION OF FERMENTS. 33 
 
 can be best explained by the assumptions (a) that the enzyme 
 or a substance closely associated with it is a powerfully 
 optically active substance ; (b) that actual combination takes 
 place between the enzyme and the ester undergoing hydrolysis. 
 Since the additive compounds thus formed in the case of the 
 dextro- and Isevo-components of the ester would not be optical 
 opposites, they would be decomposed with unequal velocity, 
 and thus account for the liberation of the optically active 
 mandelic acid. 
 
 The scanty evidence, which we have as to the composition 
 of ferments, would seem to point to a chemical similarity 
 between ferment and substrate. Thus, in the case of invertase, 
 Osborne * found that it had the composition of a carbohydrate 
 with a nitrogenous group introduced. This similarity of 
 structure between ferment and substrate is further supported 
 by the results just mentioned as to the specific effect of 
 closely related substances in inhibiting or retarding the action 
 of the ferment (see table p. 32), e.g., the fact that the action 
 of lactase is retarded by galactose, but is uninfluenced by 
 glucose or fructose. We may conclude that, in the action of 
 ferments on the food substances, whether carbohydrate or 
 proteid, an essential factor is the combination of the ferment 
 with the substrate, and it is only the part of the substrate, 
 which is thus in combination or in relation with the ferment, 
 which can be regarded as the active mass and as undergoing 
 the hydrolytic change. 
 
 These ferments however cannot be dealt with in the same 
 way as the definite chemical substances such as molybdic 
 acid. All of them are of a colloid or semi- colloid nature, and it 
 is impossible to assign to them a chemical formula, or to form 
 idea of the actual number or condition of the molecules 
 
 * Osborne, " Zeitsch. f. Physiol. Chem.," XXVIII., p. 399, 1899. 
 P.D. D 
 
84 THE PHYSIOLOGY OF DIGESTION. 
 
 involved in the reaction. In many cases too the substrate, 
 e.g., starch and proteid, is also of a colloidal character, and we 
 have therefore to consider the form of interaction which can 
 occur between such colloidal substances, and will nevertheless 
 be specific and display the limited affinities of each body 
 concerned. 
 
 To the relationship between ferment and substrate we have a 
 close analogy in that between toxin and antitoxin, or between 
 lysin and antilysin, etc. As examples of toxins we may take 
 diphtheria and tetanus toxin. These are substances produced 
 in the living bacilli and excreted by them into the surround- 
 ing medium. When introduced into the body, they cause 
 injury in various ways, generally by affecting the vital activity 
 of some special tissue or class of tissues. If small doses be 
 injected into the body, they give rise to the production in 
 the blood serum of an antitoxin, i.e., of a substance w T hich 
 not only has the power of inhibiting the poisonous effect of 
 fresh doses of toxin, but can be added to the toxin in vitro 
 and neutralise its effect when injected into other animals. 
 A close similarity exists between toxins and various other 
 substances which are produced by bacteria and other living 
 organisms. Thus the filtered extracts of tetanus or diphtheria 
 bacilli, besides the specific toxins, contain bodies which have 
 a hsemolytic action and are spoken of as haemolysins. 
 Similar hsemolytic substances are contained in the venom of 
 snakes, in abrin (the poisonous proteid obtained from the 
 plant jequirity), and in the filtered culture fluid from a species 
 of bacillus, namely, Bacillus megatherium. The injection of 
 hsemolysins into the circulation of an animal, in gradually 
 increasing doses, gives rise to the appearance in the blood 
 serum of an antilysin. 
 
 The most usual conception of the action of these bodies, a 
 conception w 7 hich we owe to Ehrlich, is that they consist of a 
 
THIS MODE OF ACTION OF FERMENTS. 85 
 
 centrally placed proteid group with two side chains, one of 
 which hy its stereomeric configuration is peculiarly adapted 
 to fit on to the organ or cell of the hody which the toxin or 
 active body attacks, and is known as the haptopkore group, 
 and another side chain, the toxophore group, which is respon- 
 sible, when the toxin is once anchored, for the destructive 
 changes wrought by the toxin on the cell of the body. The 
 antitoxins or antilysins are thus supposed to act in virtue of 
 their adaptation to the haptophore group, so as to combine 
 with the toxin or lysin and prevent these exercising their 
 injurious effects on the body. Ehrlich has shown that in 
 many toxins the toxophore group can undergo weakening or 
 destruction without any alteration of the haptophore group ; 
 such modifications he designates as toxoids. They have the 
 same combining power for antitoxins as is possessed by the 
 ordinary toxin, but are either without physiological effect, or 
 their poisonous characters are only a fraction of that possessed 
 by ordinary toxin. It seems probable that in the case of 
 enzymes we have also to deal with similar relationships. We 
 may conceive that the ferment fits on, as we have seen really 
 happens, by means of its haptophore group. The specificity of 
 the enzyme is therefore a function of its haptophore group. The 
 changes it effects in the substrate would be due to a zymophore 
 group. As in the case of toxins, this zymophore group may 
 undergo alteration or destruction without the haptophore group, 
 and modifications of enzymes may be produced by heating or 
 other means, resulting in the production of a substance which 
 may be termed zymoid. Thus Bayliss has shown that trypsin 
 on warming, or under the action of strong acid, is converted 
 into a modification which has much less proteolytic power 
 than ordinary trypsin, but still possesses the pow r er of binding 
 certain molecules of the substrate. This combining effect 
 is shown by the fact that the addition of the zymoid to a 
 
 D 2 
 
86 THE PHYSIOLOGY OF DIGESTION. 
 
 proteid solution causes a preliminary fall in the conductivity 
 of the whole solution. It has been shown moreover by 
 Korschun, that from rennin ferment it is possible, by nitra- 
 tion through a clay filter, to separate a part which has less 
 coagulating power on milk than ordinary rennin, but has the 
 same power of neutralising an anti-rennin serum produced by 
 the injection of rennin into the veins of an animal. 
 
 The question of the manner in which the antitoxin is able 
 to combine with and neutralise the toxin is one of consider- 
 able practical importance. In this process we have relations 
 presenting marked analogies with the neutralisation of acids 
 by bases. If we define a unit of toxin as that amount which 
 possesses a certain power, i.e., which will kill a guinea-pig in 
 so many days, or will cause the complete ha3molysis of 1 cc. 
 of blood in two and a half hours, we can find the amount of 
 anti-body which is just sufficient to neutralise this effect, 
 and this amount of anti-body can be regarded also as 
 one unit. If instead of one unit of each we take 100 units, 
 the neutralisation is effected in the same way. The process 
 is found, however, to be more complex when we take 
 100 units of toxin or lysin, and attempt to neutralise them by 
 the fractional addition of antitoxin. In the case of a strong 
 acid and strong alkali we know that, if 100 cc. of alkali are 
 just sufficient to neutralise 100 cc. of acid, the addition of 
 50 cc. of alkali will leave half the acid unneutralised. If, 
 however, we try the same experiment in the case of mixtures 
 of toxin and antitoxin, it will be found that the addition of 
 50 cc. of antitoxin will neutralise much more than half of 
 the toxin, and the same applies with other bodies of this class. 
 As an example, we may take the relation between a standard 
 suspension of typhoid bacilli and a serum which has the 
 power of agglutinating typhoid bacilli. In the table given 
 below are represented the results of the addition of varying 
 
THE MODE OF ACTION OF FERMENTS. 
 
 87 
 
 units of agglutinating serum to a suspension of bacilli. It 
 will be seen that the amount taken up by the bacilli is not a 
 definite quantity, but is determined by the concentration of 
 the agglutinating solution. 
 
 EFFECTS OF ADDING VARIOUS DILUTIONS OF AGGLUTINATING SERUM TO 
 EQUAL VOLUMES OF A SUSPENSION OF TYPHOID BACILLI. (CRAW.) 
 
 Concentration 
 of Serum. 
 
 Units of agglutinin 
 added. 
 
 Units of agglutinin 
 absorbed. 
 
 Units of agglutinin 
 free. 
 
 1/20 
 
 2000 
 
 1300 
 
 730 
 
 1/30 
 
 1333 
 
 1133 
 
 200 
 
 1/40 
 
 1000 
 
 840 
 
 160 
 
 1/60 
 
 666 
 
 646 
 
 20 
 
 1/200 
 
 200 
 
 200 
 
 
 
 Ehrlich has attempted to explain this result by assuming 
 that in any toxin there is a mixture of substances, some 
 having a strong affinity for the antitoxin, and others, 
 which he calls toxones, possessing only a slight affinity. In 
 the 50 cc. of toxin first added, the toxins would satisfy 
 all their combining powers, whereas the toxones would not 
 begin to combine until they were present in large excess. 
 Arrhenius and Madsen have drawn an analogy between the 
 neutralisation of toxin by antitoxin and the neutralisation of 
 a weak acid, such as boracic acid, by a weak base, such as 
 ammonia. They show that in this case the general course of 
 events would be similar to that observed by Ehrlich. At no, 
 time would there be complete neutralisation, owing to the 
 fact that hydrolysis constantly occurs, so that, when equivalent 
 quantities of each substance had been added, the fluid would 
 still contain a certain amount of free base alongside of free 
 
38 THE PHYSIOLOGY OF DIGESTION. 
 
 acid, in addition to the salt produced by the combination of the 
 two. It is impossible, however, to account for all the pheno- 
 mena presented in the neutralisation of toxin by antitoxin 
 in this simple manner. Thus the results given in the above 
 table could not be explained on any hypothesis of chemical 
 combination. Seventeen parts of ammonia would neutralise 
 exactly an equivalent quantity of boracic acid, whether these 
 substances were dissolved in 10 cc. or in 100 cc. of water. 
 If, however, it be found that 1 cc. of antilysin exactly 
 neutralises 1 cc. of lysin, these two substances will no 
 longer be in equilibrium when the whole is diluted up to 
 10 cc. with water. If a neutral mixture of lysin and 
 antilysin be taken and filtered under pressure through 
 a gelatin filter, no lysin or antilysin passes through 
 the filter, so that the residue on the filter becomes con- 
 centrated. On examining this residue it is found that it 
 has a strong haemolytic action, and the same is true of the 
 substance which may be obtained by melting the gelatin out 
 of the pores of the filter. It is evident that, even in a neu- 
 tralised mixture, both free lysin and free antilysin, or free toxin 
 and free antitoxin are present, and it needs only the alteration 
 of the physical conditions of the mixture in order to display 
 the action of one or other of these bodies. How then are we 
 to regard this combination of toxin with antitoxin? Craw 
 points out that the combination is in all respects comparable 
 to that which occurs between adsorbing surfaces and many 
 dye-stuffs. If we place some filter paper in a solution of 
 fuchsin or Congo red, the filter paper will take up a large 
 amount of the dye substance. The amount taken up by the 
 paper will increase with increase in concentration of the 
 solution. There will, however, be a tendency to the formation 
 of false equilibrium points, as in the case of the reaction of 
 toxin and antitoxin. Thus if two solutions of fuchsin be made, 
 
THE MODE OF ACTION OF FERMENTS. 39 
 
 and to each a sheet of filter paper be added, but in one case 
 the paper be added at once, in the other case in three parts 
 at intervals of twelve hours, at the end of thirty-six hours 
 the paper which has been added in parts will have removed 
 more dye-stuff from the solution than is the case where the 
 whole amount of paper was added at once. In the same way, 
 when treating a suspension of bacilli with an agglutinating 
 serum, it is found that the successive addition of the bacil- 
 lary suspension to the serum removes more agglutinin from 
 the solution than when the addition is made at one time. 
 
 The interactions, therefore, between these bodies must be 
 looked upon as special examples of the group of phenomena 
 known as adsorption, such as the adsorption of iodine from 
 solutions by charcoal, of iodine from water by starch, or 
 of ammonia by charcoal. 
 
 Is the combination between ferment and substrate of the 
 same nature? Though it is impossible to give a decisive 
 answer to this question at the present time, it seems probable 
 that the specific combination of ferments with certain definite 
 substrates is in all respects analogous to the combination of 
 toxin or lysin with their corresponding anti-body, and it is 
 noteworthy that the assumption of the colloidal condition a 
 condition in which there is an enormous exaggeration of 
 surface seems to be an important condition in deciding the 
 catalytic effect of any given substance. Thus platinum, which, 
 in the metallic state, has a marked power of condensing 
 oxygen and hydrogen on its surface, has also a strong catalytic 
 action. The same catalytic power can be imparted to other 
 metals such as gold, silver, lead, cadmium, or silver, by bringing 
 them into colloidal solution. As Bredig has shown, the 
 passage of a small arc between metallic wires under distilled 
 water leads to the metal being thrown off in clouds of 
 fine ultra-microscopic particles, which remain in perpetual 
 
40 THE PHYSIOLOGY OF DIGESTION. 
 
 suspension in the fluid. The ' sol ' thus obtained has all the 
 properties of a colloidal solution, and it shares with platinum 
 ' sol ' the power of quickening various chemical processes, 
 especially the decomposition of hydrogen peroxide. We know 
 that the molecules which are in immediate contact with a 
 surface are in a different condition of aggregation, and the mere 
 exaggeration of surface, which occurs in these colloidal solutions, 
 seems to be sufficient to bring a large number of molecules 
 into the condition in which they are able to interact chemically, 
 and so hasten any chemical interaction which would otherwise 
 go on with an extremely slow velocity. This influence of 
 surface is not, however, absolutely general. Even platinum 
 * sol ' is not a universal catalyser, and although in every case 
 we must regard adsorption by a surface as the essential 
 factor, the exact adsorption which takes place is evidently a 
 function of the chemical configuration of the substance forming 
 the surface. We cannot otherwise account for the specific 
 interaction between toxins and antitoxins, or for the specific 
 action of the different ferments on their various substrates. 
 We have here, therefore, a special class of interactions, not 
 entirely chemical and not entirely physical, but depending for 
 their existence on a co-operation of both chemical and physical 
 factors. To definitely assign ferment actions to this class 
 would be premature. There is, indeed, evidence that ferments 
 act on the substrate by forming intermediate combinations 
 with it, but whether these compounds are to be regarded as 
 chemical or as adsorptive we have not yet sufficient evidence to 
 determine. The facts that the ferments all belong to the 
 class of imperfect colloids, and that in many cases, e.g. 
 proteolytic ferments and diastase, their action is on complete 
 colloids, would certainly suggest that the combinations must 
 be of the physical type. 
 
