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Hl i HA ii HPT Te ET Hae) 1 f i it Hit IMT HH I) i Hit | Wil ure ATMA AT Wn HUE i Hi UGH it Alii Nh) MA ci HANH | il WPA Kail Hii i 1) nN i AHI nat HH it MIL i i 4 HAART | il Hii Wi Hh ue : ili Wit | } ; j He EU il il uTPPERTAS AL Ue TE a ih 1 Hil I} il I init i it i HH Hill We HHT EL it MI ij Hil Mitt HHH Hil H Ha eat Edd i] u HT Hi il nt PI RPLEARL EHP TUTED : WA HH! WHT , iit Wat it HN j HIN | WN rai iii ai Hil i Ht wth] j HHH WE WH] iil ii AAA i iy uli] aT Hil} i Hil i Hit i Ht Hi i] Me | HE il Hill ANH it il} ii} | | Wh nt ti iH it | 1} | | 1) WaT HH) ena Hi! 1 i it uM " HU Teh th Hi Hefei Niet HH Cia ie On Mi pHa Ter ' Ua HIATT AE Gd THA nin Mi iii ni ij iit wii | hi iii] ii Mil SHIH! Ah i HH) Hh | iy i") iH iil i Wilh} ity EL ik hh | AGN AANA AMAMAMIARARRAT MU HRA MTEAICIRS UHH i il Hit i} WN Hi i ah} Wi! i} i} i i} HHT ah MUTE ih DAT HEM THAN TTLURLANUUAPLTTRTT HOTU CHTABHSGLACHGHURHGOLCHETUTICGH HA 1 HERP L ee TH Ht "i V Hi HH a it! i yal it i i iil i ali POLL th! j Tt HARA Lindl (STU TVOHHE MUTE ATTPTU GUT MUIETCT ERATE PAVE iy hh Lees 4 ¢ i THE HARVEY LECTURES Delivered under the auspices of THE HARVEY SOCIETY OF NEW YORK Now Published FIRST SERIES . . 1905-4906 SECOND SERIES . 1906-1907 THIRD SERIES. 1907-1908 « AP Ph et | ~ ’ 7} - 7 7 i} wy - 4 {> CopyriGHT, 1909 By J. B. Lippincorr Company 4 : [ve hy ' wm ti = baie libel Ae i Pie er Seri - yr. we wee? itp Mery Os oly: oie OFFICERS AND MEMBERS OF THE SOCIETY OFFICERS COUNCIL GRAHAM Lusk, President Simon FLEXNER JAMES Ewinea, Vice-President THEODORE JANEWAY Epwarp K. DuNHAM, Treasurer Puiniep Hanson Hiss GrorGE-B. WALLACE, Secretary The Officers Ex-Officio ACTIVE MEMBERS Dr. JOHN AUER Dr. Freperic S. LEE Dr. S. P. BEEBE ‘ Dr. P. A. LEVENE Dr. Hermann M. Biaes Dr. E. Lipman Dr. Hartow Brooks Dr. GRAHAM LUSK Dr. R. Burton-Opirz Dr. JoHn A. MANDEL Dr. JoHN G. CuRTIS Dr. S. J. MELTZER Dr. Epwarp K. DuNHAM Dr. ADOLF MEYER Dr. HAvEN EMERSON Dr. Hipryvo NogucHi Dr. JAMES EWING Dr. CHARLES NorRRIS Dr. Stmon FLEXNER Dr. Horst OERTEL Dr. AustTIN FLINT Dr. EvuGEne L. OPIE Dr. WILLIAM J. GIES Dr. WiuuiAM H, Park Dr. R. A. Hatcuer Dr. T. MitcHeLL PRUDDEN Dr. C. A. Herter Dr. A. N. RicHarps Dr. Pump Hanson Hiss Dr. A. J. WAKEMAN Dr. Evcenet HopENPYL Dr. Grorce B. WALLAGE Dr. Houtmss C. JACKSON Dr. Rosert J. WILSON Dr. THEODORE C. JANEWAY Dr. C. G. L. Wor Dr. Francis CARTER Woop 5 ASSOCIATE MEMBERS . CHarues F. ADAMS . Isaac ADLER . SAMUEL ALEXANDER . S. T. ARMSTRONG . PEARCE BAILEY . L. Bouron Banes . JOSEPH A. BLAKE . Davin BovatrRpD . JOHN W. BRANNAN . NATHAN E. Britu . Epwarp B. Bronson . F. Trnpen Brown . S. A. BROWN . JOSEPH D. BRYANT . GLENWoRTH R. BUTLER . C. N. B. Camac . Ropert J. CARLISLE . JOHN H. CLAIBORNE . WARREN COLEMAN . WILLIAM B. CoLEy . JOSEPH COLLINS . Lewis A. CONNER . Fuoyp M. CRANDALL . B. Farquyar Curtis . CHARLES L. DANA . THomMaAs DARLINGTON . D. Bryson DELAVEN . Epwarp B. DencH . W. K. DRAPER . ALEXANDER DUANE . THEODORE DUNHAM . Max ErInHORN . Georce T. EvLuior . CHARLES A. ELSBERG . Evan M. Evans . Epwarp D. FISHER . JoHN A. ForDYCE . JOSEPH FRAENKEL . Woutrr FREUDENTHAL . ARPAD G, GERSTER Vircit P. GIpney . CHartes L. Gipson . J. RippLe Gorre . FREDERICK GWYER . A. McL. Hamitton . GRAEME M. Hammond . T. Stuart Hart . FRANK HARTLEY . JOHN A. HARTWELL . THomas W. Hastines . Henry Herman . Aucustus Hoc# . L. Emmett Hour . JOHN HOWLAND . JOHN H. HuppLeston . GEorGE S. HUNTINGTON . ABRAHAM JACOBI . GEORGE W. JACOBY . Water B. JAMES . Epwarp G. JANEWAY . FREDERIC KAMMERER . JACOB KAUFFMANN . CHARLES G. KERLEY . Putuie D. KerRison . EveaAnor B. KILHAM Francis P. Kinnicutr . ARNOLD KNAPP . HERMAN KNAPP . L. E. La Ferra . ALEXANDER LAMBERT . SAMUEL W. LAMBERT . Gustav LANGMANN . Eapert Le Frevre . Isaac LEVIN . CHARLES H. Lewis . Rosert Lewis, JR. . Wituiam C. Lusk . Stamunp LuUSTGARTEN . Davin H. McArpin . CHARLES McBuRNEY . ArtHuR R. MANDEL . Morris MANGES ASSOCIATE MEMBERS—Continued . GEORGE MANNHEIMER . Witpur B. Marple . FRANK S. Megara . Victor MELTZER . Water MENDELSON . ALFRED MEYER > . Witty Mryer . MicHArL MIcHAILOVSKY . JOHN P. Munn . VAN Horne Norrie . Henry 8S. PAaTTrerson . GeorGE L. PEABODY . FREDERICK PETERSON . WinuiAm M. PoLK . SIGISMUND POLLITZER . NATHANIEL B. PoTTer . Wiuui1Am B. PRITCHARD . WituiAM J. PULLEY . Francis J. QUINLAN . EDWARD QUINTARD . CHARLES C. RANSOM . ANDREW R. Rosinson . JULIUS RuDISCH . BERNARD SACHS . THomas E. SarrerTHWAITE . REGINALD H. SAYRE . Max G. SCHLAPP . Orro H. ScHULTZE . Fritz SCHWYZER . Newton M. SHAFFER . WiiuiAm K. Simpson . A. ALEXANDER SMITH . M. ALLEN STARR . GeorceE D. STEwarRT . Lewis A. Stimson . Wiuu1AMm 8S. STONE . PARKER SyMS . JOHN S. THACHER . W. Gruman THOMPSON . Wiuu1AM H. THOMSON . RicHARD VAN SANTVOORD . JOHN B. WALKER . JOSEPHINE WALTER . JOHN E. WEEKS . FREDERICK H. WIGGIN Dr. Dr. Dr. Dr. Dr. Hersert B. Wincox W. R. WILLIAMS MarGaret B. WILson JOHN VAN DorREN YOUNG Hans ZINSSER HONORARY MEMBERS Pror. CHARLES §. MINOT Pror. J. G. ADAMI Pror. Leweiiys F. BARKER Pror. F. G. BENEDICT Pror. W. T. CouNCILMAN Pror. G. W. CriLe Pror. D. L. Epsauu Pror. Orro Foun Pror. Ross G. Harrison Pror. W. H. Howeiu Pror. JOSEPH JASTROW Pror. E. O. Jorpan Pror. LAFAYETTE B. MENDEL Pror. Hans MryER Pror. T. H. Morcan Pror. FRIEDRICH MULLER Pror. CARL VON NOORDEN Pror. FREDERICK G. Novy Pror. W. T. PoRTER Pror. E. A. SCHAFER Pror. THEOBALD SMITH Pror. E. H. Star.ine Pror. A. E. TAyLor Pror. J. CLARENCE WEBSTER Pror. E. B. WiLson Str AutMRotH WRIGHT PREFACE ITH the appearance of this third volume of the Lectures of the Harvey Society it would seem that the hope of the founders of the Society that the lectures should play an important part in the diffusion of our knowledge of scientific medicine had been realized. It is believed that the lectures maintain the high standard set by the two preceding” volumes, and that the scientific world is beginning to evince a lively in- terest in the possibility of obtaining in concise form the author- itative views of specialists in a large number of medical and biological subjects upon their own particular field of research. It is a pleasure to announce that the fourth volume will shortly appear. The thanks of the Council of the Society are due to the Editors of the Journal of the American Medical Association and the Archives of Internal Medicine for the use of plates for illustration and for permission to reprint lectures which were published in those journals, to the Editors of the Boston Med- wcal and Surgical Journal and of the Anatomical Record for the use of plates and for permission to reprint, and, lastly, to the Royal Society of Edinburgh for the use of plates to illustrate Dr. Schifer’s lecture. CONTENTS PAGE MieeProplems of Sanitation. ...........csecueceeeecveenewes IZ Epwin O. Jorpan, Pu.D.—University of Chicago. PE TANMOTS: LF 55 clack ss cs ¢ “ s OS re x wD Yat x aya ty Fic. 24.—Transplanted carcinoma of mouse. Infiltrative and expansive growth of metas- tases in lung twenty-six days after intraperitoneal implantation (after Bashford). CANCER PROBLEMS 71 Haaland, however, described the transformation of pulmonary epithelium into tumor cells in metastases of mouse carcinoma. This interpretation of Haaland has not been confirmed and will doubtless meet with energetic opposition. Such a process is not recognized in human tumors; but, notwithstanding the determined position of Ribbert and Borrmann,”° based chiefly on the study of gastric cancer and superficial epitheliomata, many (Virchow,*! Hauser **) believe that there may be a gradual extension of the originating focus of a tumor. In primary adenocarcinoma of the intestine, and in melanoma, I believe that there may be a gradual transformation of normal epithelium into tumor cells. Ribbert ** has lately modified his former rigid position on this important question by admitting that cancers may arise from several foci, some of which appear later than others, and that there may be a gradual fusion of the tumors growing from these foci. It is obvious, however, that the distinction between primary tumors arising successively from adjoining foci and the gradual extension of a tumor process through normal cells is a matter of two interpretations of the same appearances. Immunity.—Evidences of a peculiar type of immunity have from the first appeared in the observations on experimental tumors. Wehr? in 1883 deseribed the spontaneous regression of the lymphosarcoma of dogs, a fact repeatedly verified for the same tumor by Sticker and Beebe. Loeb noted the complete absorption of many of his transplanted sarcomata in rats. Gay- lord and Clowes ** reported 20 per cent. of spontaneous cures of the Jensen mouse tumor, and they first drew attention to the significance of this fact as an indication of acquired immunity. The exact meaning is, however, obscured by the fact that some tumors regress while others grow in the same animal, and some after regressing for a time recover and go on to a fatal termina- tion. A slight deterioration in the general health of the animal may interrupt the regression. That local factors play a part in the limitation of the growths is indicated by the histologic study of regressing tumors. Such tumors are usually surrounded by a connective- 72 HARVEY SOCIETY tissue capsule which invades the cellular edges, blocks the blood- vessels, which are often sheathed with round cells, and euts off the nutrition. In regressing dog tumors we find fatty degenera- tion, transformation of large lymphocytes into small, compres- sion atrophy at the periphery, and foci of liquefaction necrosis in the centre, mingled with areas of actively multiplying cells. If no other factor than anemia were present these would be the logical changes. Loeb ® found that if a regressing tumor were subdivided and replanted in the same animal it would often begin to grow rapidly. This observation is not in aecord with the view that specific immune substances are present in the blood of animals recovering from tumors. In July, 1905, Gaylord and Clowes ** reported that thirty mice which had spontaneously recovered from definite tumors had proven immune to further inoculation with the same tumor, and that ten had resisted a third inoculation with a more viru- lent tumor. There were thus indicated: (1) The existence of acquired immunity against mouse cancer, (2) the possibility of increasing this immunity by a process of vaccination. In later experiments they were able to reduce the proportion of successful implantations of the Jensen tumor from 30 to 50 per cent. in the first series, to 10 per cent. for the second series, and to complete immunity in all surviving animals to the third inoculation. Yet, by vaccination with the Jensen tumor, they could not fully protect against the highly malignant Brooklyn eancer. Ehrlich,?> by employing a hemorrhagie tumor which produced smal! abortive growths or none, was able to protect against tumors of maximum virulence. By repeatedly inocu- lating either the mouse sarcoma or the carcinoma he was able to protect against both sarcoma and carcinoma, and to a less extent against a chondroma, whence he concluded that the resistance established constituted a sort of pan-immunity against tumors. Bashford also obtained a high proportion of immune mice after spontaneous cure of tumors, and to a less extent after a negative inoculation of cancer tissue, which was promptly absorbed. On the other hand, Haaland,™ by inoculation of Jensen’s CANCER PROBLEMS 73 tumor, could not immunize Berlin mice against Ehrlich’s very virulent sarcoma; and Michaelis?" could not immunize white mice by means of cancers from gray mice, nor Berlin mice by tumors from animals bred in Copenhagen. It is possible that differences in technic and ‘in the tumors employed may explain these conflicting results. At any rate, the large number of observations recorded show that a certain type of resistance against cancer has been produced in mice. That a true specific immunity against tumors has been dem- onstrated beyond question cannot at present be claimed, for there are many disturbing factors which must be considered in the interpretation of the results of vaccination. The methods employed involve a process of elimination of weaker animals, which succumb to the treatment, and some of the animals which appear to have been rendered immune by the vaccination may always have been naturally immune to all the tumors employed, and this source of error can hardly be eliminated from statisti- eal studies in which the condition of individual animals is not fully determined. Or non-specific variations in the general health of the animals may determine the result in mice, as it often does in dogs, and this factor cannot be estimated accu- rately in such small animals as mice. Again, Bashford ** has shown that different portions of the same tumor, and the same tumor at different periods of growth, vary in rate of growth, and that highly virulent strains may suddenly decline in virulence; but most of the experiments in immunization depend for validity on the assumption of uniform virulence of the tumor strains. Much depends on the dosage employed to test immunity. Successful results may follow mul- tiple inoculations when a single implantation is negative; and Michaelis has seen a mouse, inoculated three times without re- sult, take the fourth inoculation. Finally, the artificial resistance against tumors does not appear to be specific. The pan-immunity observed by Ehrlich is a suspicious feature, suggesting the action of unknown and complex factors. Michaelis,?’ by the injection of normal mouse liver, was able to secure considerable immunity against tumors. 74 HARVEY SOCIETY Schone,** with the liver of mouse embryos and normal mice; Borrel and Bridré,*® with liver or spleen; and Bashford,*° with mouse red cells, all sueceeded in rendering mice quite refrac- tory to the growth of cancer cells. Bashford found that mice convalescent from infectious diseases were refractory to tumor cells, and he and Tyzzer * record the very interesting observa- tion of the spontaneous development of cancer in mice which resisted inoculation. Lately *° he reports that of all embryonal organs, inoculation by epithelial tissue gives the highest degree of immunity against cancer. Pregnancy retards the growth of mouse tumors and renders the animal less susceptible to inocu- lation. Reference may again be made to the remarkable results of increase in resistance observed by Haaland in Berlin mice transferred to Christiania, and probably due to change of diet, water and climate. All of these considerations show that resistance of mice to tumors is of exceedingly complex nature and probably not comparable to any known form of immunity. Not only may mice be made resistant to tumors, but their natural resistance may be diminished. In dogs there is a close relation between the general health of the animal and their susceptibility to inoculation with, and the rapidity of growth of lymphosarcoma, while inoculation with the filtered products of this tumor increases their susceptibility. Clowes *° and Baes- lack found that mouse tumors heated to 42° C. were more readily inoculable. This result is probably due to the greater proportion of autolytie products in the heated material. This same explanation probably applies to the results of Flexner and Jobling,** who rendered rats more susceptible to their tumor by injections of heated tumor products. They made the addi- tional observation that the animals were especially susceptible, not immediately, but from the tenth to the thirteenth days after receiving the tumor products, suggesting a form of anaphylaxis. In the same line Borrel ** suggests that perhaps mice may be made more susceptible to cancer by a diet of cancer tissue. It is known that the repeated injection of toxie proteids, both of bacteria and of organ cells, produces not immunity but in- CANCER PROBLEMS 75 creased susceptibility ; and there seems to be no reason why this susceptibility may not have the characters of anaphylaxis; but that it does has not yet been proven. The effort to determine the nature of the immune forces against cancer has led to the formation of theories which have required frequent readjustment. It was natural to suppose that the blood serum of immune animals must contain sub- stances directly antagonistic to tumor eells. This belief led Gaylord, Clowes and Baeslack ** to inject tumor mice with the serum of recovered animals. Their first results were highly en- couraging, since a minute quantity, 2 ¢.c., seemed to cause the rapid disappearance of some large tumors, while normal serum was entirely ineffective. These results, however, were not con- stant. They then mixed tumor emulsion with immune serum before injection, using salt solution and normal serum as con- trols, and found that the immune serum mixture gave 12 per cent. of successful inoculations, as compared with 31 per cent. for the controls. These results also are of uncertain value on account of many disturbing factors, but they indicate a cyto- toxic action of the immune serum. It first appeared that the active growth of a tumor was necessary to confer immunity; but Bashford *° concluded that while the resistance established by a growing tumor is greater than that following an abortive inoculation, there is no relation between the grade of resistance established and the energy of growth or virulence of the tumor inoculated, but the protection is proportional to the quantity of tumor absorbed. In this case immunity must, apparently, depend on antagonistic sub- stances produced in the body against tumor proteids. Yet, in the serum of actively-immunized mice, Michaelis ** failed to find any evidence of cytolytic or agglutinative action on the tumor cells, or of complement fixation by the Bordet-Gengou method. Tumor cells treated with immune serum, with normal rabbit serum, with rabbit serum rendered hemolytic to mouse red cells, and with serum of animals receiving injections of killed mouse tumor, grew quite as well as the controls. Bor- rel ** failed to find any immunizing or curative influence in the 76 HARVEY SOCIETY serum of a sheep receiving thirteen injections of 100 Gm. each of mouse cancer. As yet there has been no satisfactory evidence of the existence in the serum of immune animals of substances directly antagonistic to tumor cells. Beebe and Crile,*° after exsanguinating dogs suffering from advanced lymphosarcoma, have directly transfused them with large quantities of the blood of naturally immune or recovered animals. The result in nine cases was a rapid and complete disappearance of the tumors. This bold experiment would seem fully calculated to demonstrate in immune blood the presence of substances antagonistic to these tumor cells. Yet it is quite legitimate to suppose that the transferred immune blood was a more suitable nutriment for the body cells, and that as a result of the transfusion the balance of nutrition was reversed, the metabolism of the healthy tissues was improved, while that of the tumor was relatively depressed by the withdrawal of nutri- ment to such an extent that it underwent simple atrophy. Athrepsia.