POROUS RAUDDRRDDDLOUPOSAOOORERE RE \EODLICATERLIMIROLALLIREROERDLDE OOOO ES TUTST TALIM I URECLICOCIOREC ORDA IORELEOEOEILLCAROOO IDE TEUPCUTOUOREPORMTOUSHERI ELEC A TOPE TROOP RISES UE : Hill | i SS ive : a q i i | ) : a ii / 0 tl i : 4 | > i) : 1 , y i | / in i 4 i) - a a ANA | Hi y ze | h ‘ . i ae . i | y 4 | | : : Hi nT 4 ‘ a aig or i ud Hil . | TUTITATTTTTTTTETITATATTRTETATVTT STE OTTTTTTTTOTTTOTTTITTTITTTTIYRTITITTTTTTTTTTITATTTTETTTOTITTITTTTTTTITITRRTOTTRITTTITITATONTETPTITOTITTTV ET EVIVITTOTIERIRDIVR ATT ENN a bane Serene oar ~ 2 ee a i + ie. * - 7 age ie a a / . eel ‘a0) Coane ILS pre ae ‘ee a id tian cae 4 Pia | , txD a iy = 1 Du ** ‘ 5 Digitized by the Internet Archive in 2010 with funding from University of Toronto http://www.archive.org/details/harveylecturesO7harv THE HARVEY SOCIETY THE HARVEY LECTURES Delivered under the auspices of THE HARVEY SOCIETY OF NEW YORK Previously Published FIRST SERIES. 1905-1906 SECOND SERIES. 1906-19007 THIRD SERIES. 1907-1908 FOURTH SERIES. 1908-1909 FIFTH SERIES . 10909-1910 SIXTH SERIES . 1910-1911 «s The Harvey Society deserves the thanks of the profession at large for having organized such a series and for having made it possible for all medical readers to share the profits of the undertaking.’’ —Medical Record, New York. Crown 8vo. Cloth, $2.00 net, per volume. J. B. LIPPINCOTT COMPANY Publishers Philadelphia THE HARVEY LECTURES DELIVERED UNDER THE AUSPICES OF THE HARVEY SOGCIEZY OF NEW YORK IQII-19Q12 BY Dr. SIMON FLEXNER Pror. WALTER B. CANNON Pror. ALBRECHT KOSSEL Pror. HENRY FAIRFIELD OSBORN Pror. MAX VERWORN Pror. THEODORE WILLIAM RICHARDS Pror. JAMES J. PUTNAM Pror. RUSSELL H. CHITTENDEN Pror. WILLIAM T. SEDGWICK Pror. H. S. JENNINGS Pror. WILLIAM SYDNEY THAYER PHILADELPHIA AND LONDON J. B. LIPPINCOTT COMPANY * “ ‘ty ” Copyricut, 1912 en By J. B. Lipprvcotr Company tees Sey. OFFICERS AND MEMBERS OF THE SOCIETY OFFICERS Freperic 8. Lee, President Wm. H. Parx, Vice-President Epwarp K. DunHam, Treasurer Haven Emerson, Secretary COUNCIL GRAHAM LUSK S. J. MeurzEer W. G. MacCatium The Officers Ex Officio ACTIVE MEMBERS Dr. JoHn S. ADRIANCE Dr. HucH AUCHINCLOSS Dr. JOHN AUER Dr. FREDERICK W. BANCROFT Dr. SiuAs P. BEEBE Dr. StTanteY R. BENEDICT Dr. Hermann M. Bices Dr. Harrow Brooks Dr. Leo BUERGER Dr. Russe~xL Burton-Opitz Dr. E. E. Burrerrietp Dr. ALEXIS CARREL Dr. P. F. Cuark Dr. A. F. Coca Dr. ALFRED E. COHN Dr. Rurus CoLe Dr. H. D. DaxIn Dr. CHARLES B. DAVENPORT Dr. A. R. Docuez Dr. GEORGE DRAPER Dr. EvGenst F. Du Bors Dr. Epwarp K. DunHAM Dr. WituiAM J. ELSEer Dr. Haven Emerson Dr. James Ewina Dr. Cyrus W. Frevp Dr. Stmon FLEXNER Dr. AustTIN FLINT . Newuis B. Foster . J. S. FURGUSON . Witiiam J. GIEs . T. S. GrrHEeNns . FrepEeRIC M. HANES . THomAas W. HASTINGS . Ropert A. HATCHER . Puttip Hanson Hiss, JR. . JOHN HOWLAND . G. S. Huntineron . Hotmes C. JACKSON . WALTER A. JACOBS . THEODORE C. JANEWAY » JAMES W. JOBLING . Don R. JOSEPH . Davip M. KAPLAN . L. S. Kuerner . RicHarpD V. LAMAR . Ropert A. LAMBERT . Freperic S. Les . E. S. LESPERANCE . PHasus A. LEVENE . Isaac LEVIN . KE. Lipman . CHARLES C. LIEB . W. T. Lonecorre . GraHam Lusk . J. F. McCLenDoN Dr Dr . W. G. MacCattum . ArTHUR R. MANDEL . JOHN A. MANDEL . F. S. MaAnpEeLBaum . W. H. Manwarine . S. J. MEurTzEer . ADOLF MEYER . GUSTAVE M. MEYER . L. S. MILNE . Herman O. MOSENTHAL . J. R. Muruin . Hipryo NoGucHti . CHARLES NorRIS . Horst OERTEL . EUGENE L. Opie . B. S. OPPENHEIMER . WiuuiaAM H. ParK . KF. W. PEApopy ACTIVE MEMBERS—Continued. W. J. McNEAL . M. PEARCE . MircHEeLL PRUDDEN R 4h . A. N. RicHarps Cc . G. Ropinson . Peyton Rous . Orro H. SCHULTZE . H. D. SENIOR 2. HugH A. STEWART . CHARLES R. STOCKARD . ISRAEL STRAUSS . Homer F. Swirt BAT: Reeey . J.C; Torrey . DonatD D. VAN SLYKE . Kart M. VOGEL . AuGuSTUS WADSWORTH . A. J. WAKEMAN . GrorGE B. WALLACE . RicHarp WEIL . WinLIAM H. WELKER . CARL J. WIGGERS . ANNA W. WILLIAMS . Ropert J. WILSON . RupotpH A. WITTHAUS . MartHa WOLLSTEIN . FRANCIS . JONATHAN WRIGHT CARTER Woop ASSOCIATE MEMBERS . Ropert ABBE . CHARLES Francis ADAMS . IsAAc ADLER . Frep H. ALBEE . WILLIAM B. ANDERTON . S. T. ARMSTRONG . W. M. ARMSTRONG . GorHAM BAcon Dr. Dr. Dr. Dr. Prarce BAILEY L. Bouton Banas THEODORE B. BARRINGER, JR. Simon BarucHe A. W. BAstTEpo Cart Beck Dr. Dr. . ARTHUR BOOKMAN . Davin Bovatrp, JR. . JOHN W. BRANNAN . JOSEPH BRETTAUER . Georce E. BREWER . SAMUEL M. BRICKNER . NatHan E. Briuu . Wu. B. BrINSMADE . Epwarp B. BRONSON . SAMUEL A. BROWN . JOSEPH D. BRYANT . JESSE G. M. BULLOWA JosEPH A. BLAKE Geo. BLUMER Dr. Dr. ASSOCIATE MEMBERS—Continued. GLENWoRTH R. BUTLER C. N. B. Camac . Wm. F. CAMPBELL . Ropert J, CARLISLE . Hersert S. CARTER . ARTHUR F.. CHASE . T. M. CHEESEMAN . CORNELIUS G. COAKLEY . Henry C. Cor . WARREN COLEMAN . WILLIAM B. CoLEYy . CHARLES F. CoLuIns . Lewis A. CoNNER . Epwin B. CRAGIN . Fuoyp M. CRANDALL . GEORGE W. CRARY . Conman W. CUTLER . CHarLES L. Dana . THoMAS DARLINGTON . D. Bryson DELAVAN . Epwarp B. DENCH . W. K. DRAPER . ALEXANDER DUANE . THEODORE DUNHAM . Max EINHORN . CHARLES A. ELSBERG . ALBERT A. EPSTEIN . Evan M. Evans . SAMUEL M. Evans . Epwarp D. FISHER . Roure FLoyp . JOHN A. ForDYCE . JOSEPH FRAENKEL . Ropert T. FRANK . RowLanp G. FREEMAN . WoLFF FREUDENTHAL . Lewis F. FRIsseLL . ARPAD G. GERSTER . Virgin P. GIBNEY . Coartes L. Gipson . J. RmpLE GOFFE . SIGISMUND S. GOLDWATER . MALCOLM GOODRIDGE . NATHAN W. GREEN . JAMES C. GREENWAY . Emin GRUENING . F. K. Hantock . GrAEME M. Hammonp . T. Stuart Harr . FRANK HARTLEY . JoHN A. HARTWELL . JAMES R. HAYDEN . Henry HEIMAN . ALFRED FI’. HESS . Augustus Hoc# . AustTIN W. Ho.uis . H. Srymour HouGHtTon . FRANCIS HUBER . JOHN H. HvuppLEston . Epwarp L. Hunt . Woops HutTcHINSON . LEOPOLD JACHES . ABRAM JACOBI . GeorGeE W. JACOBY . J. RALPH JACOBY . WALTER B. JAMES . SmirH Ey JELLIFFE . FREDERIC KAMMERER . Lupwia Kast . JACOB KAUFMANN . CHARLES GILMORE KERLEY . Puiuip D. KERRISON . Epwarp L. KrysEs . Epwarp L. Keyes, JR. . EveANOR B. KILHAM . Orro KILIANt . Francis P. KiInnicurr . ARNOLD KNAPP . Linnagus E. LA FEtra . ALEXANDER LAMBERT ASSOCIATE MEMBERS—Continued. . SAMUEL W. LAMBERT . Gustav LANGMANN . BoLEsLAwW LAPOWSKI . Burton J. Ler . EcBert Le FrEvre . CHarLes H. Lewis . Rosert Lewis, JR. . Ett Lone . Winuiam C. Lusk . HAM vie . D. Hunter McApin . CHARLES McBuRNEY . JAMES F. McKernon . GrorcE McNauGuTon . Morris MANGES . GrorGE MANNHEIMER . WILBUR B. MARPLE . Frank S. Meara . ViIcTOR MELTZER . WALTER MENDELSON . ALFRED MEYER . Witty Mryer . MicHAarL MICHAILOVSKY . GEORGE