LECTUKE III. 
 
 SECRETION OF SALIVA. 
 
 THE taking of food into the mouth is at once followed by the 
 pouring out of a large quantity of saliva into this cavity. 
 This fluid is the product of secretion, partly of a multitude of 
 small glands scattered over the surface of the tongue and the 
 mucous membrane forming the lining of the mouth cavity, 
 but to a larger extent of three pairs of salivary glands which 
 pour their fluid into the mouth by means of long tubes or 
 ducts. These glands are the parotid, the submaxillary, and 
 the sublingual. The fluid which moistens the food is there- 
 fore a mixture of the secretions of these various glands. Its 
 average composition has been given by Maly as follows : 
 
 Water 992'9 
 
 Total solids . . 7'1 
 
 Suspended solids (epithelium, mucus, etc.) . . . . 1*4 
 
 Soluble organic matter (chiefly proteid and mucin) . . 3*8 
 Inorganic salts . . . . . . . . . . . . 1'9 
 
 * 
 
 The composition, however, varies according to the nature of 
 the food which has been taken in. 
 
 The use of this admixture of food with saliva is chiefly 
 mechanical. The saliva not only moistens the food and thus 
 aids its mastication by the teeth, but also, in virtue of the 
 mucin that it contains, lubricates all the passages, and so 
 facilitates the process of swallowing, and the passage of the 
 food bolus into the stomach. In dogs the mechanical action 
 of saliva is its only one. In herbivora and in omnivora, such 
 
42 THE PHYSIOLOGY OF DIGESTION. 
 
 as man, the saliva has a further action, and is an important 
 agent in the digestion of starch. The saliva secreted by the 
 parotid gland contains an amylase known as ptyalin. Under 
 the action of this ferment, boiled starch is transformed into 
 dextrin and maltase. It might be thought that the stay of the 
 food in the mouth is of too short duration to admit of any 
 appreciable degree of starch solution taking place. The 
 action of saliva is not, however, confined to the period that 
 the food remains in the mouth. When a meal is taken, the 
 food, after mastication, is swallowed in a succession of boluses, 
 and collects in a mass, moistened throughout with saliva, in 
 the stomach. It is true that the taking of food determines 
 the pouring out of an acid juice in the stomach, a juice which 
 not only prevents the digestive action of ptyalin but actually 
 destroys this ferment. It takes, however, a considerable time 
 for this acid gastric secretion to penetrate the mass of food 
 lying in the stomach, and the saliva in the interior of the 
 mass has from twenty to forty minutes at its disposal to act 
 on the starchy constituents of the food, before the acid gastric 
 juice can penetrate and destroy the ptyalin. The main 
 digestive action of saliva therefore occurs in the stomach. 
 
 The mixed saliva, whose composition I have given above, is 
 the product of secretion of the different glands, and is composed 
 of fluids which vary in their composition according to the 
 gland from which they are derived, and according to the 
 conditions which have determined the activity of the gland. 
 Thus the saliva obtained from the parotid gland contains 
 water, salts, traces of albumin and globulin, and in many 
 animals ptyalin. Mucin is however absent. On the other 
 hand, the secretion of the submaxillary gland, especially in the 
 dog, consists essentially of a solution of mucin in a weak salt 
 solution. This secretion can vary considerably in quality 
 according to the conditions determining the activity of the 
 
SECRETION OF SALIVA. 43 
 
 gland. Thus by a suitable admixture of these various secre- 
 tions it is possible to adapt the saliva to the nature of the food 
 in the mouth. In order to determine the nature of the saliva 
 which is poured into the mouth in response to the physiolo- 
 gical stimuli of various kinds of food, the best method is to 
 divert the ducts of the submaxillary and parotid glands and 
 make them open on the exterior of the cheek.* By attaching 
 receptacles to the orifices of these displaced ducts, it is possible 
 to collect separately the saliva of each gland and to study its 
 modifications with variations in the food. By such means it 
 has been found by Pawlow that, on administration of meat to 
 a dog, the saliva which is secreted is derived mainly from the 
 submaxillary gland and is thick and viscid, containing a 
 relatively large amount of mucin. If, on the other hand, dry 
 powdered biscuit be introduced, the resulting secretion is thin 
 and watery, and is obtained from both sets of glands. The 
 introduction of stones into the animal's mouth evokes no 
 secretion at all. The animal can get rid of the stones by 
 movements of the tongue without any preliminary moistening. 
 The introduction of sand into the animal's mouth is, however, 
 followed by a copious secretion of a thin watery sajiva, which 
 serves the purpose of washing the sand from the surface of 
 the mouth and enabling this substance to be rejected by the 
 animal. These facts reveal a differential activity of these 
 glands according to the needs of the animal. Such a differen- 
 tial secretion, adapted as it is to the nature of the substances 
 present in the mouth, involves the intermediation of some 
 complex reactive mechanism, and the rapidity with which the 
 reaction takes place indicates that we must seek for the 
 mechanism in the central nervous system that, in fact, we 
 
 * This method, which has been much employed by Pawlow, was first 
 used by De Graaf, as will be seen from the figure on p. 81. 
 
44 THE PHYSIOLOGY OF DIGESTION. 
 
 have here a complex reflex arc. The nervous channels of the 
 reflex have been determined in the case of all three pairs of 
 salivary glands. The afferent channels are represented by 
 the special gustatory nerves, as well as the nerves of common 
 sensation, which run chiefly in the fifth and ninth cranial 
 nerves to the brain. The efferent channels vary in the case 
 of the different glands. Each gland receives a double nerve 
 supply, viz., from the cranial nerves and from the sympathetic 
 system. The impulses which travel along the sympathetic 
 pass out from the spinal cord along the upper two or three 
 dorsal nerve roots ; thence they travel in the cervical sympa- 
 thetic to the superior cervical ganglia. Here there is a new 
 relay of fibres, which start from the cells of the ganglia and 
 travel up in the walls of the branches of the external carotid 
 artery to be distributed with the arteries to the salivary 
 glands. The cranial supply of the parotid gland arises from 
 the ninth nerve and passes through the tympanic plexus into 
 branches of the fifth nerve, with which it is distributed to the 
 gland. The fibres to the submaxillary and sublingual glands 
 leave the brain with the intermediate nerve of Wrisburg and 
 pass with the facial into the chorda tympani, the branches of 
 which nerve carry the impulses to the gland. The centre 
 must be located somewhere in the lower part of the cranial 
 axis, in the neighbourhood of the pons and medulla. 
 
 This reflex mechanism can be set into activity, not only by 
 stimuli applied to the surface of the mouth, but also, in default 
 of such stimuli, by processes which must be located in the 
 cortex cerebri. Pawlow has shown that the specific secretion is 
 evoked, not only by the introduction of different substances 
 such as meat, biscuit powder, or sand into the dog's mouth, 
 but also by merely showing the dog the substances in question, 
 so that the calling up of the psychical images of these sub- 
 stances has the same effect as their actual introduction into 
 
SECRETION OF SALIVA. 45 
 
 into the mouth. As soon as the animal realises that it is 
 being played with, and that there is no intention of really 
 giving it these things, the psychical secretion of saliva ceases. 
 
 What is the mechanism of this secretion ? What are the 
 changes which are actually responsible in each gland for the 
 production of a secretion ? The chief experiments bearing on 
 the mechanism of secretion have been made upon the salivary 
 gland, since this forms a compact organ, which can be easily 
 isolated from other tissues without injury to its blood and 
 nerve supply. Moreover, a state of activity is readily induced 
 in the gland, either by the injection of drugs such as pilocarpin, 
 or by excitation of its nerves, which are easily accessible. In 
 investigating the action of its nerves upon the gland, a small 
 tube or cannula is placed in the duct, so that the saliva can be 
 led off and measured and its qualities determined. At the 
 same time the chorda tympani and the sympathetic nerves 
 are dissected out and prepared so that they can be stimulated 
 electrically. It is found that these two sets of fibres differ 
 in their results on the gland. The stimulation of the peri- 
 pheral end of the chorda is at once followed by a copious flow 
 of thin watery saliva which contains only a small amount of 
 mucin. There is also great dilatation of all the arterioles of the 
 gland, so that the blood-flow through it is increased five- to 
 eight-fold. Stimulation of the sympathetic evokes a scanty 
 secretion of thick viscid saliva, generally opalescent in appear- 
 ance and containing a relatively large amount of mucin. On 
 the blood-vessels the action of the sympathetic is the reverse 
 of that on the chorda. The sympathetic carries vaso-constrictor 
 fibres to all parts of the head and neck. The arterioles of the 
 gland are therefore constricted, and the flow of blood through 
 the gland very largely reduced. 
 
 The question arises whether, in these two sets of nerves, 
 we have two distinct varieties of secretory fibres influencing 
 
46 THE PHYSIOLOGY OF DIGESTION. 
 
 different parts of the gland cells, or whether the differences 
 between the two kinds of secretion may not be determined by 
 the coincident changes in the blood supply. Heidenhain 
 stated that the histological results of stimulating the sym- 
 pathetic nerve were much more pronounced than those 
 obtained by stimulating the chorda tympani, and sug- 
 gested that the nerves to the glands ought to be divided 
 into two classes, namely (1) trophic nerves, e.g., sym- 
 pathetic, which influence chiefly the metabolic changes in 
 the cells themselves, and (2) secreto-motor fibres, which deter- 
 mine the secretion of water and salt by the glands. Langley 
 however has been unable to confirm the statement of Heidenhain 
 as to the peculiar effects of the sympathetic on the structure 
 of the glands. According to Langley the histological results 
 of stimulating either set of fibres are of the same order. On 
 the other hand, the secretion obtained on stimulating the chorda 
 can be approximated to sympathetic saliva by diminishing the 
 blood- flow to the gland, while secretion is going on, either by 
 clamping of the arteries or by bleeding the animal. Under 
 these conditions the saliva becomes thicker and more viscid, 
 and its percentage of solids increases. Langley therefore is 
 inclined to regard all the fibres going to the gland as of 
 essentially the same character, namely secretory; and considers 
 the differences between the two kinds of saliva as determined 
 entirely by the concurrent vascular changes induced by stimu- 
 lation of the two sets of nerves. It has been urged against this 
 view of the identity of the chorda and sympathetic secretory 
 fibres that, whereas the chorda fibres are paralysed by a minute 
 dose of atropin, it is very difficult to affect the action of the 
 sympathetic even by large doses of this drug. This difference 
 in the susceptibility of the two sets of fibres to the action of 
 atropin might however point to a morphological rather than 
 to a functional distinction. For the present, therefore, we may 
 
SECRETION OF SALIVA. 47 
 
 regard the glands as supplied by one kind of fibre, namely 
 secretory, in addition to the fibres which exercise their main 
 influence on the blood-vessels of the gland ; and we may treat 
 the effects of stimulation of the chorda tympani as typical of 
 the state of activity of the gland. 
 
 On investigating the conditions of secretion, it very soon 
 becomes manifest that this process cannot be determined by 
 the blood pressure within the blood capillaries of the gland, how- 
 ever much the changes in the blood supply may modify the 
 character of the secretion. Saliva cannot be regarded as a 
 simple filtrate from the blood circulating through the glands. 
 This is shown, in the first place, by the specific composition of 
 the saliva. Although amylase, albumin, and globulin, as well 
 as salts, are present in the surrounding plasma, this fluid 
 contains no trace of mucin. Moreover, though it is possible, 
 under a pressure comparable to that in the blood capillaries, 
 to separate by filtration from the blood plasma a fluid con- 
 taining only the water and salts of the plasma, it would be 
 impossible to separate off a salt solution of the composition of 
 saliva without the application of a force far transcending in 
 extent even the arterial blood pressure. Whereas blood 
 plasma contains a mixture of salts in such proportions as to 
 be isotonic with a '9 per cent, solution of sodium chloride, 
 the concentration of salts in the saliva is only equivalent to 
 about '45 per cent, sodium chloride, or even less, i.e., the 
 molecular concentration of the saliva is only about half that 
 of the blood plasma. Even supposing that we could conceive 
 of a filter capable of keeping back one-half the salts of the 
 blood plasma, it would require a pressure of several atmo- 
 spheres in order to effect the separation and to force any fluid 
 at all through the filter. The osmotic pressure of the blood 
 plasma is about 4,500 mm. Hg. The osmotic pressure of the 
 saliva would be less than 3,000 mm. Hg., so that a minimum 
 
48 THE PHYSIOLOGY OF DIGESTION. 
 
 pressure of 1,500 mm. Hg., i.e., two atmospheres, would be 
 necessary to effect the separation of a fluid from blood plasma 
 having the molecular concentration of saliva. 
 
 The impossibility of explaining the process of secretion as 
 in any way determined by the blood pressure was pointed out 
 long ago by Carl Ludwig. Ludwig showed that, if a mercurial 
 manometer be connected with the carotid artery of an animal, 
 and another with a cannula placed in the duct of the sub- 
 maxillary gland, the occurrence of secretion on stimulation of 
 the chorda causes the manometer attached to the duct to rise 
 to a height much greater than that of the manometer con- 
 nected with the carotid artery. While the blood pressure 
 in the arteries going to the gland may be 120 mm. Hg., the 
 pressure in the salivary duct may rise to 210 mm. Hg. This 
 experiment proves conclusively that, somewhere between 
 blood-vessels and duct, there must be living cells which are 
 themselves taking an active part in the process of secretion, 
 and furnishing energy for the process energy which can 
 be derived only from the metabolism of the cells, and 
 ultimately from the oxidation of their food- stuffs. 
 