—The observations on the viability of tumor cells in related animals has, from the first, suggested that the growth or regression of a tumor is determined by very slight variations in the soil, and that the problem of immunity is here one of the nutrition of the tumor cells. Ehrlich is the legitimate spokes- man in this field, and he has designated 14; °° this form of im- munity as ‘‘athreptic.’’ Transplanting mouse carcinoma into rats, he observed that the plant grew for several days, as in the mouse, but thereafter regressed. If, after a sojourn in the rat, the piece was transferred back to the mouse, it grew with undiminished vigor, after which it was again susceptible of considerable growth in another rat, but not in the one first receiving it. This zigzag transplantation he maintained for several generations. From these observations he concluded that the mouse tumor carried over into the rat a specific substance, or ‘‘X-stoff,’? which enabled the tumor cells, for a time, to absorb nutriment from the rat, but on the consumption of which the tumor ceased to grow and required a renewal of the specific substance in the mouse. Since a rat once serving as temporary host for the mouse tumor became thereafter entirely refractory CANCER PROBLEMS 77 to the growth and could not serve a second time, it appeared that the tumor must soon absorb the limited supply of suitable nutriment in the rat or else that the rat once inoculated devel- oped antibodies against the mouse cells. Two forms of athreptic immunity are, therefore, possible. In one the specific substance is not itself the nutrient molecule, but merely facilitates absorption, although it is slowly consumed in the process. This theory finds an analogy in the relation of corpus luteum secretion to the chorionic epithelium. In the other view the specific substance is the nutrient molecule and is consumed in the growth. To what extent these hypotheses will prove adequate to explain immunity in tumors it remains for the future to decide. That mouse tumors transplanted into rats fail to grow is doubtless due, to some extent, to the unfavorable soil. Here ‘the influence of athrepsia seems obvious. But the fate of mous? tumor in rats recalls the experiment of Cohnheim and Maas,** who injected into the jugular vein of rabbits fragments of periosteum and saw them develop in the lung into islands of bone which grew for two or three weeks, but thereafter were absorbed. There is good reason to believe that these same islands of bone replaced beneath the periosteum would have retained their vitality. Here the influence of athrepsia is not so obvious, but other factors concerned in tissue organization seem to be at work. It seems to be a fact also that tumors often regress in inocu- lated animals in which the soil is fully capable of supporting the growth, as is shown by successful reinoculation, but in which other factors, some of them local, interfere with the growth and effect a cure. A study of the conditions under which tumors naturally develop and grow indicates that suitable soil is of vastly wider distribution than is the occurrence of tumors, and that the fate of man or animal suffering from a malignant tumor depends chiefly on the characters of the cells and not on the soil. Outside of the experimental laboratory the soil seems to bear much the same relation to appropriate tumor cells as it does to the tubercle bacillus, 78 HARVEY SOCIETY It might be supposed that tumor cells grow, not because they possess increased avidity for nutriment, but because the general body cells are deficient in this function. Yet tumor cells grow rapidly in young animals which show no such constitutional basis for the growth of tumors. Chemistry of Tumors.—The chemical study of tumors forms a necessary preliminary to the construction of theories of immunity. If chemical or biochemical distinctions ean be found between tumor cells and other tissues, then, and not till then, can a chemical or biochemical theory of immunity be established. Several interesting lines of research have extended into this field. In rapidly-growing tumors, free from necrosis, Beebe ** found an excess of potassium and a deficiency of calcium, while opposite conditions held in old and necrotic tumors. Clowes *® observed the same relations in mouse tumors. The proteids of tumors are said to differ in construction from those of normal tissues. On analysis, by Wolf,*® cancer tissues yielded a high proportion (35 per cent.) of glutaminic acid; while alanin, phenylalanin, asparaginic acid, and diamino- acids were increased, and leucin diminished, in the results of Bergell and Dorpinghaus.*t These results conflict with those of Petry,** Neuberg,**® and Beebe.*4 Nucleohiston is present only in lymph-nodes among normal tissues, and its appearance in cancers secondary in lymph-nodes suggests that metastatic tumors receive a chemical impress from the tissue in which they are growing (Beebe **). Cellular tumors often appear to undergo autolysis more rapidly than many normal tissues, but it is doubtful if there is any normal tissue with which a comparison may properly be made. Petry*® observed that antiseptic autodigestion of a breast cancer proceeded more rapidly, but in the same manner, as that of a normal breast tissue. Yet he is extensively quoted as having proven that tumors, in general, autolyze more rapidly than normal tissues. Comparing the increase in non-coagulable nitrogen in a carcinoma of the liver with that of the remaining liver tissue, during autolysis, Beebe ®* noted a considerable excess in favor of the tumor. Ss a Oe CANCER PROBLEMS 79 It is well known that tumors are very subject to softening and necrosis from infection and imperfect blood supply, but I do not think it has yet been proven that well-nourished tumor tissue undergoes autolysis more rapidly than an equivalent nor- mal tissue. Beebe and the writer *° passed dog blood by arti- ficial circulation through test tubes containing fragments of dog sarcoma. Under these conditions the sarcoma cells remained alive for eight or ten days, but dog liver and kidney cells be- came necrotic and autolyzed extensively in forty-eight hours. The study of special ferments in tumors was introduced by Buxton,*® who, with Shaffer,*? found no distinct differences in quantity or quality from those of normal organs. Harden and McFayden ** found in tumors proteolytic ferments acting in acid and alkaline media, respectively, thus disproving Beard’s supposition that proteolysis of tumor ferments is exclusively acid. A strongly hemolytic activity of extracts of degenerat- ing, and especially of necrosing tumors, has been demonstrated by Weil *° as a factor in tumor cachexia, but this action is not specific. Petry °° found that the injections of extracts of fresh or of autolyzed cancers failed to disturb the nitrogen elimination in dogs, and he doubted if any of the cancer extracts were really active in the living body. Blumenthal and Wolf *! submitted five cancers to acid peptic and alkaline tryptic digestion. Two of them resisted pepsin, but three were digested readily in it, while all five were readily digested by trypsin. Yet they state that resistance to peptic and susceptibility to tryptic digestion is characteristic of cancer. Their results probably depended on a high proportion of nucleo- proteids in some of the tumors and not on any significant pecu- liarity of tumor proteids. In two trials emulsion of cancer tis- sue not only dissolved itself but hastened the autolysis of liver pulp, whence they conclude that tumor ferments are not merely autolytic, as are those of normal tissues, but heterolytic. From these observations, which Neuberg *? endorses, Blumenthal does not hesitate to draw far-reaching conclusions regarding the action of ferments in tumors, claiming that their infiltrative 80 : HARVEY SOCIETY growth and the cachexia which they produce are dependent entirely on the above characters of their ferments. The pos- sible presence of bacteria, accidental necroses, and post-mortem decomposition in the tumors examined is not mentioned by these writers; and until their observations are reasonably con- trolled and greatly extended their conclusions cannot be trusted. There are chemical problems in tumors, but the problem of tumors is not chemical. An experiment in antiseptic autolysis of comminuted cells, prolonged over several months, may be sound for chemistry, but is it fruitful for pathology? In these and other experiments the language employed and the con- ditions secured are those of chemistry, but the conclusions are drawn in a physiologic sense. Yet between the two there is a wide gap of assumption. The help of the chemists is needed, but until their technic approaches more closely to physiologic requirement it would seem that some of their results need not detain us long. The present studies do not, as a whole, offer a satisfactory demonstration that tumor cells possess chemical peculiarities sufficient to justify the assumption: that they represent a specific biologie series. In a biochemical sense the efforts to demonstrate specific qualities in tumor cells have not been fully successful. Mention has been made of Michaelis’s failure to produce cytolytic, agglu- tinating, or precipitating agents specific for mouse tumor cells. Working with purified neucleoproteids, Beebe ** has been some- what more successful. From the nucleoproteids of a leukemic spleen he produced a serum which agglutinated the emulsified cells of this spleen and also those of a lymphosarcoma, and precipitated the nucleoproteids from these sources, but acted very feebly and only in strong concentration on cells and nucleoproteids from normal spleen and other tissues, as well as from cancer and spindle-cell sarcoma. Similar results were obtained from nucleoproteids of cancer. If these indications prove trustworthy, then a biochemical basis for immunity against tumors may be within reach. If any general criticism of the recent trend of cancer re- search is to be made it must apply to the exclusive relation of a a CANCER PROBLEMS 81 these studies to the nature of the established tumor process and their failure to deal with the origin of tumors. These problems seem to be entirely distinct. Tumors grow readily in young dogs, rats and mice, although these young animals seldom or never develop such tumors spontaneously. From this standpoint the more fundamental character and permanent value of the long line of studies on cell autonomy become conspicuous, for these deal with the origin of tumors. No one has yet succeeded in originating a malignant tumor ex- perimentally, although the occasional effects of the X-ray may be so regarded. Very broad theoretic deductions have been drawn in the elaborate study by Von Dungern and Werner * regarding the response of epithelial cells to various stimuli. Fischer *° has shown that extensive epithelial hyperplasia may be induced in the rabbit’s ear by forcible injection of oil con- taining Sudan III, which seems to exert a peculiar attraction for certain epithelial cells of the skin. These observations may later be of value in the experimental production of tumors; but the essential character of a neoplasm, progressive growth, is so far lacking in the process excited by this method in the hands of many experimenters.** The long history of efforts to produce tumors experimentally indicates that many have been in control of single factors in tumor genesis, but no one has combined enough of these factors to secure the concrete result of a growing malignant neoplasm. I am strongly of the opinion that information of funda- mental importance in this field is still to be obtained by the very minute observation and analysis of the general and local conditions surrounding the early stages of cancer. This is the exclusive opportunity of the clinician, medical, surgical, and special, but it is often neglected. In it lies the chief hope, for the present generation, of a reduction in the mortality from eancer, by the earlier recognition of the precancerous stage of the disease and the elimination of some of its accessible factors. The new era has not succeeded in devising a cure for cancer. While some are very confident, there does not seem to be 82 HARVEY SOCIETY legitimate ground for hope that any will shortly be discovered. The chief definite limitation of the knife has come from a most unexpected quarter, in the form of the X-ray, which affects favorably only superficial tumors of moderate malignancy. Standardized B. prodigiosus toxins, as now used by Coley, are applicable only to a limited group of sarcomata. The X-ray, bacterial toxins, vaccination with Micrococcus neoformans, inoculation with the substance of thyroid, thymus, liver, and other toxie proteids, serum prepared against cancer tissue or its proteids, and Beard’s pancreatin, all produce more or less destruction of the older portions of true cancers, with deceptive reduction in the size of the tumor, while the patient goes on to die from progressive infiltration by the more resistant tumor cells, and with accelerated metastases and cachexia. The recent studies of artificial immunity to tumors in lower animals touch closely on the problem of the control of tumor erowth in man, but the highly artificial conditions which form the basis of these experimental studies may cause disappoint- ment when the attempt is made to transfer to man the results secured in lower animals. Yet the situation is encouraging in the present fixed determination to acquire more facts, in which field the experimental method is truly epoch-making; and cancer research may justly be stimulated, now more than ever before, by the reflection that a vast practical importance may at any moment attach to the new facts that are being gathered. I. THE PARASITIC THEORY. Most of the literature on Cancer is accessible in Wolff, Die Lehre von der Krebskrankheit, Jena, 1907. *Loeb: Medicine, Detroit, 1900, vi, 286; Centralbl. f. Bakteriol. u. Parasitenk., Jena, Orig., 1904, xxxvii, 235. * Borrel: Ann. de l’Inst. Pasteur, Par., 1903, xvii, 17. * Gaylord: The Journal A. M. A., 1907, xlviii, 15. *Plehne: Ztschr. f. Krebsforsch., Jena, 1904, iv, 525; Deutsche med. Wehnschr., 1906, xxxi, 1181. * Pick: Berl. klin. Wehnschr., 1905, xlii, 1435-1440. * Bonnet: Cit. by Pick. * Riechelmann: Berl. klin. Wehnschr., 1902, xxxix, 728-758. *Newsholme: Practitioner, Lond., 1899, 1xii, 371. * Haviland: Practitioner, Lond., 1899, Ixii, 400. CANCER PROBLEMS 83 * Behla: Deutsche med. Wehnschr., 1901, xxvi, 427. * Arnaudet: Union méd., Par., 1889, xlvii, 613. “ D’Arey Power: Practitioner, Lond., 1899, Ixii, 418. * Behla: Ztschr. f. Krebsforsch., Jena, 1907, v, 137. “Sticker: Ztschr. f.. Krebsforsch., Jena, 1907, v, 215. * Prinzing: Ztschr. f. Krebsforsch., Jena, 1907, v, 224. ** Hahn: Berl. klin. Wehnschr., 1888, xxxv, 413. * Cornil: Bull. Acad. de méd., Par., 3 s., 1891, xxv, 906. * Hartmann (Lecene): Ann. de Gynée. et d’Obst., Par., 1907, iv, 65. *” Butlin: Brit. M. J., Lond., 1907, ii, 255. » Alibert: Cit. from Pianese (*). * Washbourn (Smith): Edin. M. J., 1900, n.s., vii, 1. * Park: Practitioner, Lond., 1899, xii, 385. * Lanz: Deutsche med. Wehnsehr., 1891, xvii, 315. *Demarquay: Cit. by Pianese (*). “ Guelliot: Union méd. du Nord-Est, Reims, 1891, xv, 33, 106, 135, 206, 306. * Pianese: Beitr. z. path. Anat. u. z. allg. Path., Jena, I Suppl., 1896. * Boinet: Compt. rend. Soe. de Biol., Par., 1894, 10 s., 11. * Dagonet: Arch. de Méd. expér. et d’Anat. path., Par., 1904, xvi, 345. ~, Leopold : Arch. f. Gynaek, 1900, lxi, 77. ® Jiirgens: Verhandl. d. Berl. med. Gesellsch., 1895, xxvi, T. I., 99, 119, 152; Verhandl. d. deutsch. Gesellsch. f. Chir., Berl., 1896, xuy,T. I, 84; 1897, xxvi, T. I., 154. * Werner and V. Dungern: Das Wesen der bésart. Geschwiilste, Leip- zig, 1907, 146. “’ Gribaum: J. Path. and Bacteriol., 1907, Edinb. and Lond., xu, a0, * Leyden: Ztschr. f. Krebsforsch., Jena, 1904, i, 293. “Borrel: Bull. de l’Inst. Pasteur, 1907, v, 497, 545, 593, 641. * Rappin: Compt. rend. Soe. de Biol., 1887, 8 s., iv, 756. * Scheurlen: Deutsche med. Wehnschr., 1887, xii, 1033. * Francke: Miinchen. med. Wehnschr., 1888, xxxiv, 57. * Lampiasi: Riforma med., 1888, Ann. iv, 20. “Koubassoff: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1890, vii, 317. “Doyen: Verh. d. deutsch. Gesellsch. f. Chir., Berl., 1902, xxxi, pe .,68; “Darier: Annal. de Dermat. et Syph., 1889, 2 s., x, 597. “ Albarran: Compt. rend. Soe. de Biol., Par., 1889, Pe... LT. 1, A606: “Thoma: Fortschr. d. Med., Berl., 1889, vii, 413. “Sjobring: Fortschr. d. Med., Berl., 1890, viii, 529. “ Adamkiewicz : Untersuchungen iiber den Krebs und das Princip seiner Behandlung, Wien u. Leipzig, W. Braumiiller, 1893. “ Soudakiewitsch: Ann. de l’Inst. Pasteur, Par., 1892, vi, 145. “Monsarrat: Brit. M. J., 1904, i, 173. “Woa: Gazz. med. di Tori ino, 1891, xlii; Centralbl. f. Bakteriol. u. Parasitenk., beer 1892, xii, 185. 