66 



NA TURE 



[May 19, 1904 



filtered through a gelatinised Chamberland filter. It is not 

 precipitated by tannic acid, thus excluding bodies of alkaloid 

 nature as well as diamido-compounds. This evidence, 

 slight though it is, points to secretin being a body of re- 

 latively small molecular weight and not a colloid. It may 

 be compared to the active principle of the suprarenal glands, 

 adrenalin, which has been obtained in a crystalline form 

 and the chemical constitution of which has been approxi- 

 mately determined. This is, indeed, what one would expect 

 of a substance which has to be turned out into the blood 

 at repeated intervals in order to produce in some distant 

 organ or organs a physiological response proportional to 

 the dose. The bodies of higher molecular weight, such as 

 the toxins, which owe their activity, according to Ehrlich, 

 to the fact that they can be directly assimilated by the cells 

 of the body, and built up into the protoplasmic molecule, 

 always give rise to the production of anti-bodies, a process 

 which, while not preventing necessarily their utilisation in 

 the body, would prevent their acting as a physiological 

 stimulus to certain definite cells. Adrenalin and secretin 

 on the other hand belong to the class of drugs which act 

 by their physicochemical properties, and the physiological 

 effect of which is determined by the total configuration of 

 their molecule. It was suggested to us early in our experi- 

 ments that the secretion of pancreatic juice, evoked by 

 secretin, was essentially a sudden production of an anti- 

 body ; such a sudden production is unknown in the animal 

 body, and the anti-character of the secretion is at once 

 negatived by the fact that secretin can be mixed with a 

 freshly secreted juice without in any way destroying its 

 efficiency. 



Like adrenalin, secretin is extremely easily oxidised, and 

 it is probable that it is got rid of in this way from the body, 

 since, even after repeated injections of secretin, it is im- 

 possible to find this substance or any precursor of it either 

 in the pancreas, the urine, or other tissues of the body. 

 Just as in the case of adrenalin, so we find that secretin 

 is not specific for the individual or species. An extract of 

 the mucous membrane of the dog will evoke secretion in 

 the pancreas of the frog, the bird, rabbit, cat, or monkey. 

 In the same way the pancreatic secretion of the dog can be 

 excited by injection of secretin prepared from the intestine 

 of man, cat, monkey, rabbit, fowl, salmon, skate, frog, or 

 tortoise. The evolution of this mechanism is, therefore, to 

 be sought at some time anterior to the development of 

 vertebrates. 



The action of secretin is not confined to the pancreas. It 

 has long been known that the pancreatic juice, in order to 

 exert its full activity on the food stuffs, needs the simul- 

 taneous presence of bile, and the fact that in many cases 

 the two fluids are poured into the duodenum by a common 

 orifice shows the close connection which must exist between 

 them. Digestion of fats is impossible unless both fluids 

 have access to the gut, and even in the digestion of carbo- 

 hydrates, as was shown by S. Martin and Dawson Williams 

 many years ago, the presence of bile greatly hastens the 

 digestive powers of the pancreatic juice. Whenever, there- 

 fore, a secretion of pancreatic juice is required, a simul- 

 taneous secretion of bile is also necessary. It is interesting 

 to note that this simultaneous secretion is provided for by 

 the same mechanism by which the secretion of pancreatic 

 juice is evoked. If the flow of bile be determined by 

 measuring the outflow from a cannula placed in the bile 

 duct, it will be found that introduction of acid into the 

 duodenum causes a quickened secretion of this fluid. The 

 same increase in the secretion of bile can be produced by 

 injecting solutions of secretin into the blood stream. This 

 influence of secretin on the liver has been fully confirmed bv 

 Falloise. This observer has shown that acid extracts of the 

 intestinal mucous membrane cause an increase in the bile 

 secretion most marked when the extract is made from the 

 duodenum and diminishing as the extract is taken from 

 the lower parts of the gut, that from the lower section of 

 the ileum being quite ineffective. 