 Between the blood and the duct there are two layers of cells, 
 namely the delicate endothelial cells forming the capillary 
 wall, and the much larger cells which form a continuous 
 lining to the ultimate ramifications of the gland-ducts, the 
 .alveoli. It has often been suggested that, in the process of 
 secretion, the endothelial cells and vessels must take an 
 important part, and this view was not directly negatived by 
 the action of atropin. Atropin, as is well known, prevents 
 .altogether the action of the chorda tympani upon secretion, 
 i.e., it paralyses the secretory fibres of the chorda tympani. 
 It has no action, however, upon the vaso-dilator fibres of this 
 nerve, so that stimulation of the chorda after administration 
 -of atropin evokes an increased flow of blood through the gland 
 
SECRETION OF SALIVA. 49 
 
 without any corresponding secretion. The absence of secretion 
 might be ascribed equally well to an action upon the endothe- 
 lial cells of the vessels as to an action upon the cells of the 
 secreting alveoli. To decide this point Gianuzzi attempted to 
 paralyse the secretory cells by the injection of acid into the 
 duct. On then stimulating the chorda tympani no secretion 
 was obtained, but the gland swelled up and became oedematous. 
 This observer concluded that the effect of the injection of the 
 acid was to paralyse the secretory cells of the gland, without 
 paralysing the process of secretion as effected by the endo- 
 thelial cells and blood-vessels. This explanation is, how- 
 ever, incorrect. The injection of acid injures, not only the 
 cells of the : alveoli, but also the endothelial cells of the blood- 
 vessels, and, as in any other injury, the production of vaso- 
 dilatation causes a copious transudation of lymph through the 
 injured vessel wall, and therefore the production of oedema. 
 A consideration of the other changes occurring in the gland 
 coincidently with secretion shows conclusively that the active 
 cells are not the vascular endothelium, but the cells lining the 
 alveoli themselves. In the process of secretion there is an 
 evolution of energy. We have to determine the seat and 
 conditions of production of this energy. In order to do 
 this, we must examine more carefully the various changes 
 which occur in the gland concurrently with the process of 
 secretion. 
 
 1. Blood-flow through the Gland. We have already seen 
 that stimulation of the chorda tympani nerve causes active 
 vaso-dilatation in the vessels of the gland, and a largely 
 increased flow of blood through this organ. The same 
 quickening of the blood-flow is observed when the gland is 
 excited to secrete reflexly, by the application of stimuli to the 
 mucous membrane of the mouth, or by the injection of drugs 
 such as pilocarpin. During active secretion the blood-flow 
 
 P.D. E 
 
50 THE PHYSIOLOGY OF DIGESTION. 
 
 through the vessels of the gland is increased on the average 
 to five times the amount which obtains during rest. 
 
 As a result of stimulation a very large amount of water is 
 turned out through the gland ducts. In one experiment of 
 Heidenhain's * 220 cc. of saliva were secreted by a gland 
 weighing about 6 grammes. This water cannot come from 
 the gland itself, and must therefore be furnished ultimately 
 by the blood which circulates through the vessels of the gland. 
 The loss of water by the blood in passing through the gland 
 has been determined by Barcroft,t who estimated the amount 
 of haemoglobin in the arterial blood and in the blood which 
 had flowed through the gland, taking into account at the 
 same time the variations in the rate of flow through the 
 gland. In this way it is possible to compare the quantity 
 of fluid, which has been turned out by the gland as saliva, 
 with that which has been taken up by the gland from the 
 blood. The amount of water which leaves the blood may be 
 considerable, so that the blood may be concentrated by as 
 much as 25 per cent., and Barcroft has shown that the 
 volume of water leaving the blood is always somewhat greater 
 than that of the saliva secreted. Thus in one experiment 
 the water lost by the blood during seven minutes amounted to 
 3'88 cc., while the saliva secreted during the same period was 
 only 3'52 cc. In this case the ratio of water lost by the blood 
 to the water in the saliva was as 1*12 to 1, and in all Barcroft's 
 experiments the water lost by the blood was about 10 per 
 cent, greater than the water leaving the gland in the saliva. 
 The question arises as to the destination of this excess of 
 water which leaves the blood-vessels. It does not remain in 
 the gland. If a gland be stimulated for some time, it is always 
 found to diminish in size and in weight. In two experiments 
 
 * Hermann's Handbook, Vol. V. (1), 1883. 
 t Journ. ofPhysiol. Vol. XXV., p. 479, 1900. 
 
SECRETION OF SALIVA. 51 
 
 by Heidenhain, the right gland was extirpated and weighed, 
 and then the left chorda tympani was stimulated for several 
 hours. The saliva secreted was measured, and at the end of 
 the experiment the left gland was cut out and weighed. The 
 results of these two experiments were as follows : 
 
 Saliva. Right gland. Left gland. 
 
 75 cc. 6-86 g. 5-42 g. 
 
 220 cc. 6-36 g. 5-91 g. 
 
 Iii each case there was a considerable loss of weight, and this 
 loss of weight affected the solids of the gland even more 
 than its fluid constituents. The resting glands contained 
 28*3 per cent, total solids, whereas the two active glands gave 
 only 21 '3 per cent. It is evident that all the water which 
 leaves the blood must leave the gland, and the destiny of 
 this water is at once revealed on examination of the lymph 
 flowing from the gland. The lymph passes out by the 
 lymphatic vessels in the hilus of the gland, and finally 
 makes its way into the cervical lymphatic trunk. If the other 
 vessels passing into this trunk be ligatured, a cannula can be 
 placed in the trunk towards the head, and the lymph-flow 
 obtained will represent the lymph from the submaxillary 
 gland. This experiment has been performed by Bainbridge, 
 who finds that the amount of lymph, which is practically 
 negligible in the resting gland, is markedly increased when 
 secretion takes place. The total quantity of lymph is about 
 one-tenth of the volume of saliva secreted at the same time, 
 so that, together with the saliva, it exactly corresponds to the 
 volume of water lost by the blood in passing through the 
 gland (Figs. 1 and 2). 
 
 It might be imagined that this increased flow of lymph 
 during secretion was in favour of the view put forward by 
 Gianuzzi, i.e., that the first factor in secretion was an 
 alteration of the endothelial cells of the blood-vessels and 
 
 E2 
 
52 
 
 THE PHYSIOLOGY OF DIGESTION. 
 
 an increased trans udation. That this explanation, however, 
 is not correct is shown by some experiments of Bunch, 
 carried out in this laboratory, on the changes in volume of 
 
 FIG. 1. Diagram showing : (a) Total blood flow 
 through submaxillary gland. (6) Total amount of 
 water transferred from blood to gland, (c) Total 
 secretion of saliva (Barcroft). 
 
 the gland during secretion. In these experiments the whole 
 submaxillary gland was placed in a plethysmograph, and 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 S 
 
 i vu 
 
 L*T 
 
 ION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 / 
 
 ' N| 
 
 \/ 
 
 
 ^^, 
 
 ^ 
 
 
 ^__^ 
 
 
 
 ^^ 
 
 
 
 7 
 
 r 
 
 j/^ 
 
 ^^ 
 
 
 
 
 ^ 
 
 ^1 
 
 
 > 
 
 x 
 
 
 1 
 
 
 
 
 
 
 
 5 10 15 S 30 i5 "0 4b SO S5 60 ""---. 
 
 Of CLAN D 
 
 FIG. 2. Comparison of changes in volume of submaxillary 
 gland with the outflow of saliva produced by stimulation 
 of the chorda tympani nerve (Bunch). 
 
SECRETION OF SALIVA. 53 
 
 its volume recorded by connecting the plethysmograph with 
 a piston recorder writing on a blackened surface. When 
 vasodilatation occurs in any organ, the volume of the blood- 
 vessels is increased, and therefore one would expect that the 
 vasodilatation, which accompanies activity of the salivary 
 gland, would occasion an increase in the volume of the gland. 
 This is the case in a gland in which the chorda tympani nerve 
 
 FIG. 3. Tracing of volume of submaxillary gland, showing 
 effect of stimulation of the chorda after administration of 
 10 mg. atropine. The blood pressure (lowest line) was 
 unaltered by the stimulation (Bunch). 
 
 is stimulated, after paralysis of its secretory fibres by the 
 administration of a small dose of atropine. The vasodilatation 
 which results gives an increase in the volume of the gland 
 and a rise in the recording lever (Fig. 3.) The same 
 increase in the volume of vessels must be present when 
 secretion is allowed to take place ; but a record of the volume 
 of the gland during normal secretion shows that the first 
 effect is a diminution and not an increase, as is shown in 
 Fig. 4. If the duct be clamped so as to prevent the escape 
 of saliva, stimulation of the chorda gives merely an increase 
 
54 THE PHYSIOLOGY OF DIGESTION. 
 
 in volume (Fig. 5). The diminution in volume observed when 
 the duct is free shows 
 
 (1) That the first result of exciting the secretory nerves is 
 an emptying out of the contents of the gland; 
 
 (2) That this discharge of the contents of the gland, as 
 saliva, is more than sufficient to counterbalance the swelling 
 of the gland, produced by the dilatation of its blood-vessels. 
 
 FIG. 4. Tracing of volume of submaxillary gland showing 
 decrease on excitation of chorda. The duct was free 
 (Bunch). 
 
 A primary increased transudation of lymph would cause an 
 initial expansion in the volume of the gland, and we must 
 conclude, therefore, that the first effect of stimulation is not 
 on the blood-vessels, but on the secreting cells of the alveoli, 
 causing them to empty out their contents, including solids 
 and water. Only later can the cells recoup themselves at 
 the expense of an increased transudation from the blood- 
 vessels. 
 
 This loss of gland substance is indicated by the figures I 
 
SECRETION OF SALIVA. 
 
 have quoted above on the changes in the weight and in the 
 percentage of solids of the gland during secretion. The same 
 conclusion is borne out by Pawlow's estimations of the amount 
 of nitrogen in secreting and resting glands respectively. This 
 observer found that, whereas ten resting glands contained 
 2' 18 gr. of nitrogen, ten glands from the same animals, which 
 had been stimulated for some hours, contained only 1*872 gr. 
 of nitrogen, representing a loss by these glands during 
 
 FIG. 5. Tracing of volume of submaxillary gland, showing 
 effect of chorda stimulation after obstruction of the duct. 
 It will be noticed the volume diminished as soon as the 
 duct was released, so as to allow the saliva to flow awav. 
 
 secretion of *308 gr. of nitrogen. The saliva obtained 
 during these experiments yielded *416 gr. of nitrogen, so 
 that the glands had taken up only '19 gr. of nitrogen (i.e., 
 2 1 ! of the total amount) from the blood passing through them. 
 Thus the primary result of stimulating the secretory nerves is to 
 cause the gland cells to discharge their organic matter together 
 with water and salts. The cells then recoup themselves at 
 the expense of the blood circulating through the blood-vessels ; 
 but this process, although practically complete in the case of 
 
56 THE PHYSIOLOGY OF DIGESTION. 
 
 the water and salts, is very inadequate in the case of the 
 nitrogenous constituents of the cells, which have been lost in 
 the saliva. It is on this account that the phenomena of 
 exhaustion occur on prolonged secretion. 
 
 A study of the histological changes occurring in the cells 
 of the alveoli during secretion points to the same conclusions. 
 If the salivary glands, whether parotid or submaxillary, serous 
 or mucous, be teazed with salt solution or serum and examined 
 under the microscope, the appearances observed will differ 
 according to the state of activity of the gland from which the 
 specimens have been made. If obtained from a resting gland, 
 the cells are swollen and packed full of granules, coarse in the 
 case of the mucous glands, fine in the case of the serous glands. 
 The unaltered protoplasm of the cell is small in amount and 
 situated chiefly at the periphery, away from the lumen of the 
 alveolus. The nucleus, if brought into view by the addition 
 of reagents, is embedded in the peripheral zone or is crushed 
 against the basement membrane, and becomes easily shrivelled 
 under the action of hardening reagents. If, however, the 
 cells examined be taken from a gland which has been secreting 
 for some hours, they present a totally different appearance. 
 The cells are now considerably smaller in size ; the granules 
 are reduced in number, and are confined to the part of the 
 cell immediately abutting on the lumen. The protoplasm has 
 increased in amount both relatively and absolutely, and the 
 nucleus is swollen and occupies a more central position in the 
 cell. Histologically, then, secretion consists in 
 
 (1) A discharge of the granules. 
 
 (2) A growth of protoplasm ; and 
 
 (3) Changes in the appearance of the nucleus. 
 
 During rest we must assume the occurrence of reverse 
 changes, namely, a gradual conversion of the protoplasm into 
 granules and the accumulation of these granules in the cell, 
 
SECRETION OF SALIVA. 57 
 
 until it is distended with them and swollen. The granules 
 must therefore be taken as representing the precursor of the 
 secretion. In them occur the changes which lead to the 
 taking up of water and the discharge of the granules, dissolved 
 and perhaps changed in character, into the lumen of the 
 secreting alveoli. 
 
 We have already learnt that there is an expenditure of 
 energy in the act of secretion, and it is important that we 
 should be able to arrive at some idea of the extent of these 
 energy changes. The energy balance of the whole body is 
 most easily obtained by an examination either of the total 
 potential energy presented to the body in the shape of food, 
 or better by an analysis of the excreta consisting of carbon 
 dioxide, water, and nitrogenous end-products such as urea. 
 Nine-tenths of the total energy set free in the body by the 
 combustion of the foodstuffs is represented by the carbon 
 dioxide output of the body. We can therefore probably 
 arrive at a fairly true idea of the energy changes in the sub- 
 maxillary gland by examining its intake of oxygen and its 
 output of carbon dioxide. In the whole body these two 
 amounts correspond, though there is always a small loss of 
 oxygen, about one-fifth of the whole, which is required for 
 the oxidation of substances other than carbon in the body. 
 When, however, we are dealing with an isolated organ, the 
 oxygen intake is considerably more valuable than the carbon 
 dioxide output. There is no evidence that the body in any 
 of its tissues is able to store oxygen,* so that the intake 
 of oxygen must be proportional at any time to the require- 
 ments of the body. On the other hand, all the alkaline juices 
 
 * Many physiologists might not agree with this statement. All would 
 agree, however, that the power of living tissues to store oxygen is 
 extremely limited. 
 