84 HARVEY SOCIETY “Walker (Ruffer): J. Path. and Baeteriol., Edin. and Lond., 1892, i, 198. “ Sawtschenko: Centralbl. f. Bakteriol. u. Parasitenk., Jena, xii, 17. ™ Pfeiffer: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1894, xiv, 118. “ Korotneff: Sporozoen als Krankheitserreger, 4°, Berlin, R. Fried- linder & Sohn, 1893. " Kurloff: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1894, xv, 341. “ Bose: Compt. rend. Acad. d. Se., Par., 1898, exxvi, 541. “Kahane: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1894, xv, 413. * Eisen: Med. Ree., N. Y., 1900, lviii, 6 * Schaudinn: Sitzunggeb. d. Berl. Acad. d. Wiss., 1896, xxxix, 951. “ Schiller: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1904, xxxvii, 547. “ Sanfelice: Ztschr. f. Hyg. u. Infectionskrankheit., Leipz., 1896-98, xxl, 32, 394; xxiii, 171; 1897, xxvi, 298; 1898, xix, , 463. “ Plimmer: Practitioner, Lond., 1899, Ixii, 430. “Leopold: Arch. f. Gynaek., Berl., 1900, ]xi, 77. ©Roncali: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1895, xviii, 533. “Bra: Le Cancer et son Parasite, Par., 1900; ef. Allg. med. Centr.- Ztg., Berl., 1900, lxix, 1137. “Russell: Brit. M. J., Lond., 1890, ii, 1356. “ Schmidt: Miinchen. med. Wehnschr., 1906, liii, 162. “Behla: Zischr. f. Hyg. u. Infectionskrankheit., Leipz., 1899, xxxii, 123. * Podwyssoski: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1900, xxvii, 97. “ Feinberg: Deutsche med. Wehnschr., 1902, xxviii, 43, 185. “ Gaylord: IV Report, Buffalo Cancer Laboratory, 1903. * Robertson and Wade: Lancet, Lond., 1905, i, 218. "Gaylord: J. Infect. Dis., Chicago, 1907, iv, 155. “ Calkins: J. Infect. Dis., Chicago, 1907, iv, 171. *® Robertson: Lancet, Lond., 1907, ii, 358. * Virchow: Arch. f. path. Anat., etc., Berl., 1892, exxvii, 188. * Fox: Med. Chir. Tr., Lond., 1858, xli, 361. * Klein: Beitr. z. path. Anat. u. Physiol., Jena, 1892, xi, 125. *Tubarsch: Verhandl. d. naturf. Gesellsch. in Rostok, 1892. * Darier: La Pratique dermat., Par., 1904, iv, 152. * Stroebe: Centralbl. f. allg. Path. u. path. Anat., Jena, 1894, v, 11, 60, 105. © Hertwig: Dentsche med. Wehnschr., 1902, xxvii, 221. “Lubarsch: Path. Anat. u. Krebsforschung, Wiesbaden, J. Bergmann, 1902. “V. Tubeuf: cit. by Lubarsch (”). « Busse : Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1894, xvi, 175. “ Rabinowitsch: Ztschr. f. Hyg. u. Infectionskr., Leipz., 1896, xxi, 11. ” Sternberg: Beitr. z. path. Anat. u. Physiol., "Jena, 1899, XXV, 554, ibid., 1902, xxxii, 1. ” Richardson: J. Med. Research, Bost., 1900, v, 312. CANCER PROBLEMS 85 “Nicolls: J. Med. Research, Bost., 1902, vii, 312. “ Mafucci: Ztschr. f. Hyg. u. Infectionskr., Leipz., 1898, xxvii, 1. “ Meser: Arch. f. path. Anat. (ete.), Berl., 1901, elxiii, 111. “ Borrel: Compt. rend. Soe. de Biol., Par., 1905, lix, 770. “Wenyon: J. Hyg., Cambridge, 1906, vi, 580. “ Tyzzer: Soc. of Exper. Biol., N. Y., 1907, iv, 85. *Mulzer (Hoffmann): Berl. klin. Wehnschr., 1905, xlii, 880. * Lowenthal: Berl. klin. Wehnschr., 1906, xliii, 283. * Guarnieri: Arch. per le Se. Med., Torino, 1892, xxvi, 403. * Bose: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1903, Orig., xxxiv, 413, 517, 666. * Michaelis: Ztschr. f. Krebsforsch., Jena, 1907, v, 189. * Lowenthal: Deutsche med. Wehnschr., 1906, xxxii, 678. * Halberstiidter und Prowazek: Arbeit. a. d. k. Gsndhtsamte., Berl., 1907, xxvi, 43. ™ Borrel: Compt. rend. Soe. de Biol., Par., 1904, lvii, 642. ™ Lipsehiitz: Wien. klin. Wehnschr., 1907, xx, 253. ™ Burnett: Ann. de I’Inst. Pasteur, Par., 1906, xx, 742. * Borrel: Bull. de l’Inst. Pasteur, Par., 1907, v, 511. II. THE THEORY OF CELL AUTONOMY. *Remak: Arch. f. Anat., Physiol. u. wissensch. Med., Berl., 1852, xix, 217-57. *Thiersch: Der Epithelialkrebs (ete.), 8°, Leipzig, W. Engelmann, 1865. *Lobstein: cit. from Wolff, Die Lehre v. d. Krebskrankheit, Jena, 1907, 99. “Waldeyer: Arch. f. path. Anat. (ete.), Berl., 1867, xli, 470. * Durante: Arch. di Palasciano, 1874, 28, Maggio, cit. by Pianese. *Cohnheim: Die progress. Ernihrungsstérungen, in Vorlesungen iiber allg. Pathol., 8°, Berl., Hirschwald, 1877, vol. i. "Critzmann: Le cancer, 12°, Paris, G. Masson, 1894. * Beard: Berl. klin. Wehnschr., 1903, xl, 695. *Bashford: Scientific Reports of the Imper. Cancer Research Fund, Lond., 1905, N. ii, Part II, 69. ” Ribbert: Beitriige z. Entstehung d. Geschwiilste, Bonn, 1906, 1907. “Borrmann: Ergebn. d. allg. Path. u. path. Anat. (ete.), Wiesbaden, 1900-01, vii, 833. “Mayer: Ergebn. d. allg. Path. u. path. Anat. (ete.), Wiesbaden, 1903, ix, 518. “Tubarsch: Die Metaplasiefrage u. ihre Bedeutung fiir die Ge- schwustlehre, in Arbeit. a. d. path. anat. Abteil. d. hyg. Inst. Posen, Wiesbaden, J. Bergmann, 1901, 205. “Loeb: J. of Med. Research, Bost., 1901, vi, 44. * Adami: Brit. M. J., Lond., 1901, i, 621. * Oertel: N. York M. J., 1907, Ixxxvi, 14. “ Benecke: Beitr. z. path. Anat. u. Physiol., Jena, 1891, ix, 440. * Pick: Centralbl. f. Gynaek., Leipz., 1903, xxvii, 1033. 86 HARVEY SOCIETY “Marchand: Ztsechr. f. Geburtsh. u. Gynaek., Stuttg., 1895, xxxii, 405. * Fraenkel: Arch. f. Gynaek., Berl., 1903, Ixviii, 438. * Patellani: Centralbl. f. Gynaek., Leipz., 1905, xxix, 388. * Morgan, T. H.: Regeneration, New York, 1901, Maemillan Co. *Weigert: Arch. f. path. Anat. (ete.), Berl., Ixxxviii, 1882, 308. *Roux: Arch. f. path. Anat. (ete.), Berl., 1888, lxiv, 113. * Hertwig, O.: Die Zelle und die Gewebe (ete.), 8°, Jena, G. Fischer, 1893; see Benda: Ergebn. d. allg. Path. u. path. Anat, (ete.), Wiesb., I. Jahrg., ii, 541. * Hansemann: Studien iiber die Specifitiit, den Altruismus und die Anaplasie der Zellen (ete.), 8°, Berlin, A. Hirschwald, 1893. * Farmer, Moore, Walker: Proc. Roy. Soe., Lond., 1903, Ixxii, 104; Brit. M. J., Lond., 1903, ii, 1664. *Hansemann: Brit. M. J., Lond., 1904, i, 218. ~ Klebs: Die allgemeine Pathologie (ete.), 8°, Jena, G. Fischer, 1887- 89, t. 11, 399. ” Waldeyer: Deutsche med. Wehnschr., 1887, xxx, 925. * Recklinghausen: Die Adenomyome des Uterus (ete.), Berlin, Hirsch- wald, 1896. “ Auerbach: Sitz. d. k. pr. Akad. d. Wissensch., 1891, 713. “ Bashford: Scientifie Reports of the Imperial Cancer Research Fund, Lond., 1904, i. 16. “Schleich: Deutsche med. Wehnschr., 1891, xvii, 83. * Meltzer: Jour. A. M. A., Chicago, 1907, xlviii, 655. * Ehrlich: Berl. klin. Wehnsehr., 1905, xlii, 871. * Hertwig, O. and R.: Untersuchungen z. Morphologie u. Physiologie der Zelle, 8°, Jena, G. Fischer; H. V.: Ueber den Befruchtungs und Teilungsvorgang (ete.), 1887. Hertwig, O.: Die Zelle und. die Gewebe (ete.), Jena, G. Fischer, 1893. * Loeb: Am. J. Physiol., Bost., 1901, iv, 452. * Calkins: Arch. f. Protistenk., Jena, 1902, i, 355. “ Shucking: Arch. d. ges. Physiol., Bonn, 1903, xevii, 58. “Lubarseh: Path. Anat. u. Krebsforschung, Wiesbaden, J. Bergmann, 1902. “Berent: Centralbl. f. allg. Path. u. path. Anat., Jena, 1902, xiii, 406. “Wilms: Die Mischgeschwiilste, Leipzig, 1900. Ill. THE BIOLOGICAL AND BIOCHEMICAL STUDY OF TUMORS. *Novinsky: Centralbl. f. d. med. Wissensch. Berl., 1876, xiv, 790. * Wehr: Arch. f. klin. Chir., Berl., 1889, xxxix, 226. *Hanau: Arch. f, klin. Chir., Berl., 1889, xxxix, 678. *Morau: Arch. de Méd. expér. et d’Anat. path., Par., 1894, vi, 677. * Velich: Wien. med. Bl., 1898, xxi, 711, 729. ° Loeb: J. Med. Research, Bost., 1901, vi, 28. "Herzog: J. Med. Research, Bost., 1902, viii, 74. * Jensen: Centralbl. f. Bakteriol. u. Parasitenk., Jena, 1903, xxxiv, 122. * Beebe and Ewing: J. Med. Research, Bost., 1906, xv, 209. Ay CANCER PROBLEMS 87 “ Bashford: Berl. klin. Wehnsehr., 1905, xlii, 1433. “Ehrlich: Arb. a. d. k. Inst. f. exper. Therap. zu Frankf. a/M, Jena, 1905, i, 77. “ Flexner and Jobling: Jour. A. M. A., 1907, xlviii, 420. * Sticker: Ztschr. f. Krebsforsch., Jena, 1904, i, 413; Arch. f. klin. Chir., Berl., 1906, Ixxviii, 773. “ Haaland: Berl. klin. Wehnsehr., 1907, xliv, 713. * Apolant: Arb. a. d. k. Inst. f. exper. Therap. zu Frankf. a/M, Jena, 1906, ui, 48. * Bashford: Berl. klin. Wehnschr., 1907, xliv, 1238. “ Bashford: Proce. Roy. Soe., Lond., 1906, xxviii, 195; Scientific Re- ports of the Imperial Cancer Research Fund, Lond., 1905, No. 2, 52 * Apolant: Miinchen. med. Wehnscehr., 1907, liv, 1720. * Haaland: Ann. de |’Inst. Pasteur, Par., 1905, xix, 165. ” Borrmann: Ztsehr. f. Krebsforsch., Jena, 1904, ii, 1. * Virchow: Die Cellularpathologie, 8°, Berl., A. Hirschfeld, 1858, 405. * Hauser: Arch. f. path. Anat. (etc.), Berl., 1894, exxxviii, 482; Beitr. z. path. Anat. u. Physiol., Jena, 1897, xxii, 587; Centralbl. f. allg. Path. u. path. Anat., Jena, 1898, ix, 221. *Ribbert: Beitr. z. Ensteh. d. Geschwiilste, IJ. Erg. Heft, Bonn, 1907. * Gaylord and Clowes: Johns Hopkins Hosp. Bull., Balt., 1905, xvi, 130; Med. News, Phila., 1905, Ixxxvii, 968. * Ehrlich: Arb. a. d. k. Inst. f. exper. Therap. zu Frankf. a/M, 1906, HH. II, 97. * Clowes and Baeslack: J. Exper. M., N. Y., 1906, viii, 481. * Michaelis: Deutsche med. Wehnschr., 1907, xxxiii, 826, 866; Ztschr. f. Krebsforsch., Jena, 1906, iv, 1. * Schone: Miinchen. med. Wehnschr., 1907, liv, 2517. ” Borrel and Bridré: Bull. de l’Inst. Pasteur, Par., 1907, v, 605. ” Bashford: Scientific Reports of the Imperial Cancer Research Fund., Lond., 1907. *“ Tyzzer: J. Med. Research, Bost., 1907, xvii, 155. “Flexner and Jobling: Proe. Soe. of Exper. Med. and Biol., 1907, iv, 156. * Borrell: Bull. de l’Inst. Pasteur, Par., 1907, v, 600. *“ Gaylord, Clowes, and Baeslack: Med. News, Phila., 1905, Ixxxvi, 91. * Beebe and Crile: Proe. of the Soe. for Exper. Biol. and Med., 1907, iv, 118. * Apolant: Therap. der Gegenwart, Berl. and Wien, 1906, xlvii, 145. ae te Maas: Arch. f. path. Anat. (ete.), Berl., 1877, Ixx, “Beebe: Am. J. Physiol., Bost., 1904, xii, 167. *” Clowes: Am. J. Physiol., Bost., 1905, xiv, 173. “Wolff: Ztschr. f. Krebsforsch., Jena, 1905, iii, 95. i aur and Dorpinghaus: Deutsche med. Wehnschr., 1905, xxxi, 26. “Petry: Beitr. z. chem. Physiol. u. Path., Brnschwg., 1902, ii, 94. 88 HARVEY SOCIETY “ Neuberg: Arb. a. ad. path. Inst. zu Berlin, Feier Johannes Orth, Berl., 1906, 593. “Beebe: Am. J. Physiol., Bost., 1905, xiii, 341. “Beebe and Ewing: Brit. M. J., Lond., 1906, ii, 1559. “Buxton: J. Med. Research, Bost., 1903, ix, 356. “ Buxton and Shaffer: J. Med. Research, Bost., 1905, xiii, 543. “Harden and McFadyen: Lancet, Lond., 1903, ii, 224. “ Weil: J. Med. Research, Bost., 1907, xvii, 287. “Petry: Ztschr. f. physiol. Chem. Strassb., 1899, xxvii, 398; Beitr. z. chem. Physiol. u. Path., Brnschwg., 1902, ii, 95. “ Blumenthal and Wolff: Med. Klin., Berl., 1905, i, 364; Ergebn. d. exper. Path. u. Therap., 1907, i, 65. “ Neuberg: Berl. klin. Wehnschr., 1905, xlii, 1189. “ Beebe: Communicated. “'V. Dungern and Werner: Das Wesen der bésart. Geschwiilste, Leip- zig, 1907. * Fischer: Miinchen. med. Wehnschr., 1906, liii, 2042, “ Helmholz: Johns Hopkins Hosp. Bull., Balt., 1907, xviii, 365. THE BEARING OF METABOLISM STUDIES ON CLINICAL MEDICINE * DAVID L. EDSALL, M.D., Assistant Professor of Medicine, University of Pennsylvania, Philadelphia. N a pursuit like the practice of medicine, in which we have two kinds of possible activities, one essentially very close to pure science, the other engrossing practical work, those en- gaged in the two fields are likely to draw somewhat apart. There is a strong tendency for many of those occupied with ‘scientific matters to keep their minds so closely fixed on the abstract problems they are endeavoring to solve that they forget to reconnoitre as they go along, and to attempt to determine— and they often forget particularly to point out—what practical bearings they may discover by the way. A certain number of such workers, indeed, frown very readily on frequent excur- sions into the practical application of science, as being some- what cheap and likely to mix science and empiricism. They forget that in practical medicine we make such a mixture con- stantly, and must do so. Our efforts must be to avoid hasty and unreasonable application of science, but to apply whatever we reasonably can, provided we thereby do no harm, even though it be not completely demonstrated that our reasons for the practical measures are absolutely sound, for it is but rarely that absolutely final proof can be given. The clinician, on the other hand, finds it exceedingly difficult to keep up a serious acquaintance with scientific medicine. Consequently, he often feels unable to get for himself the practical bearings of scientific work that is of a kind outside of his own immediate interests, and, hence, tends to neglect these bearings more or less entirely ; or sometimes he goes to the other extreme and draws those * Lecture delivered November 30, 1907. ; 89 90 HARVEY SOCIETY unjustifiably broad practical conclusions from scientifie work that especially offend his more scientifie brother. So far as there is any fault in this, it must be divided. It is, indeed, scarcely the fault of either, so much as of the present- day demands on both. Nevertheless it is not unfair to ask, with Oliver Wendell Holmes, that the medical scientist shall serve his knowledge ‘‘with special limitations and constant ref- erence to practical ends’’; but at the same time to demand that those of us who are clinicians remember that not only must scientific knowledge accumulate, but its principles even more than its details need to be comprehended, if practical medicine is to be benefited by it. In one of the wisest and most charming of recent medical books (‘‘Principia Therapeutica’’) Dr. Har- rington Sainsbury says: ‘‘There are many who make light of general principles, knowledge of detail their sole demand; but this point of view sees one side only of the shield, be it silver or gold, as it shall please them; for while, doubtless, general principles without detail make but a foolish business, it is no less true that details without guiding principles yield but a busy foolishness.’’ My warm sanction of this remark and my feeling that both clinicians and medieal scientists often make too indifferent a search for the practical guiding principles that may be derived from exact investigations were, indeed, the things that determined me to treat my subject in a general way rather than by going into a detailed discussion of specific facts of the subject. Studies of metabolism, in the broader sense of this term, are, I think, a more fruitful source of clinical prin- ciples than is any other form of investigation, unless it be that relating to hygiene. The most direct reason for this is that they are carried out on living beings and deal with living pro- cesses while the latter are still in action. A more prosaic but still not inconsiderable further reason is that a large part of the conclusions are derived from actual figures, often, indeed, by balancing one column of figures against another. Figures are very convincing and clarifying to the human mind, and give much less opportunity to indulge any unconscious personal bias than does clinical observation, or even morphologic or most BEARING OF METABOLISM STUDIES 91 other accurate studies into which figures do not enter, and it is in ridding him of bias that investigation is most useful to the clinician. SCIENTIFIC AND LITERARY STYLE. In his essay on ‘‘Style’’ Walter Pater describes the scientific style as presenting facts painstakingly as such, unembellished by imagination, while the literary style, ‘‘as it more closely approaches fine art,’’ becomes more and more the presentation of facts, not simply as such and as accurate truths, but in the form of truths as they appear to the writer—‘‘soul facts,’’ as he calls them. Considering that he is working for the art of medicine as well as the science, I think the medical scientist often presents his facts too little embellished, but, on the other hand, being a clinician, I may say without impertinence that, surrounded as he is by impressive human happenings and a complexity of the details of disease, the clinician’s tendency— a tendency that it is always his earnest desire to avoid—is fre- quently to make for himself ‘‘soul facts’’ that do not bear con- trast with the real thing, if the latter can be found. Nothing, to my mind, succeeds better than a few figures in determining whether our conceptions are scientific or ‘‘fine art.’’ These figures sometimes destroy idols and may leave nothing in place of them, but this is, at least, more satisfying than error. They often simply confirm vague beliefs or traditions that were based previously merely on observation, but this gives confidence in place of uncertainty. Frequently they yield new jae that could have been learned in no other manner. Among the many ways in which metabolism studies have already influenced clinical medicine and will continue to do so, I have been particularly impressed with some of those that often escape notice, chiefly, I imagine, because they are so simple and elementary that serious students of the question scarcely think any more of many of them. Among the most prominent of these, to my mind, is the effect that such studies have quietly exerted on the clinical use of changes in excretion in reaching diagnostic and therapeutic conclusions. In this point more 92 HARVEY SOCIETY than in any other, perhaps, there has been the tendency among clinicians to use details irrespective of the principles that gov- ern these details. Some of the simplest principles of metabo- lism have often been overlooked, and, as a consequence, false diagnostic premises have often been built up. A correct appre- ciation of our knowledge of metabolism has served chiefly an iconoclastic end in this connection, but it is none the less ser- viceable; for no thinking person can doubt that to destroy a false belief is quite as useful as to demonstrate a new truth. RELATION OF EXCRETION TO INGESTION. The older literature was burdened with discussions of the value of things so inevitably unreliable as the determination of the percentage of urea, of uric acid, of various other excre- tory products, and of sugar, in a specimen of urine, without any consideration of the relation of this specimen to the total amount passed in the day. Such measures are, indeed, still carried out to some extent, as indications of the excretory capacity of the kidneys, of the kind and extent of any metabolic disorder that may be suspected, or as an indication of the severity of a glycosuria. It does not take a lively imagination to realize that variations must occur in accordance with the period of the day at which the specimen has been secured, but it has been necessary to accumulate demonstrative evidence of this to convince many minds; and some persons even yet remain so unfamiliar with the basic facts of excretion that they still fail to comprehend so simple a principle, and do not realize that first of all the mixed urine of a twenty-four hour period must be studied if one is to have the slightest idea even of the real amount of any substance that is being excreted. So simple a fact as this is readily understood and ecompara- tively little neglected now by careful clinicians; but, though it would seem to be equally true without demonstration, it takes much more emphatic evidence to convince most persons that the excretion of any substance varies with the amount taken in of the substance itself, or of the foods that yield it. It is fruit- less to attempt to reach any accurate conclusions on the basis BEARING OF METABOLISM STUDIES 93 of studies of excretion unless one knows the amount taken in of those substances that influence this excretion. There is a general comprehension of the fact that a glycosuria is largely influenced by the diet; the relation is, indeed, so direct that it is traditional lay knowledge. But this knowledge is even yet too infrequently considered in judging of the severity of a glycosuria, and it has taken a long time to convince many who have little interest in metabolism that estimations of urea mean nothing unless accurately contrasted with the amount being taken of urea-yielding foods. If those who in their studies of renal cases have made urea estimations—and especially our colleagues, the obstetricians, who have devoted much discussion to this method of diagnosis—had had the opportunity to see the nitrogen excretion in a normal person vary from a few erammes to thirty or more, in accordance with mere changes in diet, the time that they have lost over this point would have been saved. Accurate metabolism studies carried out chiefly by von Noorden and his students have, indeed, shown us how impossible it is, even in marked nephritis, to reach any certain diagnostic or prognostic conclusions from the most careful at- tempts to demonstrate retention, for retention is by no means the rule even in very bad cases, and it ordinarily varies with excessive excretion; and where retention occurs it may be due to poor excretion or to actual building up of tissue, the latter, of course, being usually a good omen rather than a bad one. A number of other factors, such as the absorption and excretion of cedema fluid, also influence results so largely that clinical deductions are usually unwarranted from such studies. THE VALUE OF CRYOSCOPY. This same point of view that I have just been discussing might have saved medical and surgical clinicians much useless labor in more recent years in other studies of the functional capacity of the kidneys. A very large part, for instance, of the work that has been done regarding the excretion of sodium chloride in renal disease has been carried out without any consideration of the diet, and all that work is, therefore, nearly O4 HARVEY SOCIETY or quite worthless. In most of the work on eryoscopy also the diet has been neglected, and the results are, therefore, especially in eryoscopy of the urine, almost entirely valueless. Indeed, because things are excreted in different form from that in which they were ingested, we have no way of telling accurately what effect changes in diet would have on eryoscopy of the blood even, and especially on eryoscopy of the urine, except that we can test the influence of an absolutely exact standard diet in numerous different individuals, and ean take an average of this and call it a normal. While the results would perhaps be reasonably accurate in normal persons, changes in metabolism as well as in excretion would largely affect the result, and we have no means in any cases under observation of telling whether the abnormalities are the consequence of metabolic or of exere- tory conditions. Therefore, a method that is in itself so exact as to fascinate the mind becomes clinically of little value in studying disorders of excretion, except in contrasting the con- centration of the urine as secured separately from the two kid- neys. Neglect of this view of the question has, it appears to me, led to a great deal of time being wasted in attempts to use this method for the elucidation of questions that it could not clear up. Similar remarks apply to various similar studies and con- elusions. Theories, and even descriptions of distinct diseases, have, for example, been built up on the mere presence of pre- cipitates of oxalates and phosphates in the urine. There are some interesting questions, as yet not solved, regarding the relation of oxalates to digestive disturbance; and, to my mind, there is a much broader and more interesting relation than is usually admitted now-a-days between so-called oxaluria and metabolic disturbance. I have seen some exceedingly curious examples of a close relationship between oxalate precipitates and clinical symptoms ; such, for instance, as a mania of a few days’ duration in the convalescence from an acute pneumonia, the urine containing oxalate erystals during the period of mental disturbance, but not before or after. The oxalate precipitates, T take it, are BEARING OF METABOLISM STUDIES 95 merely an index that something else is going wrong; they are, of course, almost certainly not the evidence of oxalic-acid poisoning, and usually not evidence that the amount of oxalic acid in the urine is increased. As to the phosphates, theorists have even gone so far as to describe distinct nervous disorders due to a loss of phosphates from the system, basing this almost solely on the presence of precipitates of phosphates in the urine. Real studies of metabo- lism have, of course, in most such cases, shown that there is no excess in the urine; that the phosphates precipitate because of conditions unfavorable to their solution, or if the amount happens to be large it is ordinarily because an excess has been taken in the diet. There are unquestionably peculiar and in- teresting problems to be worked out in connection with some of these cases of phosphate precipitates. In some instances they present almost a definite syndrome, particularly certain eases in which I have been much interested in which the urine periodically becomes alkaline, phosphates precipitate out, and this is soon followed by a migrainous headache, and subse- quently by symptoms appearing to indicate that the individual is eliminating toxic material through vomiting, diarrhea, or diuresis. The attack is then over. In some eases with phos- phate precipitates I have found the rather curious condition of an excessive excretion of ammonia, without any apparent reason _for it. Ordinarily excess in ammonia excretion means, of course, the presence of an undue amount of acid in the system, and the excess of ammonia is present in the urine simply be- cause it has been used to neutralize the acids, but in these cases there is no evidence of acidosis. The conditions, indeed, are so far from it that the urine is alkaline when passed. What such conditions mean I do not know. A similar instance of a hasty conclusion that was soon set right by real investigations of metabolism is the claim made a few years ago by some of the French school that pulmonary tuberculosis is associated with and more or less dependent on a ‘‘demineralization”’’ of the tissues; that there is a regular loss of mineral salts from the tissues. This statement was soon 96 HARVEY SOCIETY corrected by accurate metabolism studies by Ott and others, and it need never have been made had a proper contrast betweer intake and outgo been worked out in the beginning. THE ‘‘URIC ACID DIATHESIS.”’ In no relation in the whole range of medicine has this point of view been so thoroughly obscured and so often lost sight of as in all the labor that has been expended on the building of idols of uric acid and in breaking these same idols afterward. A very large part of this labor might have been saved could both clinicians and physiologists have started with the same conception that we have long had regarding other excretory products, that is, that the excretion is largely influenced by the amount of uric-acid-yielding foods taken. Whatever direct relation to the causation of disease uric acid may ultimately be shown to have,—and this, I think, will probably be slight,—we have, at least, learned that mere studies of its excretion are of little, if any, clinical value; first of all, because the amount excreted is, in large part, directly de- pendent on the kind of food taken, and, worse than this for the clinician, because a certain amount is formed in the organism, and not only directly from tissue breakdown, but also, almost certainly, synthetically. We do not know how much this is nor- mally, and cannot tell at all, therefore, how much it may be in disease. To add to the complexity of the question, we have learned that some of that derived from the food, and some that is formed in the organism, is altered to other substances in its travels through the body, but we do not yet know how much, and we know almost nothing about the way in which some of these variable factors are influenced by most diseases. We cannot, therefore, by the most exact methods of studying excretion tell more about uric acid or the total purin metabolism than that the amount of the various purins in the urine is larger or smaller than it should be on the diet then being used; and that this may be due to abnormalities of excretion or to disor- ders of oxidation, synthesis, or other metabolic processes. We- BEARING OF METABOLISM STUDIES 97 have no accurate scientific conception as to which is at fault in any particular instance. When I was graduated in medicine, stress was still often laid on uric-acid precipitates as indicative of disease depending on uric acid. Yet it was apparent, even long before this time, that such precipitates mean of themselves nothing regarding the amount of uric acid in the urine, but are due to the effects of low temperature or chemical changes in the other components of the urine that affect the solubility of the uric acid. Traces of such elementary error in teaching, however, still remain in some medical writings that carry authority. When we learned laboriously the striking influence of diet on uric-acid excretion, the door appeared to be open .to some definite knowledge; but the relative effects of abnormalities of synthesis, oxidation, and excretion cannot yet be reckoned with at all. So far as I can see, of all the clinical uric-acid idols, at least of all those relating to the excretion of uric acid, but one remains—the recently determined fact that gouty persons ex- erete but a small amount of endogenous uric acid, and they excrete the uric acid derived from the food slowly or imper- fectly, if one makes careful quantitative studies of the excretion over a period of many days. This idol, too, I strongly suspect, will in large part fall. The diagnostic, and to some extent at least the therapeutic, conclusions built on it will, in that case, fall with it. I have already observed cases other than gout in which the same thing occurs strikingly, and other persons have done the same. Probably this will prove to be frequently true, and the abnormality will be shown to be the result of so many eauses that it can have no important significance in relation to gout from the diagnostic standpoint. Yet, though the status of the studies of the excretion of uric acid is what I have indi- eated, I am still frequently met with the request, from some of my most respected clinical associates, to point out to them how they can get help in their diagnoses by making studies of the amount of uric acid in the urine. It may be that better results will be obtained from studies of the exact amount in the blood, a method that has recently been systematically used for diag- 7 98 HARVEY SOCIETY nostic purposes, but the value of such studies is not yet clear, for many of the above-mentioned objections apply to it also and it is too difficult for ordinary clinical purposes. Such are examples of ‘‘soul facts’’ that have been demon- strated to be such through metabolism studies, and as a conse- quence of our better knowledge, the false diagnostic and thera- peutic conclusions built on them have more or less completely disappeared. The influence of metabolism studies, however, has been by no means solely iconoclastic. Probably in no line of medical work have the methods followed been more purely empirical until recent years than those used in dietetics, and yet in searcely another line of work has so much labor been expended in the last generation in accumulating facts. These facts are, however, only beginning to be widely appreciated. Dietetics is much less a matter of mere experience and personal opinion than it was. All humanity finds it much more difficult to make use of new knowledge and laws relating to the things that we have grown up with than in connection with matters that are themselves new and strange, and food is so old a story that it is difficult to teach ourselves to examine into its use in medical practice in much the same way that we study the use of other therapeutic measures. DIETETICS. In dietetics we remain much more prone than in most other medical practices to work with details, regardless of principles, instead of using whatever principles we have in leading us to correct details. Indeed, it appears to me that a writer to whose wisdom I have already emphatically referred comes very close himself to recommending in dietetics the ‘‘busy foolish- ness’’ that he so scorns in drug therapy, when he practically advises us not to bother our heads about the discussion of food standards, but to attend to the details that suit the individual. We must always arrange our diet for individuals and not for a mere average human being. But in dealing with serious conditions by using drugs we are dependent, first, on knowl- edge of what the action of a drug really is, and, in the second BEARING OF METABOLISM STUDIES 99 place, on knowledge of the dose that is usually effectual and safe. If we would be accurate in regard to the much more vital question of foods,—and particularly if we would be accu- rate in dangerous cases, in which we ourselves are largely responsible for the amount and character of the diet and in which, if any grave errors occur, we alone are at fault,—we must know, first of all, what the actual nutrient powers of the food we use are, and how much of it an average individual ought to have, if he is to be neither starved nor overburdened. It is quite true that the physiologist asks a little too much of us when he presents the matter to us, as he often does, in such a form that it would appear that to arrange a diet with reasonable accuracy is almost the same as to conduct a laborious physio- logic experiment, and both the physiologist and the clinician discuss these standards too much as if they were absolute things, that are meant to be followed literally, instead of being simple guides; and yet at the same time that he demands abso- lute rules the clinician sees the impossibility of constant stand- ards, for he knows that we deal with complexities of disease and temperament that make absolute accuracy a thing that even the physiologist cannot reach with his most exact methods, and that with patients who are not seriously ill it is utterly impos- sible in ordinary practice to be more than approximately accu- rate in attempting to make dietary regulations approach stand- ards. Hence he often objects that these standards are worth- less and makes no attempt to use them. But the clinician might remember that he does not demand absolute standards in other things, as, for instance, in the use of drugs. He makes allow- ance for temperament and for peculiarities of disease in such things, but in this present day he would be looked on as a dan- gerous character if he had not learned what the pharmacologist has taught us as to the effect of drugs and the amount that may wisely be used with the average individual. If it were a general custom to look at foods, first of all, from the same point of view as drugs are looked at,—from a consideration of the kind and amount of their food value, on the one hand, and of the food demand of the average individual 100 HARVEY SOCIETY of a given size, on the other,—we should less frequently see persons fed on a diet that may be big in bulk, to be sure, and that may look impressive on the records, but that is composed of material of so little food value that the whole amount evi- dently means a considerable degree of starvation when its ealoric value is contrasted with the real demand. We should then less frequently see disease made more grave and convales- cence more prolonged through the use of such a diet, and we should have been quicker to recognize, for example, that pro- found exhaustion, fever, delirium, and other symptoms in the later stages of acute disease and in the convaleseence—particu- larly in typhoid fever—are the result of too limited a diet quite as frequently as they are due to continued toxemia, a fact that is particularly true in dealing with children. On the other hand, we should see less enthusiasm over many of the so- ealled ‘‘free diets’’ used in typhoid fever during recent years, if we were accustomed to looking at a diet list in such a way that it becomes apparent that many of these free diets are, to be sure, more solid, but at the same time less nutritious, than is a reasonably generous milk diet. Such methods can easily be used in severe disease, for, with a patient at rest, his food demand is apparent, and the diet is simple and its value easily determined. A little practice gets one into the habit of thinking¢in this way. When diets are more complex, we must trust chiefly to judgment, to the patient’s appetite, and to observation of the effects, rather than to figures, in regulating the amount of food, but even here we can avoid such gross errors as burdening a delicate child with an amount of food that