N. MILLER . JAMES A. MILLER . Ropert T. Morris . ALEXIS V. MoscHow1tz . JOHN P. MunNN . ARCHIBALD MurRAY . Van Horne Norrie . Witi1Am P, Nortrurupe ,. NATHANIEL R. Norton . AuFreD T. Oscoop . Henry McM. PAIntTER . ELEANOR PARRY . Henry S. Partrerson . Stewart Patron . Georce L. PErasopy . CHARLES H. Peck . FREDERICK PETERSON . Goprrey R. PiseK . Witu1AM M. PoLK . SIGISMUND POLLITZER . NATHANIEL B. POTTER . WILLIAM B. PRITCHARD . WILLIAM J. PULLEY . FRANCIS J. QUINLAN . EDWARD QUINTARD . A. F. Riaes . ANDREW R. ROBINSON . JOHN Rocers, JR. . JOSEPH C. ROPER . JULIUS RUDISCH . BERNARD SACHS . Tuomas E. SATreRTHWAITE . ReGgiInaLD H. SAYRE . Max G. ScHLApP . Fritz ScHWyYZER . E. W. ScRIPTURE . Newton M. SHAFFER . Montcomery H. Sicarp . Henry MANN SILVER . WiuuiAmM K. Simpson . A, ALEXANDER SMITH . FRED P. SOLLEY . FREDERIC E. SONDERN . J. BENTLEY SQUIER, JR. . NORBERT STADTMULLER . M. ALLEN STARR . RicHARD STEIN . ANTONIO STELLA . ABRAM R. STERN . GeorGE D. STEWART . Lewis A. STIMSON . Wimu1AM 8, STONE . Georce M. Swirt . PARKER SYMSs . ALFRED §S. TAYLOR . JOHN S. THACHER . ALLEN M. THOMAS . W. Gruman THOMPSON . Winuiam H. THomson PRor. PRor. Pro. ASSOCIATE MEMBERS—Continued. . SAMUEL W. THURBER . WisnER R. TOWNSEND . PHILIP VAN INGEN . RicHARD VAN SANTVOORD . JAMES ID. VOORHEES . Henry F. WALKER . JOHN B. WALKER . JOSEPHINE WALTER . JAMES SEARS WATERMAN Dr. R. W. WEBSTER Dr. JOHN E. WEEKS Dr. Ropert WEIR Dr. Hersert B. WILCOox Dr. Linsty R. WILLIAMS Dr. WILLIAM R. WILLIAMS Dr. MarGcaret B. WILSON Dr. GEORGE WOOLSEY Dr. JOHN VAN Doren YouNG Dr. Hans ZINSSER HONORARY MEMBERS, 1912 Pror. J. GrorGeE ADAMI Pror. Lewetutys F. BARKER Pror. Francis G. BENEDICT Pror. T. G. Bropie Pror. A. CALMETTE Pror. W. E. CaAstTue Pror. WALTER B. CANNON Pror. Hans CHIARI R. H. CuHrrrenpen OTto COHNHEIM W. T. CouncILMAN Pror. GEorGE W. CRILE Pror. Harvey CUSHING Pror. ArtHuR R. CusHny Pror. Davin L. Epsauu Pror. W. W. Fata Pror. Orro Foun PROF. Ross G. Harrison Pror. Lupvicg Hex Torn PrRor. Pror. Pror. W. H. Howetuu G. Cart HuBER JOSEPH JASTROW Pror. Hersert §. JENNINGS Pror. Epwin O. JorDAN Pror. ALBRECHT KosseL Pror. Joun B. Leatugs Pror. A. Macnus-Levy Pror. JACQUES LOEB Pror. A. B. MacatLuM Pror. LAFAYETTE B. MENDEL Pror. Hans MEYER Pror. CHARLES §. MINoT Pror. S. Weir MircHELL Pror. THomas H. Morcan Pror. FRIEDRICH VON MULLER Pror. CARL VON NOORDEN Pror. FREDERICK G. Novy Pror.. HENRY FAIRFIELD OSBORN Dr. THomas B. OSBORNE Pror. RicHArD M. PEARCE Pror. WILLIAM T. PORTER Pror. JAMES J. PuTNAM Pror. THEODORE W. RICHARDS Pror. E. A. SCHAEFER Pror. WILLIAM T. SEDGWICK Pror. THEOBALD SMITH Pror, Ernest H. STARLING Pror. A. E. TAYLOR Pror. W. S. THAYER Pror. MAx VERWORN Pror. J. CLARENCE WEBSTER Pror. H. Grpron WELLS Pror. EpmunpD B. WILSON Sm Autmroto E. WRIGHT i ° ry ) \ h ey if ee hy an PREFACE WHILE the Harvey Society becomes responsible to a larger audience each year, the prestige and character given to its undertaking by the generous services of the lecturers makes the work of arranging for the annual series and the publication of the volume progressively easier. The lectures of Dr. Flexner, Prof. Kossel, Prof. Richards, Prof. Chittenden, and Prof. Thayer have not appeared in previous publications. The Editor acknowledges