58 THE PHYSIOLOGY OF DIGESTION. 
 
 of the body contain carbonates or bicarbonates. Any change 
 in reaction of these fluids will alter their power of taking up 
 carbon dioxide, and the mere production of acid may therefore 
 give rise to an evolution of C0% which has not been imme- 
 diately formed by the cells. On the other hand, increased 
 alkalinity of the juices will enable these to take up more C0 2 , 
 and prevent therefore the output of carbon dioxide to the 
 blood circulating through the capillary vessels. 
 
 The question of the gaseous exchanges of the submaxillary 
 gland has been investigated by Bar croft.* The following table 
 represents the average figures obtained from a number of 
 observations. In these experiments the blood gases were 
 estimated in the arterial blood and also in samples of blood 
 obtained from the veins of the submaxillary gland. From the 
 difference between these two figures it was possible to reckon 
 the amount of oxygen taken up and the amount of carbon 
 dioxide discharged. 
 
 GASEOUS EXCHANGE OF SUBMAXILLARY GLAND (Barcroft). 
 
 O-2 taken up. CO^ output. 
 
 Resting . . '25 cc. per minute. . . *17 cc. per minute. 
 Active . . *86 cc. ,, . . '39 cc. ,, 
 
 It will be observed that, whereas the flow of blood through 
 the gland may be increased five or six times during activity, 
 the quantity of oxygen taken up by the cells is increased 
 about three and a half times. Although the total loss of 
 oxygen from blood to gland is increased, the relative loss is 
 diminished, and the blood flowing from the veins of a gland 
 during activity is more arterial in colour and contains more 
 oxygen than the blood obtained from a resting gland. If we 
 assume that the total oxygen taken up is employed in the 
 oxidation of a food substance such as glucose, and that the 
 
 * Journ. ofPhysiol Vol. XXVII., p. 31, 1901. 
 
SECRETION OF SALIVA. 59 
 
 whole of the energy of the chemical changes is set free in the 
 form of heat, we find that a resting gland weighing about 6 
 grammes produces about 1*1 calories per minute, whereas an 
 active gland produces about 3'8 calories per minute. We 
 know, however, that a certain amount of external work is per- 
 formed in the secretion of a saliva containing less salts than 
 the original blood, and also, when there is any resistance to 
 the flow of saliva through the duct, in raising the hydrostatic 
 pressure of the saliva in the duct to a height greater than that 
 in the blood capillaries. 
 
 Can we from all these data form a conception of the total 
 changes occurring in the gland and involved in the formation 
 of the secretion ? Even during rest, changes are going on in 
 the gland cells, changes which involve the taking up of food 
 material and its assimilation under the influence of the 
 nucleus, perhaps into the nucleus itself, and certainly into 
 the undifferentiated cytoplasm. In this cytoplasm a further 
 change occurs, leading to its transformation into granules. 
 When activity is excited by the stimulation of secretory 
 nerves, the primary change appears to involve simply the 
 granules. These structures must absorb water, apparently 
 against osmotic pressure. Those nearest the lumen swell 
 up, become converted into spheres containing water and 
 salts in smaller proportion than exists in the lymph bathing 
 the cells (and presumably in the protoplasm surrounding 
 the granules), and in this swollen form are discharged or 
 ruptured on the periphery of the cell into the lumen, so 
 giving rise to secretion. This discharge of a fluid with a 
 smaller molecular concentration than the cell or surrounding 
 blood plasma must lead to an increased concentration in 
 the remaining parts of the cell. The increased concentration 
 would naturally induce a flow of water from lymph into 
 cell, and the consequent concentration of the lymph would 
 
60 THE PHYSIOLOGY OF DIGESTION. 
 
 in the same way cause a flow of water from blood to 
 lymph. This pull of water by the cell from the blood is 
 still further increased in another way. The act of secretion, 
 involving as it does the expenditure of energy, can be carried 
 out only at the expense of chemical changes in the cell. 
 These chemical changes, as in all other metabolic processes 
 of the body, will result in the formation of a number of small 
 molecules from the great colloid molecules of the protoplasm 
 with its side-chains. The products of metabolism, or meta- 
 bolites, will therefore accumulate in the cell, pass into the 
 lymph, and increase the concentration of the latter. The 
 increased concentration will call forth an increased transuda- 
 tion of fluid, e.g., water, from the blood vessels, and the 
 transudation thus evoked will be greater than that necessary 
 to provide the water of the saliva, and will therefore produce 
 a distension of the lymphatic spaces of the gland, and an 
 increased discharge of lymph along its efferent lymphatics. 
 As a secondary result of the activity, perhaps in consequence 
 of the removal of the products of the resting metabolism of 
 the gland, there is increased growth of protoplasm, increased 
 activity of the nucleus, and therefore a tendency to increased 
 assimilatory changes and a preparation of the cell for further 
 secretory changes either immediately or hereafter. 
 
 In the gland however, as in muscle, when we attempt to 
 form a conception of the mechanism of the chemical machine 
 in the living cell, we are brought up against insuperable 
 difficulties. One might perhaps conceive of the secretory 
 granules being bounded by a membrane, impermeable to inter- 
 mediate metabolites and salts, but permeable to carbon dioxide. 
 If the first effect of stimulation of the secretory nerves were to 
 produce an explosive disintegration of the complex molecules 
 making up the granules, we should have a sudden multiplica- 
 tion of molecules within the granules. This would cause a 
 
SECRETION OF SALIVA. 61 
 
 large rise of the osmotic pressure in these granules and the 
 consequent absorption of water from the surrounding pro- 
 toplasm. This process however could only result in the 
 production of a fluid in the granules, having the same osmotic 
 pressure as the surrounding medium, whereas we know that 
 saliva has a molecular concentration which is only one-half 
 that of the blood or lymph. We should therefore have to 
 make a second assumption ; namely, that, before the extrusion 
 of the solution from the granules, there is a further break- 
 down of the metabolites by a process of oxidation, with the 
 production of carbon dioxide which diffuses into the sur- 
 rounding protoplasm. We have however no evidence of 
 either of these processes or for any of these assumptions, and 
 I have only adduced them in order to show how far we are 
 still from the actual comprehension of the events occurring in 
 every living cell, and determining its conditions of rest and 
 activity. 
 
LECTUEE IV. 
 
 DIGESTION IN THE STOMACH. 
 
 THE food, which has been masticated in the mouth and 
 thoroughly moistened with saliva, is swallowed at successive 
 intervals, and collects to form a mass lying in the fundus of 
 the stomach. This mass, impregnated with saliva and kept 
 at the body temperature, is penetrated only with difficulty by 
 any juice secreted in the stomach, so that, in those animals 
 whose saliva contains ptyalin, the process of salivary digestion 
 can go on unchecked, at any rate in the centre of the mass, 
 for twenty to forty minutes. 
 
 Even before the food reaches the stomach, a special digestive 
 fluid, the gastric juice, is poured out into the stomach. This 
 juice is strongly acid in character. As it penetrates the mass 
 of food, the acid first checks the action of the ptyalin and 
 finally destroys it. The gastric juice is the product of secre- 
 tion of a number of tubular glands, which are set thickly 
 over the whole surface of the stomach, and form the 
 greater part of the mucous membrane. On examining the 
 internal surface of the stomach, there is seen to be a difference 
 between the appearance of the mucous membrane over the 
 four-fifths of the stomach nearest to the cardiac end and 
 that covering the fifth immediately adjoining the pyloric 
 orifice. In the latter position the mucous membrane is 
 somewhat different in hue, being less pink than the fundus 
 mucous membrane, and presents much fewer folds owing to 
 its closer attachment to the subjacent muscular tissues. 
 
DIGESTION IN THE STOMACH. 63 
 
 In the dead stomach there is no external sign of this differ- 
 ence between the mucous membrane at the two ends of the 
 stomach ; but in the living stomach, or in the stomach just 
 removed from the animal and kept in warm salt solution, 
 the line of demarcation between the two types of mucous 
 membrane is marked externally by a deep furrow, often 
 spoken of as the ' transverse band.' In many cases, the whole 
 segment of the stomach between this transverse band and the 
 pyloric orifice is contracted to form a tube, which looks as 
 if it were a direct continuation upwards of the intestinal 
 tube. There is a marked difference between the movements 
 carried out by the two portions of the stomach. The 
 cardiac end and fundus represent a sort of reservoir, which 
 is distended by, and slowly contracts upon, the mass of food, 
 driving all its fluid portions towards the pyloric end. In the 
 pyloric fifth of the stomach there is a continual series of waves 
 of contraction, which pass from near the transverse band to the 
 pylorus and provide for a thorough admixture of the fluid 
 parts of the food with the secreted gastric juice, finally 
 expelling the semi-digested chyme through the pyloric orifice 
 into the duodenum. Although both parts of the stomach are 
 beset with tubular glands, there are important differences in 
 the structure of the glands in the two parts. In man and dog 
 the tubular glands in the fundus present a neck or duct which 
 is lined with simple columnar cells and forms one-third of the 
 whole gland. Into this duct open one or two secreting 
 tubules, which are lined by epithelial cells of two kinds, 
 namely, the central or peptic cells, and large oval cells lying 
 between them and the basement membrane, the parietal or 
 oxyntic cells. At the pyloric end the ducts form from one-half 
 to two-thirds of the glands and divide into three or four 
 secreting tubules. The latter present only one kind of cell, 
 which is similar to the peptic or central cell in the fundus 
 
64 THE PHYSIOLOGY OF DIGESTION. 
 
 glands. Since it has been found that the secretion of the 
 fundus glands contains hydrochloric acid as well as the pro- 
 teolytic ferment, pepsin, whereas that obtained from the 
 pyloric glands contains no free hydrochloric acid, but only 
 pepsin, it has been concluded that the parietal cells secrete 
 the acid, while the central cells in both types of gland 
 secrete the pepsin. The changes in the latter cells, which 
 accompany activity, are exactly analogous to those we have 
 already studied in the salivary glands, the resting cells 
 being loaded with granules which are discharged during 
 activity. 
 
 In order to determine the characters of gastric juice, we 
 must have some method at our command of obtaining it in 
 sufficient quantity, free from admixture with food substances, 
 or other secretions such as saliva. In the case of the stomach 
 we cannot connect a cannula with a main duct and so lead 
 away the secretion obtained during a meal. We must there- 
 fore take the secretion which is poured into the whole cavity 
 of the stomach, and adopt some method which, while retaining 
 the normal stimulus of. a meal, will prevent the entry of food 
 into the stomach or into that portion which we use for our 
 experiment. 
 
 It is comparatively easy in dogs to establish a fistulous 
 opening into the stomach, and so collect any juice which is 
 poured out in this viscus. In such animals it is found to be 
 impossible to evoke secretion into the stomach by mechanical 
 excitation of its internal surface, whereas it is only necessary 
 to show the dog food, or allow it to begin the mastication of 
 food, .in order to produce a flow of gastric juice. In order to 
 collect the juice poured out under such circumstances, free 
 from admixture with food or saliva, Pawlow has adopted the 
 method of dividing the oesophagus in the neck and bringing 
 the two ends to the surface. At the same time a fistulous 
 
DIGESTION IN THE STOMACH. 
 
 65 
 
 opening is established through the abdominal wall into the 
 stomach. Such animals can be fed by the introduction of 
 fluid food through the lower cut end of the oesophagus, or 
 directly through the fistulous opening into the stomach. 
 They can also take a meal in the ordinary way, but the food 
 which is swallowed will always fall out of the opening of the 
 
 FIG. 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. V. Cavity of main 
 stomach. 8. Small or sample stomach opening on to exterior. 
 A.- A. Abdominal wall. 
 
 oesophagus on the surface of the neck, none of it reaching the 
 stomach. Pawlow has shown that if such an animal be 
 given food, when hungry, it will eat with avidity, and -since 
 the food cannot reach the stomach and so satisfy its hunger, 
 it will continue to eat for two or three hours. Five minutes 
 after the beginning of this sham feeding, gastric juice begins 
 to drop from the fistulous opening; and in this way large 
 P.D. F 
 
66 THE PHYSIOLOGY OF DIGESTION. 
 
 quantities of juice, free from any admixture with other 
 substances, can be easily obtained. 
 
 By this means we obtain a secretion of gastric juice, which 
 is excited by the presence of food in the mouth. This method 
 does not, however, enable us to determine whether the 
 character of the juice will be altered in any way by the 
 changes which the food undergoes in the stomach itself. 
 In order to form an idea of the normal course of secretion 
 of gastric juice, when food is taken into the stomach in the 
 ordinary way, Pawlow has devised another procedure. A 
 small diverticulum representing about T \, of the whole stomach 
 is made at the cardiac or pyloric end, in direct muscular 
 and nervous continuity with the rest of the stomach, but 
 shut off from the main part of the viscus by a diaphragm of 
 mucous membrane. The method in which this operation is 
 carried out will be evident by reference to the diagram (Fig* 6)* 
 In a dog treated in this way it is found that the amount of juice 
 secreted by the small stomach always bears the same ratio to. 
 the amount secreted by the large stomach, while the digestive 
 power of the juice obtained from the small stomach is equal 
 to that obtained from the large. This is shown in the following 
 table.* 
 
 In this case a fistulous opening had been established into the 
 large stomach, so that the juice could be obtained simul- 
 taneously from both sections of this organ. Secretion was, 
 excited by a sham meal, in which the food taken by the 
 animal dropped out of an opening in the neck, and was not 
 allowed to reach the stomach. It will be seen that the 
 secretions in the two sections of the stomach run parallel to 
 one another, while there is an almost exact equivalence 
 
 * Pawlow, " The Work of the Digestive Glands " (translated by W. 
 Thompson, M.D.), p. 80. 
 