possesses two and a half times the amount of calories that an adult would need and wondering why his health does not improve—an example of what I have seen done. If, too, we followed some of the details of clinical studies of metabolism and absorption we should know, for instance, that over-generous feeding in conditions like pulmonary tuber- culosis is not only evidently likely to tax digestion, metabolism, and exeretion; it has also been shown often to result merely in burdening the digestive tract and in expulsion of much of the BEARING OF METABOLISM STUDIES 101 food, especially much of the fat, in the feeces; so that the end- result is merely to overwork digestion and to waste food. I can state without fear of contradiction that the number of clinicians that habitually use the available knowledge of dietary standards, food values, digestion, and absorption of foods, the behavior of foods in the course of metabolism, and the chief excretory products of food in helping them to plan their diets, is extremely small as compared with the number that employ whatever accurate knowledge we have in connection with the much less serious question of the use of drugs. I believe that quite as many patients are damaged by faulty use of foods as by faulty orders concerning drugs. Our knowledge of these various questions concerning dietetics is very imperfect in many particulars, but it is no more imperfect than is our knowledge of drugs and many other therapeutic measures. SPECIFIC DIETS. There are, it appears to me, two striking errors besides in- exactness in the general view of dietetics—errors that our knowledge of metabolism can largely set straight at once. One is that often vague, but nevertheless common, feeling that the details of a diet should be specifically suited to the disease in which it is to be used. We have got well past the point where we thought drugs to be frequently specific in their action. We should make the same confession in regard to diet, and we should: get farther. We know almost nothing about any ac- tually specific alterations of general nutrition that may occur in specific disease, and we know comparatively little of the specific effects of different foodstuffs on normal nutrition. To attempt to arrange actually specific diets is, therefore, in most diseases impossible and it is questionable whether we shall ever get to the point at which we can do this. Just as in the general treatment of particular diseases our measures are almost always directed not against the disease as such, but against certain conditions that occur in that disease (these conditions, however, usually occurring in many other diseases, in different combinations) so, in diet, do we study and treat, 102 HARVEY SOCIETY not diseases, but conditions, such as overnutrition, undernutri- tion, irritability and sluggishness of the digestive tract, exalted and sluggish metabolism, and difficulties in exeretion. Dietary studies have taught us how to meet with considerable exactness general excessive or reduced nutrition, in most instances; and also how to prevent such conditions. Such studies have also given us much knowledge of the suitability of most foods in controlling or preventing the general types of digestive disturb- ance that I have mentioned, and they have taught us an appreci- able amount concerning the reduction of the labors of metabo- lism and excretion through proper choice of foods. We have much yet to learn, but we do not make use of what we have learned. If we can start from the stand-point of learning the general type of the condition that we are dieting, and can then apply the general principles of our knowledge of metabolism and of foods to this, the question of details will afterward be- come comparatively easy and will be simply dependent on the gradual elaboration of one’s skill in details. The next most impressive dietetic error, it seems to me, is to restrict narrowly or largely exclude most or all the members of a class of foods, because there seems to be an especial diffi- culty with this class. We commonly encounter the order, for instance, to ‘‘stop using starchy foods’’; and often, as a result, carbohydrate foods are more or less completely excluded from the diet. Unquestionably we have been clearly taught that a considerable amount of protein is essential, and in recent years we have equally well learned that an even larger amount of carbohydrate is almost as necessary for the proper perform- ance of the chemistry of the body processes and especially in avoiding acid intoxication. A reasonable amount of fat is also at least extremely desirable, because of its great food value. These facts sufficiently indicate that our efforts should not be directed toward the exclusion of the whole of a peceant class of foods, in case some of the class disagree. We should, on the contrary, develop sufficient knowledge of food composition and food preparation to be able to choose from the troublesome class varieties that will themselves agree. This we can usually do. BEARING OF METABOLISM STUDIES 103 It should be our chief effort to keep the amount of each class approximately near the normal, except when temporary com- plete rest from some one class appears to be needed, as occa- sionally happens. If wide variations from the normal are very harmful, it is probably true that even moderate variations from the normal are at least disadvantageous, especially if per- sisted in. Such are some of the main principles that we can derive from dietary studies, but there are many other points that could be discussed. For instance, simple intake and outgo ex- periments have shown that it is exceedingly difficult to make a normal person gain in protein tissue by feeding, but they have demonstrated how greedily the convalescent retains pro- tein. He is in much the same state as is the growing child in this regard. A proper appreciation of such a point as this makes one realize much more clearly that by taking advantage of this tendency and wisely pushing matters in convalescence we can not infrequently transform a disease from a curse into a blessing by keeping metabolism on the run, so to speak, thus making tissue growth go farther than the previous amount, and changing a person previously ill nourished into one whose nutrition is comparatively good. The same principle holds with the infant. Not only does the infant or child retain large amounts of protein; this very fact, as well as simple reflection, indicates that large amounts are needed at this period of life, and I firmly believe that in recent years the minds of pediatrists have been so fixed on the digestive tract and on the dangers of high protein feeding that general nutritional demands have been half forgotten and many infants have been injured by giving them too little protein. There are numerous other ways in which a knowledge of metabolism; even though it cannot be so directly translated into action, is nevertheless indirectly influential in determining a broad and comprehensive action instead of a narrow and mistaken one. One of the simplest instances of this, for ex- ample, is diabetes. We are much better off clinically to know that there is no evidence, except in the late and grave stages, 104 HARVEY SOCIETY of a toxic tissue destruction in diabetes; that treatment directed to the elimination of a toxemia would be superfluous, and that the anomaly, whatever its actual nature may be, appears in ordinary instances to produce a tissue loss simply because there is a food loss due to the glycosuria, and the glycosuria largely explains all the other typical symptoms, even the acidosis and the coma that may occur. This makes much more clear the entire dependence of successful treatment on diet. The severity of the disturbance in various diseases has often been made clearer by balancing figures against each other. One of the most striking instances of this that I have ever seen is a case of simple purpura that I have recently studied, one of the type that affords no clinical evidence of constitutional disturbance and hence is said to have no constitutional symp- toms. This patient, when studied metabolically, showed a high grade of tissue loss with each outbreak of purpura, demon- strating clearly that he had severe metabolie disturbance and that some metabolic disorder produced his attacks; for the amount of hemorrhage was not sufficient to have been of itself responsible for the disturbance of metabolism. The effect of different forms of treatment can frequently be made much more apparent by studies of this sort. For in- stance, I have recently investigated a case of direct transfusion by Crile’s method, in which the clinical results and the effect on the blood indicated solely improvement in the patient’s general condition and his blood count. A metabolism study, however, showed very striking tissue destruction, with some features that indicated that it was almost certainly not due merely to a breaking down of the transfused blood, thus show- ing that the effects of this operation may at times, in diseased persons at least, be much more extensive than merely to pro- vide more blood for the patient, and it would seem that these effects may occasionally be very dangerous, for when a second transfusion was done in the same patient death speedily fol- lowed. Similarly, I have acquired a much more serious respect for the effects of the X-ray from having observed the remark- able influence that it can exert on metabolism, and having seen BEARING OF METABOLISM STUDIES 105 how easy it may be for the X-ray to cause tremendously good or dangerously bad results in ways that are not readily made apparent through ordinary clinical observation or through other methods of study. . The results of simple intake and outgo estimations often, too, make more apparent the nature of conditions, and especially whether there are or are not evidences of toxic tissue destruc- tion, and, therefore, whether we can wisely use eliminative meas- ures, or whether these would probably be positively harmful because not indicated. These are instances of the numerous ways in which metabolism studies of the simplest form—namely, balancing intake against outgo—have influenced our clinical conceptions of disease and of the manner in which various kinds of disease should be managed. There is, however, a vastly broader aspect of metabolism investigations. Beyond all other things it has always been apparent, and in recent years more and more evident, that in order to gain an intimate acquaintance with metabolic processes in normal or diseased persons we must not limit our studies to a comparison of the intake and outgo, and to a determination of the grosser changes in the excretions, the body fluids and the tissues, but must acquire a closer knowledge of the intermediate changes that occur in the course of digestion and in the synthesis and breaking down of tissue, and must learn the kinds of things that favor or interfere with these processes. Many tentative efforts were made to do this, but the tangible knowledge that they provided was slight, because the work was done somewhat blindly, until within the past few years, when two remarkable changes have occurred in our point of view and have opened the threshold to a new era in studies of metabolism. TISSUE FERMENTS. One of these is the conception we now have of the activity of ferments in tissue processes, a conception originally due to Salkowski’s initiative; the other, the conception that we now have regarding the constitution of the protein complex, the meaning of the changes in protein that occur in digestion and 106 HARVEY SOCIETY metabolism, and their bearing on the breakdown and synthesis of tissues—a conception that was in the beginning due largely to the work of Kossel and his school, and in more recent years has been elaborated to a marvellous degree by the work of Emil Fischer and numerous others that have worked with him. It is a striking facet that in the last-issued edition of Neu- meister’s ‘‘Physiologische Chemie’’ its then prominent author should have felt justified in stating that the observations of Salkowski and others concerning the presence of ferments in the tissues meant merely that these ferments were absorbed from the digestive tract in zymogen form, not that their production had any relation to the essential activities of the tissue cells, and that this statement should have been followed very soon after by the address of Hofmeister in which he predicted that it would be shown that most tissue processes, synthetic or cata- bolic, are largely dependent on the activities of ferments pro- duced in the tissues. A few years ago we looked on ferment processes as confined to the digestive tract. Now the very name ‘‘digestive tract’’ so far as it applies distinctively to the kind of processes that go on in the stomach and intestines, has be- come almost a misnomer, for it has been made apparent that the same general kind of processes go on in the tissues every- where, products similar to those produced in the alimentary tract being formed by ferments similar to the so-called diges- tive ferments. The distinction between digestive and tissue processes, even synthetic tissue processes, has grown still more indefinite since we have learned the influence of ferments on synthetic processes, and especially since it has been actually demonstrated through the work of Croft Hill, Kastle and Loewenhardt, and Alonzo Taylor, that individual carbohydrate, fat, and protein ferments do really have the function of build- ing up, as well as of breaking down—that the same ferment does either of these two apparently opposite things, the result being dependent on the conditions in which it acts, and not on the nature of the ferment itself. The profound emphasis thus laid on the importance of the study of the conditions in which ferments act, directs atten- _ BEARING OF METABOLISM STUDIES 107 tion particularly to the exaggerated optimism that has some- what generally, among clinicians, been centred on securing and using therapeutically ferments that are active in tissue pro- cesses. Even scientific workers have held forth alluring pros- pects in this connection. As a matter of fact, we cannot manu- facture substances that are so dependent on life processes for their existence as are tissue ferments—that often, indeed, are probably dependent on the unchanged structure of living proto- plasm. We cannot be sure that we shall ever be able to sepa- rate most of them in satisfactory form; and when we get them, as we do now, they are usually damaged and made more or less ineffective, often destroyed, by the processes through which they are put; and even if we secure them in satisfactory condition we have not yet obtained the slightest reliable evidence that we can, to any noteworthy degree, influence tissue processes by their therapeutic use. We even have no satisfactory evidence that their use influences digestive processes in the alimentary tract to any noteworthy degree. We have, therefore, it appears to me, excellent reasons for being very guarded about basing any serious hopes on the use of ferments themselves, in attempt- ing to influence the processes in which they are normally active. On the other hand, what a wealth of reasonable suggestions for interesting future work is given by the fact that it is not the ferment itself, but the medium in which it acts, that deter- mines so profoundly important a result as to whether the effect is to be construction or destruction; and what alluring possi- bilities in the distant future are offered by this as to the pos- sible control of nutritive processes and of disease. It is highly probable that it is merely a change in medium that causes previously existing ferments, which have been inactive, to be- come suddenly active after a pneumoniec crisis, and to digest the exudate with astonishing rapidity. The same thing is probably true regarding the involution of the uterus that be- gins with the beginning of the puerperal state. Indeed, it appears to me not improbable (though entirely unproved) that in this instance the change occurs directly from constructive action to destructive, for the growth of the uterus in pregnancy 108_ HARVEY SOCIETY is a growth, not so much, if at all, in the number of the cells, but merely in the amount of tissue in the cells. It is quite possible that in pregnancy there is a ferment-constructive process, and that in the puerperium destructive work is done by the same ferment or ferments. Such things are at the present time matters largely of specu- lation. I speak of them only in that sense and mention them merely as illustrations of what such studies may ultimately lead us to in regard to our powers of controlling normal nutritive processes and disease. We already know great numbers of things that influence ferment processes, and it is not improbable that we even now have in our armamentarium things that have much greater powers in this regard than we at all appreciate, and that we may gradually learn to make proper use of these powers, if we proceed from the correct point of view, and not merely from blind empiricism. One way in which it appears to me to be probable, though as yet undemonstrated, that we actually do control, to some extent, the medium in which the ferment action takes place, is in the management of some of those eases in which acid intoxi- cation occurs. The acidosis of diabetes appears to be largely dependent on the diet and on the inability of the organism to make use of carbohydrates, and it is possible that it is entirely dependent on these things, but there are numerous instances in which diet seems to be a factor of very little, if any, consequence in producing the acid intoxication that occurs as a part of the disorder—ceases such as phosphorus poisoning and acute yellow atrophy, uremia, the recurrent vomiting of childhood, post- anesthesia acidosis, grave anemias, and probably the per- nicious vomiting of pregnancy. A number of these disorders seem, from accumulating knowledge, to be associated with tissue lesions and with alterations in metabolism that indicate that there is an abnormal activity of