gratefully the courtesy of the Epitors of the Johns Hopkins Hospital Bulletin, the Boston Medical and Surgical Journal, the Journal of Infectious Dis- eases, the Popular Science Monthly, and the American Natu- ralist, in allowing our republication of the lectures of Prof. Verworn, Prof. Putnam, Prof. Sedgwick, Prof. Cannon, Prof. Jennings, and Prof. Osborn respectively. The Society is indebted to Dr. H. D. Dakin for his trans- lation of Prof. Kossel’s lecture, which was delivered in German. HaAvEN EMERSON, Secretary, 120 East 62d St., New York. September, 1912. CONTENTS PAGE Hecal Specific Therapy of Infections ......... 0s cccccsccccccecs 17 Dr. Smiuon FLEXNER—The Rockefeller Institute for Medical Research. The Chemical Composition of the Cell............. ga dhl eee wearer eae 33 Pror. ALBRECHT KosseL—University of Heidelberg. RRS TENI et fe 8 a Slat wat acl cn a atl wi Sia vatiel Soho wlcletaran oles Crelarene terse oie 8 52 Pror. Max VERwoRN—University of Bonn. On Freud’s Psycho-Analytic Method and Its Evolution............ 76 Pror. JAMES J. PurnamM—Harvard University. Illuminating Gas and the Public Health...................000cce. 100 Pror. W. T. SepGwick—Massachusetts Institute of Technology. A Consideration of the Nature of Hunger.................cccecees 130 Pror. WALTER B. CanNoN—Harvard University. The Continuous Origin of Certain Unit Characters as Observed by a MaPUPEIPET HERMES ete ohh chs 92 aol hai) ude gh ef ese aes afte tCoubal Spa Negeo annie e 153 Pror. Henry FarrFieELD OsBorN—Columbia University. The Relation of Modern Chemistry to Medicine................... 205 Pror. THEODORE WILLIAM RicHarpDs—Harvard University. Some Current Views Regarding the Nutrition of Man ............. 225 Pror. Russett H. CarrrenpEN—Yale University. Age, Death, and Conjugation in the Light of Work on Lower Organisms. 256 Pror. H. 8. Jennrnas—Johns Hopkins University. On Malarial Fever, with Special Reference to Prophylaxis .......... 277 Pror. Witu1AM SypNrEyY THayer—Johns Hopkins University. 13 itt Saaeeen rick Boe Vale vt iy HP Ue i reual v4 Y? a EY (hb) ee Se : 4 y li yk iia neti st y ae r j Ay rie ’ r , : i, Wl M ; ! iV 4 } y if 7 H y 4 LIST OF ILLUSTRATIONS PAGE The top record represents intragastric pressure ; the second record is time in minutes (ten seconds); the third record report is of hunger pangs; the lowest record shows respiration............. 146 The same conditions as in Fig. 1. There was a long wait for hunger to ODE SUSE Sil ene aS OBR ces, vee ene 0 Re Se eee nee 147 The top record represents compression of a thin rubber bag in the lower cesophagus. The middle line registers time in minutes (ten seconds). The bottom record is report of hunger pangs... 148 Continuous origin of allometric ‘“‘unit characters’ in the cranium A and pias on man ang titanouheres ss... 23. 5 oso cea dost cas woticex ss 177 Continuity in the ontogenesis of the horn and horn sheath in cattle in SOSTABIA (SERCO LE FR RA eee a PCa LE Oe ne Pa Ra 180 Rectigradations and allometrons in titanotheres...................... 184 Continuous origin of allometric ‘‘unit characters” in the skull of various NMR Nae IAN ve ec SS sal eg aleye eM Se, thy Ge) etere Sroe 187 Cross-breeding and imperfect blending of allometric “unit characters” of the facial bones in ass (male), horse (female), and mule ...... 