DIGESTION IN THE STOMACH. 
 
 67 
 
 between the strengths of the juices obtained from each section. 
 We may therefore regard the secretion obtained from the 
 small stomach as a sample of that produced by the large, and 
 from the changes in this small stomach judge of the effects 
 occurring in the whole organ. By this method it is possible 
 to study the effects of a normal meal in which the food is 
 swallowed, or of a sham meal in which the food is merely 
 masticated in the mouth, or of a meal in which the food is 
 directly introduced into an opening into the large stomach. 
 
 SECRETION FROM GASTRIC FISTULA AFTER SHAM MEAL. 
 
 
 Small Stomach. 
 
 Large Stomach. 
 
 
 Quantity. 
 
 Strength.* 
 
 Quantity. 
 
 Strength. 
 
 1 . . 
 
 7'6 cc. 
 
 5 '88 mm. 
 
 68-25 cc. 
 
 5'5 mm. 
 
 2 .. .. 
 
 4-7 cc. 
 
 5'75 mm. 
 
 41-5 cc. 
 
 5*5 mm. 
 
 3 . . 
 
 1-1 cc. 
 
 5*5 mm. 
 
 14-0 cc. 
 
 5-38 mm. 
 
 Total . . 
 
 13-4 cc. 
 
 
 
 123-75 cc. 
 
 
 
 The gastric juice obtained in any one of these ways is a clear 
 colourless fluid like water, containing from 0'3 to 1 per cent, 
 total solids, and having an acidity equivalent to 0*48 per cent, 
 hydrochloric acid. If obtained from the fundus, and there- 
 fore acid in reaction, it has a strong digestive action on 
 proteids. If allowed to act on proteids for prolonged periods, 
 it converts a large proportion of these bodies into aniino- 
 acids and other products. In the course of a digestion 
 
 * The strength of the juice was determined by measuring the number 
 of millimetres of coagulated egg white (in Mett's tubes) which were 
 digested in eight hours. 
 
 F 2 
 
68 THE PHYSIOLOGY OF DIGESTION. 
 
 extending over three to six hours, i.e., the time usually 
 occupied by gastric digestion, the greater part of the proteid 
 is converted only into its first products of hydration, namely, 
 albumoses and peptones, and it is in this condition that 
 the proteids of the food are normally passed on into the 
 first section of the small gut. This action of the gastric 
 juice on proteids must be ascribed to the presence in the juice 
 of a ferment, pepsin, acting in conjunction with free hydro- 
 chloric acid. If the collected juice be placed in an ice chest 
 for twenty-four hours, it will become turbid from the produc- 
 tion of a finely granular precipitate. The precipitate gradually 
 sinks to the bottom, and probably represents pepsin in the 
 purest form in which it is possible to obtain it. That pepsin 
 forms an unstable compound with the hydrochloric acid is 
 shown by the fact that, if two portions of the cooled fluid be 
 taken, one from the clear layer near the top of the vessel and 
 the other from the turbid suspension at the bottom, the latter, 
 which contains the greater part of the pepsin, contains 
 also a larger percentage of hydrochloric acid than the top 
 layer. If the hydrochloric acid were absolutely free in the 
 solution, its distribution throughout the fluid would be the 
 same. 
 
 We must now inquire into the conditions which determine 
 the secretion of the gastric juice. The method, which we 
 must adopt for its collection, shows that we have here to do, 
 in the first place, with a reflex nervous mechanism, since an 
 active secretion is excited by the presence of food in the 
 mouth and by its mastication. Moreover, a secretion, which 
 is at least as vigorous as that produced by a sham meal, 
 can be evoked by merely arousing in the dog the idea of a 
 ineal. In this case the secretion must be determined by 
 events in the brain which involve the co-operation of the 
 cerebral cortex. If the animal be hungry, it is sufficient to 
 
DIGESTION IN THE STOMACH. 69 
 
 show it the food to produce a secretion. In the experiment 
 from which the following table is taken, the dog was continually 
 excited by showing it meat during a period of an hour and a 
 half. At the end of this time the animal, which had an 
 cesophageal fistula, was given a sham meal. It will be 
 observed that the psychical secretion obtained during the 
 first period of the experiment was rather greater than the 
 secretion produced by the introduction of food into the mouth. 
 
 PSYCHICAL SECRETION OF GASTRIC JUICE. (PAWLOW.) 
 
 Time. Quantity. 
 
 8 minutes . . . . . . . . . . 10 cc. 
 
 4 .... 10 
 
 4 10 
 
 10 10 
 
 10 10 
 
 8 10 
 
 8 10 
 
 19 10 
 
 19 .. 8,, 
 
 SHAM FEEDING. 
 
 Time. Quantity. 
 
 17 minutes . . . . . . . . . . 10 cc. 
 
 9 ,, .... 10 
 8 10 
 
 The afferent channels for this reflex may be therefore either 
 the afferent nerves from the mouth, or, when the idea of food 
 is involved, any of the nerves of special sense, such as sight, 
 smell, or hearing, through which these ideas are called forth. 
 The efferent channels can only be one of two nerves, viz : the 
 vagus and the sympathetic, since these are the only two which 
 are distributed to the stomach. That it is the former of these 
 nerves which is involved is shown by the fact, recorded by 
 Pawlow, that psychical secretion, as well as the results of a 
 sham meal, are entirely abolished by division of both vagi. 
 On this account division of both vagi may give rise to entire 
 
70 THE PHYSIOLOGY OF DIGESTION. 
 
 absence of gastric digestion, and death of the animal may 
 ensue from inanition, or from poisoning by the products of 
 decomposition of food in the stomach, even when care has 
 been taken to avoid injury to the pulmonary and tracheal 
 branches of these nerves. 
 
 The converse experiment of exciting secretion by direct 
 stimulation of the vagus presents greater difficulties. Stimu- 
 lation of the vagus in the neck causes stoppage of the heart, 
 and consequent anaemia of the mucous membrane of the 
 stomach. Moreover, the stomach seems to be much more 
 susceptible than the salivary glands to the action of poisons, 
 such as anaesthetics. Its activity is also easily affected by 
 inhibitory impulses arising in the central nervous system 
 as the result of either painful impressions or emotional states 
 of the animal. In order to avoid these disturbing factors 
 Pawlow proceeded as follows : An animal with fistulas of 
 oesophagus and stomach had one vagus nerve divided. A 
 thread was attached to the peripheral end of the cut vagus 
 and allowed to hang out through the wound. Four days after 
 the operation the vagus was drawn out of the wound by care- 
 fully pulling on the thread, so as not to hurt or frighten the 
 animal in any way, and its peripheral end stimulated by 
 means of induction shocks. No effect was produced on the 
 heart, owing to the degeneration of the cardio-inhibitory fibres, 
 which is well known to occur within this period after section. 
 Five minutes after the commencement of the stimulation, the 
 first drop of gastric juice appeared from the gastric cannula, 
 and a steady secretion of juice was obtained with continuation 
 of the stimulation. This experiment furnishes the decisive 
 and final evidence that the secretory nerves to the stomach run 
 in the two vagi. There is one marked difference, however, 
 between the action of these nerves and the action of the 
 chorda tympani nerve on the submaxillary gland, namely, 
 
DIGESTION IN THE STOMACH. 
 
 71 
 
 the great length of the latent period before gastric secretion 
 occurs. The length of this latent period has not yet 
 been satisfactorily explained. It cannot be due to delay 
 occurring between the vagus fibres and the local nervous 
 mechanism in the stomach. It may be that the chemical 
 changes finally resulting in secretion require a longer period 
 for their accomplishment than is the case in the salivary 
 gland. Physiologically there is, indeed, no special need for a 
 rapid secretion of gastric juice, whereas in the mouth it is 
 essential that the introduction of food should be immediately 
 followed by the production of saliva, for the tasting and 
 testing of the food and for its subsequent mastication or 
 rejection. Another possible explanation of this prolonged 
 latent period we shall have to consider later. 
 
 These experiments show conclusively that an important 
 probably the most important part of the gastric secretion is 
 determined by a nervous mechanism. This nervous secretion 
 does not, however, account for the whole of the gastric juice 
 obtained as the result of a meal. If an animal provided with two 
 gastric fistulse, one into a diverticulum and the other into the 
 main stomach, have both its vagi divided, it is found that the 
 introduction of meat into the large stomach is followed, after 
 a period of twenty to forty-five minutes, by the appearance of 
 a secretion of gastric juice from the small stomach. More- 
 over, when an animal is given a normal meal, and is allowed 
 to swallow the food after mastication, the total amount of 
 gastric juice obtained is greater than that produced by the 
 sham feeding alone, and the flow is of longer duration. In 
 fact, we may say that the gastric juice secreted in response 
 to a normal meal consists of two parts, viz., (1) a large amount, 
 the secretion of which begins within five minutes of the taking 
 of the food and is determined by the reflex nervous mechanism 
 described above; and (2) a smaller portion, the secretion of 
 
72 
 
 THE PHYSIOLOGY OF DIGESTION. 
 
 which is excited by the presence of the food in the stomach. 
 This combined character of the gastric juice produced by a 
 normal meal is shown in the following table :* 
 
 SECRETION OF GASTRIC JUICE. 
 
 Hours. 
 
 Normal meal. 
 200 gr. meat into 
 stomach. 
 
 150 gr. meat into 
 stomach. 
 
 Sham meal. 
 
 Sum of two 
 last ex- 
 periments. 
 
 Quantity, 
 cc. 
 
 Strength, 
 mm. dig. 
 
 Quantity, 
 cc. 
 
 Strength, 
 mm. dig. 
 
 Quantity. 
 cc. 
 
 Strength, 
 mm. dig. 
 
 Quantity, 
 cc. 
 
 1 .. 
 
 12-4 
 
 5-43 
 
 5-0 
 
 2-5 
 
 7-7 
 
 6-4 
 
 12-7 
 
 2 . . 
 
 13-5 
 
 3-63 
 
 7-8 
 
 2-75 
 
 4-5 
 
 5-3 
 
 12-3 
 
 3 .. 
 
 7'5 
 
 3-5 
 
 6-4 
 
 3-75 
 
 0-6 
 
 5-75 
 
 7-0 
 
 4 .. 
 
 4-2 
 
 3-12 
 
 5-0 
 
 3-75 
 
 
 
 
 
 5-0 
 
 In the first column is given the result of a normal meal 
 on the secretion from the gastric diverticulum. In the second 
 column is given the amount and digestive power of the juice 
 which is excited by the direct introduction of 150 grs. of 
 meat into the large stomach of the animal, care being taken 
 not to excite in any way the nervous reflex mechanism. In 
 the third column is given the amount and digestive power 
 of the juice which is evoked by a sham meal of 200 grs. of 
 meat. In the fourth column is given the sum of the last two 
 experiments. It will be seen that the total effect of the 
 sham meal plus the direct introduction of meat into the 
 stomach is almost identical with the secretion obtained when 
 the food is taken in a normal way and allowed to pass through 
 the oesophagus into the stomach. 
 
 The second phase of the gastric secretion cannot be ascribed 
 
 * Pawlow, loc. cit., p. 82. 
 
DIGESTION IN THE STOMACH. 78 
 
 to the intervention of the reflex vagal mechanism. Since 
 it occurs after cutting off the stomach from its connec- 
 tions with the central nervous system, it must have its 
 causation in the gastric walls themselves. That it cannot 
 be due to mechanical stimulation is shown by the fact, 
 previously mentioned, that it is impossible by local stimula- 
 tion of the mucous membrane, by rubbing, or introduction of 
 sand, or any other method, to evoke a secretion. Moreover, it 
 is not produced by all sorts of food. The introduction of 
 white of egg, of starch, or of bread into the stomach causes no 
 secretion. On the other hand, if bread be mixed with gastric 
 juice and allowed to digest for some time, the introduction of 
 the semi- digested mixture into the stomach evokes a secretion. 
 We have already seen that meat produces a secretion ; still 
 more potent than meat, however, is a decoction of meat, or 
 bouillon, or Liebig's extract of meat, or certain preparations 
 of peptone. Pure albumoses and peptones have no effect, so 
 that the exciting mechanism must be some chemical substances 
 present in meat, and produced in various other foods under 
 the action of the first gastric juice secreted in response to 
 nervous stimuli. Popielski has shown that this secretion 
 occurs after complete severance of the stomach from the 
 central nervous system, as well as after destruction of the 
 sympathetic nervous plexuses of the abdomen. Since the 
 injection of bouillon directly into the circulation has no effect, 
 this author concludes that the second phase of secretion is 
 determined by the stimulation of the local nerve plexus, and 
 that we have here, in short, a peripheral reflex action, the 
 centres of which are situated in the walls of the stomach 
 itself. There is, however, one possible explanation for this 
 second phase of secretion which was not sufficiently considered 
 either by Pawlow or by Popielski. Although the peptogenic 
 M! stances, those substances which evoke gastric secretion 
 
74 THE PHYSIOLOGY OF DIGESTION. 
 
 on introduction into the stomach, have no effect on the gastric 
 glands when [injected directly into the blood stream, it is 
 possible that they may have an influence on the cells which 
 line the cavity of the stomach, and that they may produce, in 
 these cells, some other substance which is absorbed into the 
 blood, and acts as a specific excitant of the gastric glands. A 
 process of this nature is, known to occur in the next segment 
 of the alimentary canal, viz., the duodenum, where it deter- 
 mines the secretion of the pancreatic juice and the bile. 
 