the proteolytic tissue fer- ments, particularly in the liver, and that this autolysis probably produces the acid intoxication secondarily. The acid intoxi- eation in all probability then, in its turn, increases the autol- ysis, for Hedin and Rowland, and others, have shown that a BEARING OF METABOLISM STUDIES 109 slight acidity favors autolysis. Thus it is probable that a vicious circle is formed, and the effects increase from their own momentum. This conception is practically an application of the knowledge regarding autocatalysis to pathology. Clinically, in some of these cases, direct treatment of the acid intoxication with alkalies does good, but their action is most uncertain and unreliable. In bringing forward the evidence that acid intoxi- cation is seen in the recurrent vomiting of children, I reported cases in which alkalies unquestionably did great good, and I have observed some such eases since; but the result is highly uncertain and cannot be anticipated. It appears to me some- what probable that what we actually do in some of these cases by means of alkalies is to control whatever evil effects there may be as a direct result of the acid intoxication and, what is much more important than this, to provide a less favorable medium for the autolytic ferments to act in. If this is true, it is probable that the results are uncertain largely because the destructive changes that have already resulted from autolysis are so variable in their degree. If they have not been severe, the symptoms, no matter how severe they may be, will be con- trolled by stopping the progress of the ferment action; but if severe lesions have already occurred, no matter how mild the symptoms may be, control of the primary condition will not control its already grave destructive effects. I have suggested another direction, also, in which it is pos- sible that our study of the means of accelerating or retarding ferment action may have interesting clinical bearings. I have expressed the view that the X-ray exerts its action on the deeper-lying tissues, in part, at least, through influencing ferment action. This is by no means definitely proved, but there is some creditable evidence in favor of it. Starting with this conception, I have studied the effects of the X-ray in a condition in which our knowledge indicates that the desirable but hitherto often unattainable therapeutic measure is to accele- rate or excite ferment action ; namely, in unresolved pneumonia. Unquestionably the X-ray has had a very remarkable effect on metabolism in cases of this kind that Dr. Pemberton and I have 110 HARVEY SOCIETY studied, and there has apparently been a very strikingly good effect clinically on the consolidation in the cases that I have so far observed. My conclusions may be wrong in these in- stances, but I think that these are examples of the interest and the possible profit pertaining to systematic attempts to work out practical methods of influencing tissue ferments. Similar studies will not improbably help us to understand the manner of action of things that we have already used with- out comprehending the way in which they accomplish their unquestionable effects. Unpublished observations that Dr. Cas- par Miller and I have made indicate that the remarkable effects of mercury in acute poisoning, and probably in syphilis, are, partly at any rate, due to its causing increased autolysis, a suggestion that Dr. Flexner made publicly while we were work- ing on this matter. Also some studies that I have not as yet completed, suggest that one way in which sunlight produces its pronounced effects on nutrition is through its influence on the same kinds of processes. STUDY OF PROTEIN-COMPLEX. Closely interlaced with the investigation of the tissue fer- ments is the study of the protein-complex and the products that it yields on digestion. Biological observations have made it apparent that there are differences in the proteins of various species that simple analytic chemical methods do not show. The studies of recent years have probably demonstrated what the most important chemical differences are. Proteins of different species may or may not differ in the amounts of nitrogen, hydrogen, oxygen, sulphur, phosphorus, and other elements that they contain, but this is not the essential ques- tion. A Norman and a Gothic cathedral may contain the same amount or different amounts of stone, mortar, and glass. The essential characteristics of the architecture of such structures are not determined by the total bulk of the primary substances of which they are made, but by the manner in which the stone and mortar and glass are first put together to make columns, windows, and other parts of different forms, and by the manner BEARING OF METABOLISM STUDIES 111 in which these are then employed in completing the whole. So in various proteins are the chemical elements first put together to form simple structures, the various amino acids, and these are then joined together in various amounts and to some extent in various kinds to form the different varieties of protein. Di- gestion consists in the fragmentation of the complex structures into the simpler structures. These latter are then put together in different amounts, and to some extent, different kinds, to reconstruct the variety of protein desired. This entirely alters our conception of digestion. Previously we thought of it practically as merely the hydrolysis of pro- tein into forms that are dialyzable, and the purpose appeared to be simply to get protein into such a state that it could pass animal membranes and get into the circulation. The serious subject of discussion was chiefly where and how the building- back into native protein occurs, for albumoses and peptones could apparently not enter the circulation, since they have toxic effects. Our present conception of the chief purpose of diges- tion is that it breaks down foreign protein into the parts that make up the whole, in order that these parts may then be used in suitable amounts in reconstructing protein of the structure proper in the individual that is to be nourished. It is highly probable that in abnormalities of this process of fragmentation and reconstruction we shall find the causes of some nutritional disturbances. We are all familiar with in- stances of digestive disorder associated with more or less pro- found nutritional disturbance, and we know that the disorder of nutrition may be vastly more severe than the apparent disorder of digestion. I have recently described cases of infan- tile atrophy and other obscure forms of emaciation in which the proteolytic ferment powers of the intestine were greatly reduced—whether as the result of actual absence of proteolytic ferment, or because other conditions of the contents of the intes- tinal wall in these cases were unsuitable for ferment action, I do not know. In other forms of extreme emaciation of known causation, the ferment activities were normal. I have since investigated further cases that have given the same results. 112 HARVEY SOCIETY These observations lend some support to the hypothesis that I have suggested, that disorder in the fragmentation of the protein food or in the reconstruction into circulatory or tissue protein, or in both these processes, may prove to be the chief explanation of the nature of such conditions. In matters such as these we are wandering in regions that are as yet too little explored for us to be able to come to very definite conclusions as to the meaning of results that have already been obtained, and we cannot yet ask that the practical application of this knowledge in diagnosis and treatment should be at all clear. We have a glimpse, however, of the possibili- ties of productive work that will bear directly on our conception of normal and disease processes, and that will probably in time greatly increase our powers of recognizing the nature of dis- orders and will ultimately lead to enlarging our powers of controlling them. Our knowledge of the activities of ferments in the tissues and our present conceptions of the protein-complex and its changes in digestion have already entirely altered our concep- tions of the nature of many normal tissue processes and of numerous diseases. The manner in which the most striking lesions are produced in phosphorus poisoning and acute yellow atrophy has become clear; indeed, acute yellow atrophy has been practically transformed from an obscure disease into no distinct and separate disease at all, but a severe and striking stage of a process that occurs in varying degree in various circumstances, and that appears clinically to be a distinct disease only when the autolytic changes become so severe and progressive as to be the reigning process. We have reason to hope that this conception of acute yellow atrophy will guide us to work out clinically much more clearly the early stages of the . condition and its exciting causes, and ultimately may help us to intervene effectually at a period when dangerous lesions have not yet oceurred. I think that we may have similar hopes in such conditions as recurrent vomiting, probably in the per- nicious vomiting of pregnancy, in intoxications following anes- thesia and in some other disorders, distant though the consum- BEARING OF METABOLISM STUDIES 113 mation of such hopes may be. Indeed, the studies made by Howland and Richards, which are highly suggestive.in a num- ber of ways, have already furnished some important practical suggestions as to what should be done and what should not be done in the avoidance of the intoxication following anesthesia and to some extent in the treatment of this condition when it has actually appeared. METABOLISM OF INORGANIC SUBSTANCES. Another broad field that is only beginning to be cultivated in an understanding way is the metabolism of the inorganic substances found in the body. We know as yet very little in regard to this subject that can be used in any clinical way, but the remarkable researches of Jacques Loeb especially have led to information regarding its importance in elementary physio- logic processes, particularly in the lower forms of life. His work makes it evident that it must come to have highly impor- tant clinical relations, and the studies of Alonzo Taylor of the effects in the human being of a salt-free diet are sufficient evidence of the profound effects that alterations in salt metabo- lism may produce and of the clinical interest that attaches to investigations of the physiology and pathology of this question. Various other studies are likewise extremely suggestive in this relation and the marvellous effects of the antagonism between calcium and magnesium that Meltzer has demonstrated make the developments in this field of still more intense and imme- diate importance. CONCLUSIONS. The actual clinical bearing of all these things that I have mentioned in this latter portion of my remarks still lies chiefly in the greater breadth that they have given us in our concep- tions of the nature of normal and diseased processes. Their direct bearing on such practical things as diagnosis and treat- ment is slight. But we cannot ask that clear and especially that comprehensive clinical relations should yet be evident. They touch so closely on the things fundamental in understand- 8 114 HARVEY SOCIETY ing life itself that to ask that their bearings shall all be made clear in the span of a man’s life is equal to asking that in the same period of time all the world shall reach that ‘‘far off divine event to which the whole creation moves.’’ But, as I have indicated, we shall be able gradually to accumulate a few facts here and there that will be directly available in practice if the proper principles are followed, even though obscurity still surrounds most of the details, and at any rate broad con- ceptions that lead to a more correct general line of action are, all in all, more valuable to the clinician than are a few de- tailed additions to our direct diagnostic and therapeutic methods, even though these additions accomplish their special purposes very effectually. In witness of this I would mention the great value, on the one hand, of a general comprehension of the influence that can be exerted in the prevention and cure of many infectious diseases, for instance tuberculosis, through general measures directed toward increasing the resistance of bacterial growth and toxin action; and, on the other hand, the relatively slight importance in the general course of practice of those details that have been developed regarding the scientific special treatment of most such special infections. I have pictured a very incomplete and hasty view of the relations between metabolism and clinical medicine. If I am criticized, as may readily be done, for having made my atti- tude toward my subject one of championship rather than of exposition, I would say that I have done this deliberately, for I feel that, in past years especially, and to a large extent even now, the teaching of subjects that bear on metabolism has, much more than is the case with most other subjects in medicine, been such as to give some knowledge of details and methods, but not such as to give a comprehension of the philosophy of metabolism studies in their bearing on clinical conditions. THE CHEMICAL CONTROL OF THE BODY * ERNEST H. STARLING, M.D., F.R.S., F.R.C.P. (Lond.), Todrell Professor of Physiology in the University of London, London, England. HE desire of man for life, a necessary condition of exist- ence in a healthy animal, has led him to search out by experiment the secret workings of his own body, with a view to acquiring by more perfect knowledge a measure of control over his own functions, comparable to that which he has already obtained over the forces of inanimate nature. In this way has been founded the science of medicine, the pursuit of which is the main object of the members of this society. Among the methods devised to this end, viz., the control of the func- tions of the body, must be classed the whole treatment of man from his youth upward; and a large part of the efforts of the medical man must coincide with those of the educational- ist and the sanitarian in the endeavor to assure health by meas- ures which affect, in the first place, the environment of man, his patient. In the eyes of the general public, however, the office of the medical practitioner is often limited to the, for the present, less important role of administrator of medicines or drugs. Although this method has been the main weapon of the ‘‘medi- cine-man’’ in his fight against disease from the earliest ages, its scope is still but limited, and only within the most recent times has any attempt been made to place it on the basis of actual knowledge. The empirical character of the greater part of the treatment by drugs has proved a potent weapon in the hands of the satirist of the medical profession, and exception has often been taken to the employment of chemical remedial measures as being utterly opposed to the laws of Nature and *Lecture delivered January 11, 1908. 116 HARVEY SOCIETY the methods employed by her in the regulation of the body processes and the reaction of the organism against disease. I wish to call your attention to a whole array of facts which demonstrate the unjustifiability of this attitude. As a result: of recent investigations, we may assert that in the employment of drugs we are but imitating, although perhaps in a very im- perfect manner, the method employed by Nature herself, and, indeed, that a large share in the wonderful co-ordination of the activities of different parts of the body, which determine their mutual co-operation for the common weal of the organism, is played by the production and cireulation of chemical substances which are strictly analogous to the drugs employed during countless ages by mankind in the treatment of his diseases. The idea that chemical factors must play an important part in the correlation of function between different parts of the body is not new, but I do not think its full significance was real- ized before the discovery of a very perfect and simple example of chemical co-ordination, viz., that by means of which the activity of the pancreas is determined according to the nature or extent of processes occurring in the alimentary canal. I may, therefore, perhaps, be allowed to give you a brief account of this mechanism before treating of the numerous other in- stances of chemical correlation, many of which have been long known, although even now we cannot pretend to a full compre- hension of their significance in the body. Among the many important discoveries of Pawlow and his* school on the physiology of digestion, one of the most striking was the fact that the introduction of dilute acid into the duo- denum and upper part of the small intestine provoked secretion of pancreatic juice, just as the introduction of acid into the mouth excites secretion of saliva. Thus, as fast as the acid chyme passes into the duodenum, its presence in the latter organ provokes a flow of alkaline pancreatic juice which will continue until the chyme is neutralized. We know from the researches of von Mering, Cannon, and others that so long as the contents of the duodenum are acid the pylorus remains closed, so that we have here a chain of processes CHEMICAL CONTROL OF THE BODY 117 determining a gradual emptying of the stomach into the duo- denum and the addition to the chyme of just sufficient pancre- atic juice to neutralize it and stop the action of the gastric juice and to bring about pancreatic digestion in full activity. The ‘‘acid reflex’’ from duodenum to pancreas was ascribed at first by Pawlow to the intervention of a reflex are of which the vagus was the efferent nerve. His pupil, Popielski, almost simultaneously with Wertheimer of Lille, showed that the “*reflex’’ can be brought about after severance of all connec- tion between the alimentary canal and the nervous system. These observers regarded the phenomenon, therefore, as brought about through a local reflex are involving peripheral nerve- centres. Bayliss and I at first accepted this interpretation. We were interested in the phenomenon as possibly showing an influence of the local nerve-centres, whose action on intestinal movements we had just studied, on the chemical processes of the gut and its appendages; and we, therefore, sought to deter- mine the conditions of the reflex more closely. We found, however, very soon that the experiment could be so devised as to exclude any possible intervention on the part of either the central or the peripheral nervous system, and yet obtain secretion from the introduction of acid into the gut. Thus, if a loop of the jejunum be tied at two ends, and all its nervous connections severed, so that it remains attached to the rest of the body simply by the blood-vessels, introduction of acid into this loop evokes a flow of pancreatic juice as marked as that obtained from the introduction of acid into a normal loop. Since the message from the gut to the pancreas, arousing its activity, cannot reach it by way of the nervous system, the only possible channel left is the blood stream; and the mes- senger must, therefore, be some chemical substance discharged into the blood stream, and not a molecular change propagated along nerve-fibres. That the messenger cannot be the acid itself was easily shown by injecting acid into the portal vein, when no effect was produced. We see, then, that acid introduced directly into the blood has no effect, while if it be injected into a cavity separated 118 HARVEY SOCIETY from the blood by only the epithelial cells of the intestine it has an effect. The chemical messenger, therefore, must be something produced in the epithelial cells under the action of the acid and discharged by them into the blood stream. This conclusion was speedily realized. When we seraped off some of the epithelium, rubbed it up with acid, and injected the hastily filtered mixture into the blood stream of the animal, a flow of pancreatic juice was obtained considerably greater than any we had hitherto obtained as the result of injecting hydrochloric acid into the lumen of the intestine. To this chemical messenger we gave the name of ‘‘secre- tin.”’ In order to obtain it free from admixture with the protein constituents of the cells, the ground-up intestinal epi- thelium was boiled with 0.4 per cent. hydrochlorie acid and while boiling was neutralized. In this way all the coagu- lable protein was thrown down. The filtrate was found to exert a strong exciting effect on the secretory activities of the pancreas. This mode of preparation shows that secretin is neither a ferment nor a protein. Other experiments have shown that, while fairly stable in acid solution, it is very rapidly destroyed in alkaline solution. It is soluble in fairly strong alcohol, or alcohol and ether, but is insoluble in absolute alcohol. It is fairly diffusible through parchment paper and is not precipi- tated by the ordinary alkaloid precipitants. The ease with which it undergoes oxidation has hitherto foiled all attempts to isolate it in a pure form; but the properties mentioned sug- gest that it is a body of comparatively low molecular weight, and that it ought to be possible to obtain it in erystalloid form. In much of its behavior it resembles adrenalin, the isolation of which presented at first many difficulties, but was finally suc- cessful in the hands of Takamine. This body, secretin, can be regarded as a type of a whole group of chemical messengers, which, formed in one organ, travel in the blood stream to other organs of the body and effect correlation between the activities of the organs of origin and the organs on which they exert their © CHEMICAL CONTROL OF THE BODY Bae specific effect. For these chemical messengers we have sug- gested the name of ‘‘ hormone,’’ from épydw, I arouse or excite. It may be remembered that Ehrlich divided the chemical agents which act on the organism into two classes, which we may shortly describe as the toxins and the drugs. As a type of the first class, we may instance a poisonous constituent of jequirity, which has been called abrin; and of castor-oil seeds, ricin; as well as the toxic products of pathogenic micro-organ- isms, such as the well-known toxins of diphtheria or tetanus. All these bodies introduced in minimal doses into the organism evoke characteristic effects either local or general. The specific character of their physiologic action suggests that these toxins have special affinities for one or other tissue of the body, affinities conditioned by their chemical character as well as by that of the affected organs. In this respect they are entirely analogous to the drugs which form the main part of our pharmacopeeias, and of which we may take strychnine, morphine, or arsenic as types. There is, however, one marked distinction between the two groups. When repeated small injections are made of a body belonging to the group of toxins, the physiologic effect produced becomes progressively less, and it has been established that the im- munity to their action which is thus brought about is due partly, at any rate, to the formation of substances in the organ- ism which are the physiologic antagonists of the toxins and have the power of combining with and neutralizing these substances. Thus, if the blood-serum of an animal rendered immune by repeated doses of diphtheria toxin is mixed with some of the diphtheria toxin itself, the resultant mixture, which may con- tain many hundred times the lethal dose of toxin, may be in- jected into an untreated normal animal without producing any effect. Although in the case of certain of the drugs, such as morphine, a limited degree of tolerance may be established, there is no evidence of the production at any time of antitoxic substances in the treated animal. Now, it is evident that if a substance is to act repeatedly as a chemical messenger through the medium of the blood be- 120 HARVEY SOCIETY tween one organ and another, its function would be abolished if the discharge of the chemical message into the blood stream gave rise to the production of an antibody. These chemical substances, or hormones, must, therefore, as a necessary condi- tion of their function, belong to the class of drug substances, generally crystalline, or at any rate not belonging to the colloid class, of definite chemical composition, and in most eases of comparatively low molecular weight. Their action on the chemical basis of the protoplasm must be determined by their molecular structure, and in all probability must be ranked with the purely chemical processes, rather than with those mixed chemical and physical processes which determine the formation of absorption compounds and distinguish the interaction of one colloid with another, as well as of toxins with the animal cell or with their corresponding antitoxins. It is only necessary to remind one of a number of well- established correlations of function effected by the intermedia- tion of these hormones in order to carry conviction of the very large part that they must play in the normal processes of the body. In the alimentary canal itself, the chemical correlation between intestine and pancreas does not stand alone. Thus, Pawlow showed that the secretion of gastric juice occurs in two phases, the first phase being excited through the vagus nerve by appetite, or by impulses from the mouth, while the second phase was determined by the presence of certain substances in the stomach. Edkins has shown that the secondary secretion of gastric juice is determined by the production of a hormone in the pyloric part of the mucous membrane under the influence of the first products of digestion, and that this hormone is absorbed by the blood and carried by it to the gastrie glands of the fundus, which are thereby excited to renewed activity. The secretion of the intestinal glands is partly excited through the local nervous system by the mechanical stimulation of the mucous membrane. It is probable, however, that the pancreatic secretin formed in the duodenum, and perhaps other hormones produced in the intestine, have a direct action through the blood on the secretory processes of the small bowel. The CHEMICAL CONTROL OF THE BODY 121 simultaneous presence of bile and pancreatic juice in the duo- denum, which is necessary for the full unfolding of the diges- tive activity of these juices, is secured by the fact that the secretin formed in. the intestinal mucous membrane under the influence of the acid chyme, has a specific excitatory effect not only on the cells of the pancreas, but also on those of the liver. The postprandial rise of biliary secretion is synchronous with the postprandial rise of the pancreatic secretion, and in both eases the secretion is determined by the secretin circulating in the blood as the result of the action of acid on the cells of the duodenal mucous membrane. It is possible that chemical factors play an important part not only in arousing the secretion of the digestive juices, but also in determining the absorptive activity of the intestinal epithelium. I do not see how otherwise we are to explain the remarkable effects on the absorption of the foodstuffs which ensue on the total extirpation of the pancreas. Whereas liga- ture of the ducts of this organ leaves the absorption of food- stuffs, other than fats, practically unaffected, its total extirpa- tion diminishes by one-half the absorption both of carbohydrates and proteins and almost entirely annuls the absorption of fat. When we pass to the other functions of the body, we find many other instances of correlation by undoubted chemical means, as well as instances in which, with our present knowl- edge, we can find no other explanation of observed phenomena than the assumption of such chemical means. Perhaps the best marked case is that presented by the regulation of the respira- tory movement in accordance with the needs of the organism, especially of the muscles for oxygen. The increased depth and frequency of respiration contingent on muscular exertion are familiar to every one, and we know that the physiologic object of such changes is to secure the inereased ventilation rendered necessary by the enormous rise of gaseous metabolism which accompanies muscular exercise. Even moderate work may raise the gaseous exchanges to be- tween four and eight times their amount during rest. This increase in the respiratory movements is entirely involuntary, 122 HARVEY SOCIETY and may, in its earlier stages, when affecting chiefly depth of respiration, be unnoticed by the subject of them. How is the respiratory centre aroused to an increased activ- ity which is strictly proportional to the increased metabolism of the distant muscles? A nervous path is at once excluded by the fact that hyperpncea or even dyspnoea may be excited in an animal, after division of the spinal cord, by tetanization of the muscles of the hind limbs. Zuntz and Geppert, there- fore, came to the conclusion that the exciting agent in this in- creased activity was some acid substance or substances produced by the contracting muscles and transmitted from them through the blood stream to the respiratory centre. The subject has been investigated lately by Haldane and Priestly. In a series of masterly experiments these observers show that the chemical messenger in this case is none other than carbon dioxide. The contracting muscle, when properly sup- plied with oxygen, takes up this gas and gives out carbon dioxide in direct proportion to the energy of its contractions. The carbon dioxide, diffusing rapidly into the blood stream, raises its percentage and, what is still more important, its tension in this fluid. The respiratory centre differs from the other parts of the central nervous system in having developed a specific sensibility to carbon dioxide. Its normal activity is determined by the normal tension of this gas in the blood and lymph bathing the centre. Diminution of the tension of this gas depresses the activity of the centre, causing slackening of respiration, or even the total cessation of respiratory move- ments, known as apncea. This work by Haldane may be regarded as finally deciding a question which has been the subject of debate for nearly half a century. The dyspnoea, caused by the circulation of venous blood through the brain or by the deprival of the respiratory centre of the means of maintaining its normal gaseous inter- changes, has been’ variously attributed either to oxygen star- vation or to carbon dioxide intoxication of the centre. THal- dane shows that the centre is very little sensitive to changes in the oxygen tension of the blood. The oxygen tension in the CHEMICAL CONTROL OF THE BODY 123 pulmonary alveoli may be altered from 20 per cent. to 8 per cent. without any increase in the depth or frequency of the respiratory movements. In these circumstances the heart or circulatory system may feel the deprivation of oxygen before the respiratory centre has responded to it. On the other hand, a rise of only 14 per cent. in the tension of carbon dioxide in the alveolar air, and, therefore, in the blood circulating round the respiratory centre, will increase the volume of air respired 100 per cent. This simplest of all examples of a co-ordination of two: widely separate organs by chemical means may, perhaps, give us a clue to the mode in which the more complex of such corre- lations have been evolved. The chemical messenger is here a product of activity which is common to all protoplasm and must be excreted by the cell as a condition of its further activity. The adaptation in this case, therefore, is not the formation of a special substance which shall exert a specific influence on some distant organ, but the development in this distant organ of a specific sensibility to the common product of excretion of the first organ. We may, perhaps, assume that the more specialized messengers, which we shall have to consider in detail later, were at first accidental by-products of the selfish activity of the organ producing them, the first step in the development of a correlation being the acquisition of a sensibil- ity to the substance in question by some distant organ. The only other example of such a reaction, in which we know both the source and nature of the chemical messenger and the exact nature of the effects which it produces, is the suprarenal gland. Since the time of Addison we have known that atrophy of these glands in man leads to a disease charac- terized by the three cardinal symptoms of bronzing, vomiting, and extreme muscular weakness. Most of the attempts to repro- duce this disease in animals have failed, owing to the fact that death follows the excision of both glands within 24 hours; the extreme muscular weakness is certainly produced, and this is attended by a profound fall in the general blood-pressure. In 1894, Oliver and Schifer showed that from the medulla 124 HARVEY SOCIETY of the suprarenals a substance could be extracted which, on injection into the circulation, caused a marked rise of blood- pressure and increased strength of the heart-beat. Since the publication of these observations, our knowledge concerning the nature and actions of this substance has progressed rapidly. The researches of Jowett, of von Fiirth, and others have shown that the active substance is a definite chemical compound de- rived from pyrocatechin and having the formula: (HO),.C,H,.- CHOH.CH,.NH.CH,,. Dakin has synthesized a whole array of substances which are closely allied to this body in their chemical structure as well as in their physiologic influence on the animal organism. In order to comprehend the point of attack of adrenalin, the specific secretion of the medullary part of the suprarenal glands, we shall do well to go back to the mode of development of these organs. It was shown by Balfour that the suprarenals have in the fetus a twofold origin, the cortex being derived from the mesoblastic tissue, known as the intermediate cell- mass, while the medulla is formed by a direct outgrowth from the sympathetic system, and consists, at first, of an aggregation of neuroblasts. In some animals, e.g., teleostean fishes, the two parts of the gland thus formed remain separate throughout life ; but in the higher vertebrates the sympathetic outgrowth becomes surrounded by the cortex and the cells rapidly lose all traces of resemblance to a nerve-cell. But the medulla is genetically part of the sympathetic system, and its specific secretion, adren- alin, has an action which is apparently confined to the sympa- thetic system. In whatever part of the body we test the effects of adrenalin, we find that they are identical with the results of stimulating the sympathetic nerve fibres which run to that part. Thus, in all the blood-vessels of the body, adrenalin causes constriction; the contraction of the heart muscle is augmented, the pupil is dilated, while the intestinal muscle, with the single exception of the small ring of muscle forming the ileocolic sphincter, is relaxed. The action of the sympathetic on the bladder differs, as shown by Elliott, markedly in various ani- CHEMICAL CONTROL OF THE BODY 125 mals; but, whatever its effect, a similar one will be produced in the same animal by the injection of adrenalin. I have already mentioned that excision of the suprarenal bodies causes a profound fall of blood-pressure, which con- tinues until the death of the animal; and it has been stated that, when this fall is well established, it is impossible to raise the blood-pressure by stimulation of the splanchnic nerve, or, indeed, to produce any effect at all on stimulation of the sym- pathetic nerve. Thus not only does adrenalin excite the whole sympathetic system in its ultimate terminations, but its presence in the body as a specific secretion of the suprarenal bodies seems to be a necessary condition for the normal functioning, by ordinary reflex means, of the whole sympathetic system. We are dealing here with a problem which, betraying, as it does, an intimate relationship between nerve excitation and excitation by chemical means, promises by its solution to throw a most interesting light on the nature of the nerve process and of exci- tatory processes in general. Our knowledge of certain other members of this group of chemical reactions