190 Cross-breeding and imperfect blending of sub-allometric ‘‘unit charac- ters’’ of the nasal bones in ass (male) and horse (female)........ 193 Cross-breeding and imperfect separation of allometric ‘‘sub-unit charac- ters’’ of the nasal bones in ass (male), horse (female), and mule, 195 Cross-breeding and separation of rectigradations, distinct “unit char- acters’? in the enamel foldings and pattern of the grinding teeth POMBE Ese PIE ANG SBOPSE!.. ssc 24 «Le oo 40 tie close see oe ad Grates 200 CHARTS Death rates from measles, scarlet fever and illuminating gas poisoning, 107 Illuminating gas manufactured and deaths from gas poisoning........ 110 Percentage of water gas in total gas made. Deaths by gas poisoning per billion feet of total gas. Suicides by all methods........... 115 Death rates from illuminating gas poisoning; from suicides by gas; Ae URAL CNCTNGR YY, GEES 25h \2 Bh yin wlcta 0, ap Diels cd Slaves aba ae Geunieiats 119 Deaths from gas poisoning, deaths from suicide by all methods, and CRI ER eee ae RS ei ee SU i Naa Wu aftcate me nldiala bles 121 Seasonal distribution of deaths from gas poisoning ................... 123 LOCAL SPECIFIC THERAPY OF INFECTIONS * SIMON FLEXNER, M.D. HE specific treatment of infectious diseases has, as you are aware, made great progress during the last two decades. In this time some of the most potent curative agents have been perfected and introduced into practical medicine. However, the achievements of an earlier period in this field should not be minimized. One has merely to allude to the examples of quinine and mercury, to be reminded of the discovery of two of the most perfect drugs for the conquest of specific infections that are still at our disposal. Moreover, these specific remedies date from a period anterior to the present one, in which new remedies are worked out in the laboratories before they are applied to the relief of human suffering. Since the experi- mental method in medicine is responsible for the recent great advances that have been made, it will be of some interest to refer in passing to the circumstance that the discovery of quinine and mercury was not through magic or intuition but also by experimentation, but in this instance the experiments were conducted upon sick human beings. That is to say, the adoption of these drugs represents merely a selection out of countless hundreds of substances that had at one time or another been tested against the diseases malaria and syphilis. We are to consider briefly the subject of a specific form of treatment of disease that is distinguished by the peculiarity that it comes to be applied locally to the focus of infection. — In order that we may appreciate the purpose of this method, and also the nature of the method itself, it will be necessary to lay before you a few general data concerning the subject of ' infection and of recovery from that condition, * Delivered October 7, 1911. 