 Edkins* has carried out a series of experiments to deter- 
 mine whether such a chemical mechanism may not also 
 account for the secretion of gastric juice, which is excited by 
 the introduction of substances into the stomach. Edkins' 
 experiments were carried out in the following way. The 
 animal, dog or cat, having been anaesthetised, the abdominal 
 cavity was opened, and a ligature passed round the lower end 
 of the oesophagus so as to occlude the cardiac orifice and 
 effectually crush the two vagus nerves. A glass tube was 
 then introduced through an opening in the abdomen into the 
 pyloric part of the stomach, and fixed in this position by a 
 ligature tied tightly round the pylorus. The glass tube was 
 connected by means of a rubber tube with a reservoir con- 
 taining normal salt solution at the temperature of the body. 
 By means of this reservoir, a certain amount of fluid was intro- 
 duced into the stomach and kept here at a constant pressure ; 
 the quantity of fluid introduced varied from 30 to 50 cc. It 
 has been shown by Edkins, as well as by von Mering, that.no 
 absorption of water or saline fluid occurs in the stomach. It 
 is, therefore, possible to recover the whole of the fluid an 
 hour after it has been introduced, by simply lowering the 
 reservoir below the level of the animal's body. If secretion 
 
 * Journ. o/Physiol, Vol. XXXIV., p. 133, 1906. 
 
DIGESTION IN THE STOMACH. 75 
 
 of gastric juice has occurred into the cavity of the stomach, 
 the fluid will be increased in amount, and will contain hydro- 
 chloric acid as well as pepsin. In a series of control observa- 
 tions, Edkins showed that the mere introduction of this fluid 
 into the stomach caused no secretion of gastric juice, the fluid 
 removed at the end of an hour having the same bulk and the 
 same neutral reaction as the fluid which had been injected. 
 Edkins then tried the influence of injecting substances into 
 the blood stream. The injection of peptone, of acid, of broth, 
 or of dextrin into the blood stream produced no secretion of 
 gastric juice. If, however, in the course of the hour during 
 which the fluid was allowed to remain in the stomach, a 
 decoction made by boiling pyloric mucous membrane with 
 acid, or with water, or with peptone, was introduced in small 
 quantities every ten minutes into the jugular vein, the fluid 
 removed at the end of the hour was found to be distinctly 
 acid in its reaction and to possess proteolytic properties. 
 The injection of these substances had therefore caused the 
 secretion of a certain amount of gastric juice containing both 
 hydrochloric acid and pepsin. In order to produce this 
 positive effect, it was necessary to employ pyloric mucous 
 membrane, extracts made by infusing or boiling cardiac 
 mucous membrane with any of these substances being without 
 effect. Edkins concludes therefore that the secondary secre- 
 tion of gastric juice is determined, not, as Pawlow and 
 Popielski imagined, by a local stimulation of the reflex 
 nervous apparatus in the gastric wall, but by a chemical 
 mechanism. The first products of digestion act on the 
 pyloric mucous membrane, and produce in this membrane 
 a substance which is absorbed into the blood stream, and 
 carried to all the glands of the stomach, where it acts as a 
 specific excitant of their secretory activity. This substance 
 may be called the gastric secretin or gastric hormone. It is 
 
76 THE PHYSIOLOGY OF DIGESTION. 
 
 noteworthy that it is produced in that portion of the stomach 
 where the process of absorption is most pronounced. 
 
 The normal gastric secretion is therefore due to the co- 
 operation of two factors. The first and most important is the 
 nervous secretion, determined through the vagus nerves by 
 stimulation of the mucous membrane of the mouth, or by the 
 arousing of appetite in the higher parts of the brain. The 
 second factor, which provides for the continued secretion of 
 gastric juice long after the mental effects of a meal have 
 disappeared, is chemical, and depends on the production in 
 the pyloric mucous membrane of a specific substance or 
 hormone, which acts as a chemical messenger to all parts 
 of the stomach, being absorbed into the blood and thence 
 exciting the activity of the various secreting cells in the 
 gastric glands. 
 
 It is still a moot point whether this gastric hormone is 
 formed only in the pyloric mucous membrane, or whether it 
 may not be also produced in the lower sections of the gut. 
 Popielski has stated that the introduction of bouillon into the 
 small intestine excites a secretion of gastric juice in animals, 
 even after extirpation of the abdominal sympathetic plexuses 
 and division of both vagi. On the other hand, introduction of 
 the same substance into the large intestine has no influence 
 on gastric secretion. Popielski ascribes this secretion again 
 to a local reflex ; but it is more probable that the mechanism 
 in this case is the same as that involved in the secretion 
 which is excited by the presence of semi-digested food in the 
 stomach itself. 
 
 Pawlow has shown that the second phase of the gastric 
 secretion is largely influenced by the character of the contents 
 of the stomach. Thus the ingestion of large quantities of oil 
 diminishes considerably the amount of gastric juice secreted, 
 and Pawlow has suggested the administration of oil or oily 
 
DIGESTION IN THE STOMACH. 77 
 
 foods as a possible remedy in cases where the production of 
 gastric juice, and especially of hydrochloric acid, is in excess. 
 It has long been imagined that the secretion of gastric juice 
 was stimulated by the taking of alkalies. This idea has been 
 shown by Pawlow to be erroneous. Whereas the formation of 
 gastric juice is increased by the administration of acids, 
 especially after a meal, it is largely diminished by the admi- 
 nistration of alkalies such as sodium bicarbonate. In fact, 
 sodium bicarbonate diminishes the activity of the digestive 
 glands throughout the alimentary tract, and can be used as a 
 means of diminishing the secretion of gastric juice as well as 
 the secretion of pancreatic "juice. 
 
 A further important question has been propounded by 
 Pawlow ; namely, whether there is any alteration in the con- 
 stitution and amount of gastric juice with variations in the 
 character of the food. So far as concerns the first phase of 
 secretion, the psychical or 'appetite ' juice, this observer has 
 shown that, whatever the previous diet of the animal, this juice 
 always has the same characters, the same digestive power, and 
 the same percentage of hydrochloric acid. He finds however 
 that in the case of the second, or what we may call ' chemical ' 
 secretion, i.e. that produced by local changes in the stomach, 
 there is considerable variation in the nature of the juice. In 
 the following table are shown the relative effects of meat and of 
 milk, when introduced into the large stomach, in determining 
 a flow of juice from the small stomach of an animal with a 
 Pawlow fistula. Whereas the secretion of juice is greatest in 
 amount with the meat, the digestive power of the juice is 
 greatest with the bread, and Pawlow regards these differences 
 in the juice as determined by the variations in the stimulus 
 applied to the gastric mucous membrane. It is doubtful how- 
 ever whether these results justify us in ascribing a number 
 of specific sensibilities to the gastric mucous membrane. We 
 
78 
 
 THE PHYSIOLOGY OF DIGESTION. 
 
 have seen that the psychical juice depends merely on appetil 
 and therefore will be greater in amount the more welcome th< 
 food is to the animal. On the other hand, the juice secreted ii 
 the second phase must vary according to the quantity of gastric 
 hormone produced in the pyloric mucous membrane, and there 
 fore with the nature and amount of the substances produced ii 
 the preliminary digestion of the gastric contents by means 
 
 Hours. 
 
 Gastric secretion after 
 100 grs. meat. 
 Two experiments. 
 
 Hours. 
 
 Gastric secretion after 
 600 cc. milk. 
 Two experiments. 
 
 Quantity of juice. 
 
 Quantity of juice. 
 
 1 
 
 11-2 . . 12-6 
 
 1 
 
 8-75 . . 8-25 
 
 2 
 
 8-2 . . 8-0 
 
 2 
 
 7-5 . . 6-0 
 
 3 
 
 4-0 . . 2-2 
 
 3 
 
 22-5 . . - 23-0 
 
 4 
 
 1-9 .. 1-1 
 
 4 
 
 9-0 . . 6-25 
 
 5 
 
 O'l . . a drop 
 
 5 
 
 2-0 . . 1-5 
 
 Total 
 
 25-4 . . 23-9 
 
 Total 
 
 49-75 . . 45-0 
 
 the psychic juice. The amount of juice may vary also with 
 the salts contained in the food, according to their alkaline or 
 acid character, and the percentage of pepsin in the juice may 
 vary with the intensity of stimulus as well as with the quantity 
 of fluid available for the formation of the gastric juice. These 
 factors will co-operate in determining the characters of the 
 whole juice secreted after any given meal, and it seems pos- 
 sible to explain the variations, observed on such different diets 
 as meat and bread, without having recourse to the difficult 
 assumption of a specific sensibility of the gastric mucous 
 membrane to such inert substances as starch, dextrin, or egg 
 albumen. 
 
DIGESTION IN THE STOMACH. 79 
 
 The second phase of secretion will continue so long as there 
 are substances present in the stomach to act upon the pyloric 
 mucous membrane. As the food is gradually digested, and 
 transformed from a semi-solid into a soluble condition, the 
 fluid portions are squeezed into the pyloric end. Here a series 
 of waves of contraction are slowly passing from the transverse 
 band towards the pylorus. As these waves arrive at the 
 pyloric orifice, the sphincter surrounding this orifice relaxes 
 for a short time, and a portion of the fluid is squirted into the 
 first part of the duodenum. The arrival of the acid chyme in 
 the duodenum sets up a local nervous reflex which causes 
 contraction of the pylorus, and this orifice remains closed 
 until, by the operation of the process which we shall study in 
 the next lecture, the acid chyme in the duodenum is neutra- 
 lised by the pouring out into the gut of alkaline digestive juices. 
 Digestion in the stomach will therefore continue until the 
 whole of the gastric contents are reduced to a fluid condition > 
 and have been passed by the contractions of this viscus into 
 the small intestine ; the pylorus, towards the end of digestion, 
 relaxing so as to allow the passage of even solid indigestible 
 morsels of food into the duodenum. 
 
LECTUEE V. 
 
 PANCREATIC SECRETION. 
 
 THE fluid chyme on entering the duodenum, the first part 
 of the small intestine, is subject at once to the influence of the 
 secretions of three different sets of glands, namely : (1) The 
 intestinal glands, including those characteristic of the duodenum 
 named Brunner's glands ; (2) The pancreas ; (3) The liver. 
 The ducts of the two latter in many animals have a common 
 opening into the duodenum, and in every case there is a 
 co-operation between all three juices for the production^ the 
 intestinal digestive fluid. In discussing the mechanism of 
 secretion of these juices, it will be more convenient to take 
 each kind of gland separately. 
 
 The pancreas resembles the salivary glands, in that it is 
 composed of a mass of tubules, which pour their secretions into 
 a common duct opening into the duodenum. It is therefore 
 asy to establish a temporary pancreatic fistula, by isolating 
 the duct just before it joins the intestine, and inserting 
 & small tube or cannula into it. A permanent fistula of the 
 pancreas can be also established without difficulty. Indeed 
 this operation is one of the earliest in the history of experi- 
 mental physiology. De Graaf in his paper " De Succo 
 pancreatico," published in 1677, describes a method for the 
 formation of a pancreatic fistula, and gives a figure of an 
 animal in which both salivary and pancreatic fistulse had 
 been established. The juice in each case was collected 
 in small glass vessels tied to the tubes which had been 
 
PANCREATIC SECRETION. 
 
 81 
 
 introduced into the ducts (Fig. 7). Claude Bernard employed a 
 method resembling very closely that of de Graaf. Instead 
 however of opening the intestine as in the procedure of the 
 latter, he inserted a small metal cannula into the duct outside 
 the intestine and secured the cannula in the abdominal wound. 
 To the outer end of the tube was tied a little rubber bag, so 
 
 FIG. 7. Reproduction of Plate from Rene de Graaf's treatise " De 
 Succo pancreatico," representing a dog in which he had established both 
 salivary and pancreatic fistulas, small glass phials being attached to each 
 to collect the secretions (from " Regneri de Graaf Opera Oninia." Lugd. 
 Batav. 1677). 
 
 that any juice, spontaneously secreted, could be collected and 
 drawn off at intervals for examination. The best method for 
 the establishment of a permanent fistula is that devised by 
 Pawlow. A small quadrilateral piece of the wall of the 
 duodenum is excised, the position of the incision being chosen 
 so that the papilla, with the orifice of the pancreatic duct, may 
 lie immediately in the centre of the mucous membrane covering 
 the excised piece. The integrity of the intestine is then restored 
 P.D. G 
 
82 THE PHYSIOLOGY OF DIGESTION. 
 
 by suturing the margins of the wound in a direction transverse 
 to that of the gut, and the excised piece of mucous membrane is 
 brought to the surface and stitched into the abdominal wound. 
 The latter rapidly heals up, so that finally the animal presents 
 a scar on the abdomen, in the centre of which is a small pink 
 papilla through which the pancreatic juice can escape. The 
 juice is collected by strapping a funnel on to the belly of the 
 dog, and connecting a flask with the lower end of the funnel. 
 Although there are no technical difficulties in carrying out 
 this operation, the subsequent care of the animal demands great 
 attention. In the first place scrupulous cleanliness has to 
 be maintained in its surroundings, in order to prevent infection 
 of the duct with micro-organisms, which may spread up towards 
 the gland and set up fatal pancreatitis. In the second 
 place an animal cannot continue to lose large quantities of 
 pancreatic juice without suffering seriously in its nutrition. 
 Although the removal of one of the chief digestive juices from 
 the gut may be partly responsible for this condition, the loss 
 of the juice itself seems to be a still more serious factor. The 
 full results of this loss can be mitigated and largely prevented 
 by keeping the animals on a bread and milk diet, and by 
 administration of daily doses of sodium bicarbonate. Not 
 only does this salt replace the alkalies lost in the juice, but it 
 lowers the total amount of the digestive juices which are 
 secreted, including both gastric and pancreatic juices. By this 
 treatment, therefore, the loss of pancreatic juice is reduced to 
 a minimum. 
 
 Another troublesome feature is that the pancreatic juice, as 
 it flows over the papilla of mucous membrane, acquires strong 
 proteolytic properties, and tends therefore to digest the skin 
 and other tissues in the neighbourhood of the papilla, so seriously 
 interfering with the comfort and condition of the animal. 
 This must be prevented in two ways. In the first place, the 
 
PANCREATIC SECRETION. 
 