is so shadowy that a mere mention of them will suffice. As an antithesis to the vasoconstrictor action of adrenalin, we find that every organ, when active, is supplied with more blood in consequence of a vasodilatation of the ves- sels which supply it. In certain instances, Bayliss and I have found that boiled extracts of organs, when injected into the circulation, may evoke vasodilatation of the same organs of the animal under investigation; and we have suggested that the normal vasodilatation accompanying activity is brought about in consequence of the specific sensibility of the arterial walls to the metabolites of the organ which they supply. Too much stress, however, cannot be laid on these experiments, since a more extended series by Swale Vincent has failed to give a general confirmation of our results. The severe diabetes, which, as shown, by Minkowski, can be produced in nearly all animals by total excision of the pan- ereas, has been held to denote the normal production in this organ of some substance which is indispensable for the utiliza- 126 HARVEY SOCIETY tion of carbohydrates in the body. All efforts to obtain a more exact idea of the nature of this pancreatic substance or influence have so far proved in vain. Ordinary sugar, when placed in contact with extracts of muscular tissues, undergoes oxidation ; and Cohnheim states that this process is much accele- rated if an extract of pancreas be added to the extract of muscle. A repetition of Cohnheim’s experiments by other ob- servers has shown that the effect is so small as to be almost accidental; and we must, therefore, regard the nature of the pancreatic influence on carbohydrate metabolism and the causa- tion of pancreatic diabetes as problems still to be solved. In the case of the pituitary gland we have an organ of, as yet, unknown function, but which we must regard as concerned in determining the activity of widely differing parts of the body, probably by the production of chemical substances or hormones. Pathologically, all we know is that disease of this organ is apt to be associated with overgrowth of the osseous system. As a result of physiologic experiment, we know that from the nervous part of this organ we can extract, as Schafer has shown, a substance which, like secretin, is unaltered by boil- ing, and which has a specific action on the secretory activity of the kidney, producing diuresis, which cannot be ascribed simply to the concomitant changes in the circulatory system. This ex- tract, moreover, has a marked infiuence on the uterus. What part is played by this pituitary influence on these distant organs in the normal working-life of the body we do not know as yet. So far the chemical adaptations which I have described have resulted almost exclusively in increasing the activity of the responding organ. We cannot, however, draw a sharp line between reactions involving increased activity or dissimi- lation and those which involve increased assimilation or growth, since under physiologic circumstances the latter is always an immediate sequence or accompaniment of the former. In a certain number of chemical correlations the primary effect of the hormone is increased growth or assimilation. In these cases, since the assimilative stimulus builds up the re- aaa. ~ -— . ae - CHEMICAL CONTROL OF THE BODY 127 sponding organ, its final effect is to increase the activity or functional capacity of this organ. Just as dissimilation brings about later increased assimilation, so increased assimilation brings about later increase of dissimilatory capacity. The most familiar example of a chemical correlation, evok- ing the building up of tissues, is that presented by the thyroid gland, though the effects of the chemical substance formed by the thyroid are so widespread, and differ to such an extent according to the age of the animal employed, that a physiologic analysis of its results is still difficult to give. In the growing animal the chemical substance secreted by the thyroid evidently influences the growth of tissues, among others, of the bones; and it.is a familiar fact that injection or administration of thyroid to cretins will result in a restoration of the child toward normal, in increased growth of bones, and in development of various functions, including those of the brain and central nervous system. In adults, on the other hand, the most pro- nounced effect of injection of thyroid is increased activity of the chemical changes of the body, as instanced by the increased nitrogenous metabolism and disappearance of all overgrowth in the subcutaneous connective tissue, such as is present in myxedema. Although, therefore, the main result of thyroid treatment is to restore normal growth where such has been pre- viously wanting, it is difficult to say whether its primary effect should be regarded as dissimilative or assimilative. The fact that the thyroid gland can be administered by the mouth shows that the active principle is not destroyed by the gastric juice, and would, therefore, remove this from the pro- teid class of bodies, and would diminish very largely any proba- ' bility of the hormone furnished by this gland being of the nature of a toxin. Whether it is represented by the thyroiodin, the organic iodine compound extracted from the gland by Baumann, though probable, is still unproved; and we can only conjecture that in all probability, when isolated, it will be found to belong to the drug class rather than to the toxin class. We are still quite without knowledge as to the conditions which determine the amount of active substance produced in the thy- 128 HARVEY SOCIETY roid gland. All we know is that the activity of the thyroid, like that of the suprarenal gland, is essential to the normal development of the functions of the body. Whether we are dealing here with a constant process, or with a chemical reflex similar to those we have studied in the alimentary canal and evoked by some event affecting directly the thyroid gland, we cannot say. The largest group of correlations between the activity of one organ and the growth of others is formed by those widespread influences exercised by the generative organs on the body as a whole and on parts of the body. The effects of removal of the testes in the male animal on the growth and disposition of the individual have been known for centuries. The experiments of Shattock and Seligman show that the formation of the so- called secondary sexual characters must be due to chemical influences from the gland and not to metabolic changes set up by a nervous reflex arising from the function of sperm ejaculation. Corresponding results have been obtained in the female by extirpation of the ovaries, double odphorectomy before pu- berty not only preventing the onset of puberty and the occur- rence of menstruation, but also modifying the future growth of the whole body in the direction of the male character. It has been shown recently by Marshall and Jolly that the changes in the uterus which determine menstruation are probably due, not to ovulation, but to an internal secretion arising from the ovary. More definite evidence of a direct influence of the ovary on the growth of the uterine mucous membrane has been furnished by the experiments of Fraenkel, as well as those of Marshall and Jolly. At the suggestion of Born, Fraenkel removed the ovaries of rabbits from one to six days after copulation, in order to decide whether the ovary exercised any influence on the growth of the mucous membrane of the uterus and its prepara- tion for the fixation of the ovum. In every ease, on subse- quently killing the animal, it was found that extirpation of the ovaries had prevented the fixation of the ova, On the other CHEMICAL CONTROL OF THE BODY 129 hand, if the ovaries were removed on or after the fourteenth day of pregnancy, which in the rabbit lasts about thirty days, the animals went on to full time and healthy fcetuses were produced. The fact that the corpus luteum of pregnaney grows enor- mously during the first third of pregnancy and then diminishes in size, suggests that this hypertrophy and growth of cells are for the express purpose of influencing the mucous membrane; and Fraenkel states that destruction of the corpora lutea by means of the galvanocautery is as efficacious as is total removal of the ovaries in determining the end of pregnancy. The cells which form the corpora lutea are derived, not from connective- tissue cells, but from the interstitial cells lying immediately outside the Graafian follicles. Their origin is, therefore, iden- tical with that of the interstitial cells of the ovary, viz., from the primitive germinal epithelium. A still more striking example of growth in response to chemical stimulation from distant organs is afforded by the mammary glands. As is well known, at birth these organs are limited to a few ducts in the immediate neighborhood of the nipple and equal in extent in both sexes. At puberty, in the human female, there is a growth of the breasts, associated with some gland growth, the main increase in size, however, being due to fat. With the occurrence of pregnancy, a true hyper- trophy of the gland begins at once and continues steadily up to birth. In the rabbit, in which we have studied the changes in the gland, it is extremely difficult to find in the virgin even a trace of mammary gland. The nipple is small and undeveloped, and on making serial sections through the nipple the gland is found to be confined to a few ducts not extending more than a few millimetres outside the nipple. No trace of secreting alveoli is to be observed. With the occurrence of pregnancy a rapid growth of the gland appears to begin at once. Five days after impregnation, when it is still impossible to find the impregnated ovum with the naked eye in the enlarged uterus, the mammary glands are marked out as small pink patches about two centi- metres in diameter just under each nipple. 9 130 HARVEY SOCIETY On microscopic section the gland is found to be made up chiefly of ducts, which, however, are undergoing rapid pro- liferation. The cells lining the ducts are about three deep and present numerous mitotic figures. At about the fourteenth day the whole of the front of the abdomen is covered with a thin layer of mammary tissue. Branching ducts, with proliferating epithelium, are still the predominant feature on section; but here and there, especially toward the margins of the gland, small secreting alveoli, lined with a single layer of epithelium, are to be seen. After this time the gland grows with ever increasing rapidity, so that at birth, at the thirtieth day after impreg- nation, the mammary glands form a layer about half a centi- metre thick over the whole of the abdomen. In the virgin rabbit it is impossible to obtain by expression any fluid from the nipples, but from the fifth to about the twenty-fifth day pinching the nipples results in the expression of a clear, colorless fluid. From the twenty-fifth day onward this fluid becomes opalescent, and during the second and third days immediately preceding birth the fiuid obtained is typical milk. The appearance of milk is earlier in multiparous rabbits, and in animals where pregnancies succeed each other rapidly it may be possible to express milk throughout the whole of pregnancy. In the primiparous rabbit termination of pregnancy at any time after the fifteenth day results in the appearance of milk in the mammary glands, a result which has also been observed in the human female under corresponding conditions. That this onset of lactation is not due to any stimuli, chemical or ner- vous, received by the mammary glands from the involuting uterus or ovaries is shown by the fact that it may be brought on by performing total extirpation of ovaries and pregnant uterus. The essential feature therefore seems to be in this case the removal of the growing fcetuses. In order to determine the nature of this connection, Miss Lane-Claypon and I carried out a number of experiments in which extracts made from different parts of the immature rabbit foetuses were injected into virgin rabbits. In a certain han CHEMICAL CONTROL OF THE BODY 131 number of cases, where the injections had been sufficiently numerous, we got well-marked hypertrophy of the mammary glands similar to that observed during the earlier stages of pregnancy. From our results we came to the conclusion that the growth of the mammary glands during pregnancy is due to the assimilatory or inhibitory effects of a specific hormone produced in the body of the fetus and carried thence through the placenta by the fetal and maternal circulations. The re- moval of the inhibitory stimulus at the end of pregnancy determines the spontaneous breakdown of the built-up tissues, i.e., activity, which in these cells is expressed by the formation of milk. It is probable that many other instances of chemical corre- lation will be revealed by future research. Already, however, an enormous material for experimental investigation is afforded by the facts I have already brought to your notice. In only two of the instances of chemical correlation do we know the chemical nature of the hormone. Future research must deter- mine the chemical nature of the hormone in each ease, as also the conditions of its formation and the part it plays in the normal chain of events or adaptations which make up the life of the animal organism. In working out these problems we may look forward to the prospect of increasing power over the functions of the body. The whole of medical science is but a struggle for control of the processes which determine the life of man, and no field seems to me more promising than that over which we have to-day cast a fleeting glance. A knowledge of the whole field would place us in command of the means employed by Nature herself for determining the activities of most of the functions of the body, viz., drugs, or hormones, which effect their purpose and are then destroyed. It was in view of the prospective impor- tance of this field of studies in the future work of the medical man that I have ventured to present the subject at this time. SURGICAL SHOCK * GEORGE CRILE, M.D., Professor of Clinical Surgery, Western Reserve University, Cleveland, Ohio. ie previous communications, especially in the monographs entitled, ‘‘ An Experimental Research into Surgical Shock,’’ ‘*An Experimental and Clinical Research into Clinical Prob- lems Relating to Surgical Operations,’’ ‘‘An Experimental Re- search into the Surgery of the Respiratory System,’”’ and ‘‘An Experimental Research upon Blood-pressure in Surgery,”’ I have set forth in detail certain experimental and clinical data relating to surgical shock. With this published work, and cer- tain experimental and clinical researches soon to be published in detail, as a basis, I shall omit theoretic discussion and en- deavor to discuss only certain phases of shock in their relation to surgical practice. We shall assume as our premises that the fall in the arterial blood-pressure is the essential phenomenon; that without a fall in the arterial pressure there is no surgical shock; that the fall in the blood-pressure is due to traumatism of the nerve- tissue and psychic stimuli. We further assume that the ulti- mate lesions of shock are the same as those of hemorrhage and that for all practical purposes the phenomena of shock are ex- pressions of altered physiologic functions. We shall assume that death from shock, like death from hemorrhage, presupposes the failure of the circulation, producing certain degeneration of the central nervous system; that there is, indeed, but little essential difference, except as to causation, between death from hemorrhage and death from shock. We shall further assume that the fall in the blood-pressure is mainly due to a functional impairment or breakdown of the vasomotor centres; that the * Lecture delivered January 25, 1908, 132 — ee eins ie SURGICAL SHOCK 133 heart and blood-vessels themselves are only secondarily affected, principally by reason of the anemia of low blood-pressure ; that the cause of the functional impairment or breakdown of the vasomotor centres is due in part to the effect of excessive affer- ent stimuli and in part to the progressive anemia of these centres, there occurring a species of vicious circle. We shall further assume that these shock-producing afferent impulses are but little influenced by general anesthesia, but are totally blocked by cocainization of their conducting paths. We shall dismiss without consideration the symptomatology of shock and shall now briefly consider the differential diagnosis between concealed hemorrhage and shock. DIFFERENTIAL DIAGNOSIS BETWEEN CONCEALED HEMORRHAGE AND SHOCK. In the absence of a history of either trauma or bleeding, without evidence of free fluid in cavities, and without a blood examination, is it possible to differentiate with certainty be- tween shock and hemorrhage? We believe it cannot with cer- tainty be done. Are there any characteristic changes in the . blood picture which will serve to differentiate ? In shock, the arterial circulation has failed because the blood has accumulated in the veins, especially in the venous trunks; in hemorrhage, the arterial circulation has failed because the blood has left the vascular system. In the one case there is an intravascular hemorrhage, in the other an extravascular hemorrhage. The circulatory phenomena are virtually identi- eal. In a number of clinical observations of the donors during fifty-one transfusions, and in subjects of intentional bleeding, as well as in experimental research in which the blood-pressure of two animals was simultaneously reduced at approximately the same rate by shock and by hemorrhage, and in which con- tinuous observations were made, we were able to draw the fol- lowing conclusions: Heamoglobin.—In shock, there is either slight or no fall, or a rise, in hemoglobin from the beginning to the end of the ex- periments; in hemorrhage, there is first a period during which 134 HARVEY SOCIETY there is little or no fall in the hemoglobin ; this period may con- tinue until the loss of a fourth, a sixth, or a tenth of a fatal amount of blood.