The discovery of secretin has placed in the hands of 

 physiologists the power of controlling the activity of a gland 

 by purely physiological means, and we have taken oppor- 

 tunity of the control thus acquired to investigate the exact 

 character of the changes induced in the pancreas under this 

 physiological stimulus. So far as we can tell secretin has 

 no specific influence on any one constituent of the pancreatic 



NO. 1803, VOL. 70] 



juice. When injected it causes secretion of a juice which 

 is normal in that it resembles the juice secreted on entry 

 of food into duodenum, and contains a precursor of trypsin, 

 amylopsin, and steapsin. Secretin, in fact, appears to cause 

 the pancreatic cells to turn out the whole of the mesostates 

 which they have accumulated during rest in preparation for 

 the act of secretion. If secretin be injected at repeated 

 intervals until the gland will no longer respond to the in- 

 jection, it is found on microscopic examination that the cells 

 have discharged the whole of their granules. In sections 

 stained with toluidine blue and eosin the whole of the cells 

 stain blue in marked contrast to the normal resting gland, 

 where one-half or two-thirds of the inner margin of the 

 cells is taken up with brilliantly stained red granules. This 

 effect is not produced in all cases. In some animals we 

 have injected secretin at frequent intervals over a period 

 of eight hours, and obtained at the end of the experiment 

 a secretion as vigorous as after the first injection. The 

 pancreas in this case was evidently not fatigued, and on 

 killing the animal and examining this organ microscopically 

 it was found to give the typical picture of a resting pancreas. 

 One may say, therefore, that under healthy conditions the 

 activity of the pancreas is two-fold in character, and that 

 the normal stimulus of secretin excites not only a breaking 

 down of the protoplasm and a discharge of granules, but 

 also a building up of the protoplasm and a new formation 

 of granules. So marked, in fact, is this power of self- 

 restitution that it is often advisable to diminish the resist- 

 ance of the animal by bleeding or other means if it is desired 

 to obtain a specimen of exhausted gland. 



A study by Mr. Dale of the stages of exhaustion carried 

 out in this way has brought to light a remarkable behaviour 

 in the cells of the pancreas, to which we have no analogies 

 in other secreting glands of the body. After the discharge 

 of the granules the cells seem to undergo a still further 

 involution, losing the whole of their chromophile substance, 

 diminishing in size or undergoing vacuolation, and finally 

 being transformed into cells undistinguishable from those 

 which have long been known as forming the so-called 

 " islets of Langerhans." Mr. Dale has, in fact, shown that 

 in all probability these " islets," which are generally re- 

 garded as pre formed structures, really represent stages in 

 the functional activity of the secreting cells of the gland, 

 and he is of opinion that the activity of the gland is always 

 associated with a cycle of changes in which the islets are 

 formed, to be afterwards regenerated into secreting tissue. 

 Other observers have noted in the embryo a development of 

 secreting tubules from tissue undistinguishable from the 

 " islets of Langerhans," and it is interesting to note that 

 the depletion of the gland caused by long starvation has 

 a similar effect to that caused by over-excitation, namely, 

 the conversion of a large proportion of the gland tissue into 

 " islet " tissue. 



So far we have dealt only with the correlation of the 

 activities of the cells lining the intestinal tube with those 

 forming the masses of the pancreas and liver, and have seen 

 that a very large part in this correlation is played by a 

 chemical substance which acts, so to speak, as a chemical 

 messenger between these various organs. A striking 

 feature, however, of the pancreas is its alleged power of 

 adapting its secretion to the nature of the food taken in 

 by the animal. It has been stated by Pawlow that accord- 

 ing as the food consists chieflv of proteids, carbohydrates, 

 or fats, so do we find a relative preponderance of the fer- 

 ments acting respectively on each of these three classes of 

 foods. The evidence on which this statement is based, 

 although lending to it considerable support, is not absolutely 

 convincing. Vasilieff {Archives des Sciences Biologiques, 

 St. Petersburg, 1893) examined the pancreatic juice of dogs 

 which were fed on meat, or bread and milk alternately for 

 periods extending over several weeks for each kind of diet. 

 This observer found that the transition from bread and milk 

 diet to a meat diet caused a rapid rise in the proteolytic 

 power of the juice, which reached its maximum after several 

 days of meat feeding. A return to a diet of bread and milk 

 caused a slower fall in the proteolytic power of the juice, 

 but a rise in the amylolytic power. Similar results were 

 obtained by another pupil of Pawlow — Jablonsky (ibid., 

 1896) — who also extended his observations to the fat-splitting 

 ferment. At the time that these observations were made 

 the function of enterokinase was unknown, and it is there- 