 83 
 
 proteolytic powers of the juice can be reduced to a minimum 
 by removing the greater part of the mucous membrane 
 surrounding the papilla. In the second place, care must be 
 taken that, whenever the juice is not being collected, the animal 
 is provided with a heap of sand or other absorbent material in 
 its cage, so that the secretion may be absorbed and any 
 moistening of the surface of the abdomen prevented. 
 
 In such an animal the normal relation of the secretion of 
 pancreatic juice to the process of digestion can be determined. 
 In the following table (Pawlow) the secretion of pancreatic juice 
 resulting from a meal of 600 cc. of milk is compared with the 
 secretion of gastric juice evoked by the ingestion of 100 gr. of 
 meat. The gastric secretion was taken from a dog having a 
 sample stomach, and therefore represents about T \jth of the 
 whole gastric juice. The pancreatic secretion represents, on 
 the other hand, the total secretion of the gland. 
 
 Gastric Secretion after a meal of 
 100 gms. Meat. Two Experiments. 
 
 Pancreatic Secretion after a meal of 
 600 cc. Milk. Two Experiments. 
 
 Hour after 
 Feeding. 
 
 Quantity of Juice in cc. 
 
 Hour after 
 Feeding. 
 
 Quantity of Juice in cc. 
 
 1st .. 
 
 11-2 .. 12-6 
 
 1st .. 
 
 8-75 . . 8-25 
 
 2nd . . 
 
 8-2 . . 8-0 
 
 2nd .. 
 
 7-5 . . 6-0 
 
 3rd . . 
 
 4-0 . . 2-2 
 
 3rd . . 
 
 22-5 . . 23-0 
 
 4th . . 
 
 1-9 . . 1-1 
 
 4th .. 
 
 9-0 . . 6-25 
 
 5th .. 
 
 O'l . . a drop. 
 
 5th .. 
 
 2-0 . . 1-5 
 
 Total 
 
 25-4 . . 23-9 
 
 Total 
 
 49-75 . . 45-0 
 
 It will be noticed that, whereas the greatest quantity of 
 gastric juice is poured out in the first hour after the meal, 
 
 G2 
 
84 THE PHYSIOLOGY OF DIGESTION. 
 
 the maximum flow of pancreatic juice occurs in the third 
 hour, at a time, that is to say, when (on this diet) the largest 
 amount of chyme is passing from the stomach into the duo- 
 denum. There must be some causal relationship between the 
 passage of the food through the pylorus and the secretion of 
 pancreatic juice. It is only of late years that the nature of 
 the connection between these two events has been brought to 
 light. It was shown long ago by Bernard that a flow of juice 
 could be provoked by the introduction of ether into the stomach 
 or intestine. This, as well as the flow occurring when the 
 acid chyme passed into the duodenum, was ascribed to the 
 intermediation of a reflex arc ; but much difficulty was 
 experienced in the search for the channels of the reflex. 
 Thus Heidenhain, who devoted special attention to this point, 
 was unable to produce any secretion by stimulation of the 
 vagus or splanchnic nerves, and though, in a few cases, some 
 secretion was obtained on stimulation of the medulla oblongata, 
 the results were quite inconstant. Pawlow ascribed the failure 
 of previous experimenters to the unphysiological conditions 
 under which their operations were carried out. Here, as in 
 the stomach, he imagined that it was necessary to operate on 
 an animal unpoisoned by anaesthetics, with a normal blood 
 pressure, and free from pain or discomfort, and that the ill 
 success of previous observers was due, either to the existence 
 of these disturbing factors, or to t the actual inhibition of the 
 glandular activity by reflex means. When, by the employment 
 of methods similar to those I described in the case of the 
 stomach, Pawlow avoided the possibility of such disturbing 
 factors, he succeeded in obtaining on stimulation of the vagus 
 a flow of pancreatic juice. In a few cases a similar flow was 
 obtained on stimulation of the splanchnic nerves, and Pawlow 
 therefore regarded pancreatic secretion as determined, either 
 reflexly or psychically through the cortex, by impulses leaving 
 
PANCREATIC SECRETION. 85_ 
 
 the central nervous system and travelling to the gland along 
 one of these two sets of nerves. 
 
 It is difficult, however, in the case of the pancreas to be 
 certain of the existence of a real psychical secretion. There 
 is no doubt that a flow of juice may be observed within three 
 or four minutes of the taking of food, but it is difficult to 
 eliminate in this case the possibility of some motor reaction 
 of the stomach having driven a certain amount of acid juice 
 into the beginning of the small intestine, and therefrom started 
 reflexly a flow of pancreatic juice. The most potent method 
 of producing a flow of juice is the introduction of acid into the 
 duodenum or small intestine, and this method has until lately 
 been adopted, whenever it has been desired to obtain pan- 
 creatic juice. The importance of this long reflex arc, namely 
 from intestine to central nervous system and back along vagus 
 or splanchnics, was later much diminished by the work of 
 Wertheimer* of Lille, as well as of Popielski,t a pupil of 
 Pawlow. Both these observers showed that the secretion of 
 juice, evoked by introduction of acid into the small intestine, 
 was absolutely unaffected by division of both vagus and 
 splanchnics, by excision of the spinal cord, or by extirpation 
 of the abdominal sympathetic. They therefore regarded the 
 secretion as being due to a local reflex, started in the mucous 
 membrane of the gut, and travelling thence to the collections 
 of ganglion cells which are found in large numbers in the 
 pancreas. These collections acted as reflex centres which 
 transmitted secretory impulses directly to the cells of the 
 pancreas. 
 
 This explanation was of considerable interest to Bayliss 
 and myself, since we had been lately studying the local motor 
 
 * Wertheimer, Compt. rend., cxxix. 19. p. 737, 1899. 
 t Popielski, Pfluger's Archiv., Ixxxvi. p. 215. 
 
86 THE PHYSIOLOGY OF DIGESTION. 
 
 reflexes of the intestine, and we therefore instituted a research 
 with a view to determining the conditions and paths of this local 
 secretory reflex. The research was rendered easier by the fact, 
 discovered by "Wertheimer, that the intensity of the secretion, 
 evoked by the introduction of acid into the small intestine, 
 diminished the further down in the gut the acid was intro- 
 duced. The greatest flow was obtained when the acid was 
 injected into the duodenum, while, if it were introduced into 
 a loop composed of the lowest foot or two of ileum, no secretion 
 whatever was obtained. In one experiment, therefore, we 
 ligatured a loop of the upper part of the jejunum at two 
 ends, and then introduced 25 cc. of '4 per cent. H.C1. A flow 
 of pancreatic juice was obtained. We then proceeded to destroy 
 all possible nervous connections between this loop and the 
 pancreas. Both splanchnics and vagi were divided, the 
 abdominal sympathetic ganglia round the big vessels extir- 
 pated, and all the nerve filaments travelling along the vessels 
 to the ligatured loop were dissected away. The mesentery was 
 divided at the same time, so that the loop of intestine was 
 connected to the rest of the body only by its blood vessels. 
 Acid was then introduced for a second time into the lumen of 
 the gut (cp. Fig. 8). Although all nervous connections between 
 gut and pancreas had been destroyed, the reaction was the same 
 as in a normal animal, and a copious flow of pancreatic juice 
 was obtained. This experiment proved at once that there 
 could be here no question of a nervous reflex, either central or 
 peripheral, but that the connection between mucous membrane 
 and pancreas must be chemical and be effected through the 
 blood. We knew already, from Wertheimer's researches, that 
 the direct introduction of acid into the blood produced no 
 flow of pancreatic juice. What was the difference between 
 the introduction of acid into the gut, which did produce 
 a flow, and its introduction into the blood, which did not 
 
PANCREATIC SECRETION. 
 
 87 
 
 produce any flow ? The sole difference must lie in the layer 
 of epithelial cells, which intervene between the lumen of the 
 gut and the capillary blood vessels in the intestinal villi. In 
 these cells some substance must be produced under the action 
 of acids which, on absorption into the blood, acts as the 
 chemical messenger to the pancreatic cells. The testing of 
 this hypothesis was very easy. The loop of intestine was cut 
 out, the cells lining its mucous membrane scraped off and 
 
 FIG. 8. Effect of injection q/ acid into loop of small intestine after 
 destruction of its nervous connections. Upper curve blood pressure. 
 Uppermost of three lines drops of pancreatic juice secreted. Middle 
 line signal marking injection of 50 cc. 0'4 per cent. HC1. Lowest line 
 time in 10". Blood pressure zero level of time marker. 
 
 pounded up with some of the dilute hydrochloric acid. This 
 extract was filtered, and the injection of the filtrate into the 
 animal's veins was found to produce a flow of juice even 
 greater than that excited by the introduction of acid into the 
 lumen of the gut. This substance, formed in the cells under 
 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 
 
88 THE PHYSIOLOGY OF 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 
 
PANCREATIC 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 action 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 THE 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 that 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 6p/xaw, 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 
 
PANCKEATIC 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 proper 
 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, 
 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 
 ordinary physiological processes of the organism are carried 
 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 OF 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 as 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 vagus is to cause 
 
PANCREATIC SECRETION. 8 r 
 
 movements of the stomach, and either relaxation or contraction 
 of the pyloric orifice. The first effect, therefore, of stimulating 
 this nerve may be 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. Wh^n 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. 
 
LECTURE 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 PANCREAS DURING SECRETION. 
 
 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 anaesthetised 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 
 
96 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 ha3motoxylin 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 
 isecretion, 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 OF 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 Russian 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 accelerated 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 DIGESTION. 
 
 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 
 
 FIG. 10. Formation of islet of Langerhans from secretory alveoli. 
 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 basophile 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 chromo- 
 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 ceiitro-acinar cells, thus bringing about a reversion to 
 the embryonic type. Complete exhaustion thus causes, not 
 
CHANGES IN 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- 
 plete neutralisation require between 10 and 15 cc. of JQ 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 OF THE PANCREATIC JUICE. 103 r 
 
 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 
 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 erepsiu. Its chief function in this 
 situation appears to be the further digestion of albumoses and 
 peptones, and their conversion into ammo-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. 
 
104 THE PHYSIOLOGY OF DIGESTION. 
 
 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 these physiologists, of whom Kiihne, 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 enterokinase, 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 
 in contact with the intestinal mucous membrane, the liquid 
 so obtained contains no trypsin at all, and is without effect on 
 coagulated proteid. We may say therefore that juice, as it is 
 secreted normally by the pancreas, contains no trypsin, but 
 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 
 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 
 for months ; but at any time it can be activated by the 
 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 
 Delezenne, 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 
 combination or association of two bodies, trypsinogen and 
 enterokinase. They have thought that, just as two bodies, 
 called the amboceptor and the complement, are involved in the 
 * Archives internat. de Physiol., Vol., I., p. 86, 1904. 
 
106 THE PHYSIOLOGY OF DIGESTION. 
 
 destruction of red blood corpuscles by foreign sera, so in the 
 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 from 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 reirivestigated 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 
 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- 
 ing it with the cytases, and the results of our investigations 
 
108 THE PHYSIOLOGY OF DIGESTION. 
 
 have been to confirm entirely the view of Pawlow, with regard 
 to the action of this " ferment of ferments." 
 
 THE QUALITATIVE ADAPTATION OF THE PANCREATIC 
 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. 
 Substances which are difficult of digestion will remain long in the 
 stomach and will probably excite a greater flow of gastric juice. 
 The flow of pancreatic juice will be determined by the flow of 
 gastric j uice. The greater the amount of acid chyme entering the 
 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 fistulse showed variations in the relative quantities 
 of 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. 
 
 ferment amylase is preponderant. The figures obtained by 
 this observer are given in the following tables : 
 
 Diet. 
 
 Quantity 
 of 
 Juice. 
 
 Proteolytic 
 Ferment. 
 
 Amylolytic 
 Ferment. 
 
 Fat-splitting 
 Ferment. 
 
 f-gJ 
 
 S 3 
 
 H-3 >~S 
 
 CQ 
 
 Total 
 units of 
 Ferment. 
 
 to o5 
 
 rl 
 
 GQ 
 
 Total 
 units of 
 Ferment. 
 
 t 
 
 CQ 
 
 3-S 
 Si 
 
 Milk 600 cc. 
 
 48 cc. 
 
 22-6 
 
 1085 
 
 9 
 
 432 
 
 90-3 
 
 4334 
 
 Bread 250 gins. . . 
 
 151 cc. 
 
 131 
 
 1978 
 
 10-6 
 
 1601 
 
 5-3 
 
 800 
 
 Meat 100 gnis. . . 
 
 144 cc. 
 
 10-6 
 
 1502 
 
 4-5 
 
 648 
 
 25 
 
 3600 
 
 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 proteoly tic 
 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, 
 
110 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 
 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 
 juice 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 PROPERTIES OF THE PANCREATIC JUICE. 
 
 iir 
 
 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 which 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, 
 and is only poured into the gut during digestion, we find on 
 opening a fasting animal that the gall bladder is distended, 
 whereas 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 
 duct. 
 
 ANALYSES OF BILE (HUMAN). 
 
 From a biliary fistula (Yeo and Herroun). From the gall bladder (Hoppe-Seyler) 
 
 in 100 parts. 
 
 Mucin and pigments . . 0'148 Muciii . . . . . . l - 29 
 
 Sodium taurocholate . . 0'055 Sodium taurocholate . . 0'87 
 
 Sodium glycocholate . . 0'165 Sodium glycocholate . . 3'03 
 
 Cholesterin . . . . \ Soaps . . . . . . 1-39 
 
 Lecithin . . [ 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 
 other constitutents of bile, the pigments must be regarded 
 simply as waste products. They pass into the intestine and 
 are there converted by the processes of bacterial reduction into 
 stercobilin, which is excreted for the most part with the 
 fasces, 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 
 constituents, it will be interesting to determine the time 
 P.D. i 
 
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 the 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.CL, 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 
 may possibly be adherent to the mucous membrane of the 
 
 i2 
 
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 011 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 
 
 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 110 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. 
 Further 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. 
 
THE BILE. 
 
 in 
 
 From the fact that the secretion of bile runs parallel with 
 that of pancreatic juice, and is excited by the same 
 mechanism, we should expect it to alter with variations in 
 the diet. The secretion of bile on various diets has been 
 studied by Barbera. He finds that, whereas the secretion of 
 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 case 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. 
 
LECTURE IX. 
 
 THE INTESTINAL JUICE. 
 
 WE have seen that for the 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 fistulas. These fistulas are 
 
THE INTESTINAL JUICE. 121 
 
 of two kinds. Thiry'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 fistulae, 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 THE 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 
 small 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 hypersemia will tend to 
 
 * Mendel, Pfliiger's Archiv., Vol. LXIIL, p. 425, 1896. 
 
 f 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. As 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 entericus is 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 that 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 succus entericus is also necessary for the 
 intestinal digestion, we might anticipate that the secretin, 
 which excites both bile and pancreatic secretion, w r ould also 
 excite a secretion of succus 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. 
 
 Eecently 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 enect 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 be 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- 
 Idnase we have already studied in detail. Possessing no 
 action itself .on proteids, it is a necessary condition for the 
 development of the full proteolytic 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 small 
 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. 
 
LECTURE X. 
 
 THE MOVEMENTS OF THE ALIMENTARY TRACT. 
 
 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 years 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.P. K 
 
130 THE PHYSIOLOGY OF DIGESTION. 
 
 nervous system, this control gets less and less with the onward 
 progress of the food ; and that, in the duodenum and small 
 intestine, the mechanism for evoking the secretion of the 
 digestive juices, at the exact time and place where they are 
 required, is local or chemical, and occurs in the entire absence 
 of any connection with the central nervous system. In the 
 same way the motor reactions, which affect the beginning of the 
 canal, are subject to the central nervous system. This direct 
 control is also manifested in the reactions of the lowest por- 
 tions of the gut, which are concerned in the act of defsecation. 
 The middle of the alimentary canal however, although 
 capable of being affected by the central nervous system through 
 the splanchnic and vagus nerves, depends for the greater part 
 of its activity on a nervous mechanism situated in the wall of 
 the gut itself. The mechanism is apparently in all cases 
 nervous, and we have, at present, no evidence of motor 
 reactions being evoked by the circulation in the blood of 
 chemical substances or hormones.* There must naturally 
 be a wide variation in the details of the motor reactions of the 
 alimentary canal, according to the nature of the food-stuffs 
 chiefly made use of by the animal ; and we find great 
 differences in this respect, as in the anatomy of the canal, 
 between a carnivorous animal such as the dog and a herbi- 
 vorous animal such as the rabbit. In the following account I 
 shall deal chiefly with those facts which, though determined by 
 experiments on animals of both classes, can be directly 
 applied 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 
 structures. Adrenalin, the hormone manufactured by the suprarenal 
 bodies, seems to be necessary for the normal display of the functions of 
 the sympathetic system, and its motor or inhibitory effects on the gut are 
 produced through this system. 
 
THE MOVEMENTS OF THE ALIMENTARY TRACT. 131T 
 
 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 
 
 K 2 
 
132 THE PHYSIOLOGY OF DIGESTION. 
 
 a lengthening as the result of the application of the stimulus. 
 In the same way a movement of extension of the leg, in 
 response to a particular tactile stimulus applied to the ball of 
 the foot, can be properly carried out only by a two-fold dis- 
 charge causing inhibition of the flexor muscles, and contraction 
 of the extensor muscles. The uncoordinated spasms which 
 distinguish strychnine poisoning are due to the abolition of 
 the inhibitory part of each reflex and its conversion into a 
 contractile reaction, so that antagonistic muscles are set into 
 contraction by one and the same sensory stimulus. The 
 physiological purpose of a peristaltic contraction is the pro- 
 pulsion of a solid or semi-solid object along a tube. A simple 
 contraction of the tube, even if propagated along its walls, 
 would probably pass over the object, squeezing it in its course 
 but not effecting an onward movement. In order that the 
 object or bolus may be moved from one end of the tube to the 
 other, it is necessary that a process of contraction of the 
 muscle 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 
 a process of contraction behind the object, and a process of 
 inhibition and relaxation in front of the object. Such a 
 double process can be effected only by a co-ordinating centre. 
 In the case of the oesophagus this co-ordinating centre is 
 situated in the medulla, and the orderly progression of the 
 peristaltic wave of inhibition plus contraction along the walls- 
 of 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 
 
THE MOVEMENTS OF THE ALIMENTARY TRACT. 138 
 
 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. 
 
134 THE PHYSIOLOGY OF DIGESTION. 
 
 The acid juice cannot, however, penetrate the great mass of 
 food which is lying in the fundus, and in the interior of this 
 mass salivary digestion can go on from thirty minutes to one 
 and a half hours after the food has been swallowed. A very 
 considerable portion therefore of the salivary digestion occurs 
 in the stomach itself. For the understanding of the sub- 
 sequent movements of the gastric wall, it is important to 
 remember its functional division into two parts, namely, 
 fundus and pyloric end or antrum. Although the dead 
 stomach appears to form one sac, observation of a stomach, 
 recently removed from the living animal and placed in warm 
 salt solution, shows distinctly this division into two parts, 
 namely, a tubular part at the pyloric end and a bag-like 
 portion, forming four-fifths of the stomach, at the cardiac end. 
 The division between the two is marked by what has been 
 called the * transverse band ' of the stomach, a region where 
 there is almost always contraction of the circular muscle 
 fibres. So marked is this in the living stomach that one 
 would expect on dissection to find evidence of sphincter-like 
 thickenings at this point. It is, however, a physiological and 
 not an anatomical condition. 
 
 The movements of the stomach can be best studied by 
 Cannon's method, that is, by direct observation of the move- 
 ments in a living unanaesthetised animal, by means of the 
 Rontgen rays. In order to make the shape of the stomach 
 visible, the food bread and milk is mixed with a quantity 
 of 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. 
 It 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. 
 
 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 salt 
 
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 w r ave 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 THE 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 stomach 
 causes relaxation of the orifice, whereas acidity on the duodenal 
 side causes 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 Rontgen 
 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, loc. cit., p. 164. 
 
138 THE PHYSIOLOGY OF 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 coats ; 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 OF THE ALIMENTARY TRACT. 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.! On examining under the Rontgen rays 
 the intestines of a cat, which has taken a large meal of bread 
 and milk 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 Ringer's fluid. If, however, the plexus has 
 been left behind in stripping off the muscle, no rhythmic contractions are 
 to be observed, aHhough contraction can still be excited by artificial 
 stimulation. Magnus concludes that even the rhythmic ' peiidular ' con- 
 tractions depend for their occurrence an the integrity of the connection 
 between local ganglionic centres and muscle fibres, and cannot therefore 
 be strictly regarded as myogenic (Pfliiger's Arch-ir., GIL, p. 349, 1904). 
 
 t Cannon. Amer. Journ. of PhysioL, Vol. VI. p. 251, 1901. 
 
140 
 
 THE 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 
 
 FIG. 12. Diagram (from Camion) 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 translatory 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 OF THE ALIMENTARY TRACT. 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 aboi'c 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-crecal valve. On the other hand, pinching 
 
 FIG. 13. Rhythmic 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 (I), the 
 intestine was gently pinched one inch above the balloon. The effect was 
 immediate and lasting inhibition. At (2) and (8) the intestine was 
 pinched half an inch below the balloon with the result of causing in each 
 case increased contractions at the leyel 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. 18). 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 b} T 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 hrain 
 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, the 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 Reports, Vol. I. p. 37, 1896. 
 
THE MOVEMENTS OF THE ALIMENTARY TRACT. 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 
 trout 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 
 ijhe rest of the small intestine, produces a strong contraction 
 of the muscle fibres forming the ileo-colic sphincter. 
 
144 THE PHYSIOLOGY OF DIGESTION. 
 
 MOVEMENTS OF 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 ententes, 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, Journ. of Physiol. Vol. XXXT. 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 
 Rontgen 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 defecation. 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 PAPEES, 
 
 Bearing on the Subjects treated of in the preceding Lectures, 
 ivhich have been published since 1899 by Workers in the 
 Physiological Department, University College. 
 
 LECTUEE I. 
 
 (1) " Some Eesearches 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) "Eesearches on the Autolytic Degradation of Tissues." By 
 
 S. B. Schryver. Pt. II. (Journ. of PhysioL, Vol. XXXII., 
 1905.) 
 
 LECTUEE II. 
 
 (3) " The Kinetics of Tryptic Action." By W. M. Bayliss, F.E.S. 
 
 (Archives des Sciences Biol., Vol. XL, Suplt. St. Petersburg, 
 1901) 
 
 (4) "The Effect of Electrolytes on Adsorption." By W. M. 
 Bayliss. (Biochemical Journal, Vol. L, 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, F.E.S. (Journ. of PhysioL, Vol. 
 XXXIII., p. 439, 1906.) 
 
150 APPENDIX. 
 
 LECTUEE 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 Flow from the Submaxillary 
 Gland of the Dog." By F. A. Bainbridge, B.A., B.Sc. 
 (Journ. of Physiol, Vol. XXVI., 1900.) 
 
 LEGTUEE 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 Eecent 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. LXXIII., 1904, and Phil. 
 Trans. Boy. Soc., Series B, Vol. CXCVII., 1904.) 
 
 (14) " The Oxygen Exchange of the Pancreas." By J. Barcroft 
 and E. H. Starling. (Journ. of Physiol., Vol. XXXI., 1904.) 
 
 (15) "The Lymph Flow from the Pancreas." By F. 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 Food-stuffs." 
 (Preliminary communication.) By F. A. Bainbridge. (Proc. 
 Boy. Soc., Vol. LXXIL, 1903.) 
 
 (20) " On the Adaptation of the Pancreas." By F. A. Bainbridge. 
 (Journ. of Physiol, Vol. XXXI. , 1904.) 
 
 (21) " On the Alleged Adaptation of the Pancreas to Lactose." 
 By K. 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) For " Action of Secretin on Bile " v. Paper No. (9) in Journ. 
 of Physiol, Vol. XXVIII., 1902. 
 
 (25) " The Contractile Mechanism of the Gall Bladder and its 
 Extrinsic Nervous Control." By F. A. Bainbridge and 
 H. H. Dale. (Journ. of Physiol, Vol: XXXIII. , 1905.) 
 
 (26) " A Note on Burner's Method of Preparing Pure Glycocholic 
 Acid." By W. A. Osborne. (Proc. Physiol Soc., 1900.) 
 
 (27) "On the Formation of Lymph by the Liver." By F. A. 
 Bainbridge. (Journ. of Physiol, Vol. XXVIII., 1902.) 
 
152 APPENDIX. 
 
 LECTURE IX. 
 
 (28) "The Presence of Lactose in Animals." By R. 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.) 
 
 LECTURE X. 
 
 (30) " The Movements and Innervation of the Small Intestine." 
 Pt. I. By W. M. Bayliss and E. H. Starling. (Journ. of 
 Physiol., Vol. XXIV., 1899.) 
 
 (31) Idem. Pts. II. and III. (Journ. of Physiol, Vol. XXVI., 
 1901.) 
 
 (32) " The Movements and Innervation of the Large Intestine." 
 By W. M. Bayliss and E. H. Starling. (Journ. of Physiol, 
 Vol. XXVI., 1901.) 
 
 (33) " On the Movements and Innervation of the Stomach." By 
 W. Page May, M.D. (Brit. Ned. Journ., Sept. 13, 1902.) 
 
 (34) " The Innervation of the Sphincters and Musculature of the 
 Stomach." By W. Page May. (Journ. of Physiol, Vol. 
 XXXI., 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. 
 
 Arrhenius, on toxins and antitoxins 
 
 37. 
 Atropin, 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, 112119. 
 analyses of. 113. 
 
 digestive functions of, 110. 
 
 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, 15. 
 Colon, movements of, 144. 
 Craw, on interaction of toxins and 
 antitoxins, 30. 
 
 Dakin, on lipase, 32. 
 Dale, on gall-bladder, 115. 
 
 on islets of Langerhans, 98. 
 
 Dastre, on enterokinase, 105. 
 
 Defalcation. 140. 
 
 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, 6279. 
 
 Edkins, on gastric secretion, 74. 
 Ehrlich's theory of hasmolysins, 34. 
 Elliott, on movements of large intes- 
 tine, 144. 
 Emulsin, 31. 
 Energy of food-stuffs, 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, 
 
 110. 
 
 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, 04. 
 
 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, 120128. 
 
INDEX. 
 
 Intestinal juice, characters of, 125. 
 Intestine, distribution of prosecretin 
 
 in, 88. 
 law of, HI. 
 
 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 of 
 
 glands, 58. 
 Oxyntic cells, 63. 
 
 salivary 
 
 Pancreas, changes during secretion, 
 94101. 
 
 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, 8093. 
 
 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 of, 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. 
 
 Keaction, modes of studying velocity 
 
 of, 22. 
 
 velocity of, 11, 20. 
 Reactions, bimolecular, 21. 
 
 monomolecular, 21. 
 
 reversible, 29. 
 
 Reflex secretion of pancreatic juice, 84. 
 Kennin, 3G. 
 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, 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 enterokinase, 
 
 105. 
 
 Vagus, effect on gastric secretion, 70. 
 
 intestinal movements, 
 
 142. 
 
 oesophagus, 132 
 
 gastric movements, 
 
 136. 
 Velocity constant, 21. 
 
 Weinland, on antitrypsin, 107. 
 
 on lactase, 109. 
 Wertheimer, on pancreatic secretion, 
 
 85. 
 
 Zymoids, 35. 
 
 BRADBURY, AGNEW, & CO. LD., PRINTERS, LONDON AND TONBRIDGE. 
 
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