18 HARVEY SOCIETY In the pursuit of knowledge of the subject of infection, no aspect of the problem has been more enlightening and re- warding than that relating to the reasons for spontaneous re- covery from infectious disease. The leading physicians have rarely failed to appreciate the unexcelled power of Nature her- self to heal her self-inflicted wounds, and to recognize that many diseases tend of themselves, when not quickly fatal, to progress toward recovery. There resides, therefore, within the animal body, a set of potential forces capable, when aroused, of exer- cising a highly effective control over disease. You are familiar with the fact that these powers have been traced to a group of substances contained within the blood and passing from the blood into the lymph, where they exert influence on the cells composing the organs and on parasites in the interstices of their tissues.1 What these substances consist of has already been ascertained in good part, so that they may be classed briefly into soluble, complex chemical bodies, probably of protein nature, that are contained dissolved in the fluids, and of certain mobile white cells, the so-called leucocytes or phago- eytes. In virtue of the soluble form and the motility of the cells, these healing substances are able to reach most parts of the body where their special properties may be exerted. Moreover, not only are these curative substances, technically called ‘‘immunity principles,’’ preformed in all individuals in which they operate against intending infection, but they *The native curative powers of the blood have been invoked to heal local diseases through the creation of a condition of artificial hyperemia or congestion. “All organs that functionate are hyperemic during activity. In every form of growth and regeneration local hyperemia is present and in a degree corresponding to the rapidity and energy of the growth..... All reactions to foreign substances, whether erude bodies or minute parasites or their chemical products, are associated with hyperemia. There is no lesion which the body tries to and is capable of removing by rendering harmless, that pro- duces anemia. Hence if we accept the reactions of the body as useful efforts of Nature, we must admit that hyperemia is the most common of all autocurative agents” (Bier, Hyperemia, Translation by G. A. Bleek). LOCAL SPECIFIC THERAPY OF INFECTIONS 19 become quickly increased in amount when an infection has been established; and the ultimate issue of the condition in spontaneous recovery or the reverse depends upon the degree of this response to infection and the competency of the cura- tive principles evoked to reach and to suppress the infectious agent. These principles come to operate equally against all classes of microbic parasites, whether protozoa, bacteria, or that re- markable class the import of which we are just learning— the so-called submicroscopie or filterable organisms or viruses.” But the effectiveness of their operation is determined not only by the intrinsic qualities of parasite and of host, but also in a high degree by the manner of location and distribution of the parasites themselves within the infected host. Whether they have a general distribution throughout the blood and tissues or whether they are confined within a pathological process in the interior of an important organ or part, may be the factor determining whether not only the native curative prin- ciples shall gain ready access to them, but whether also ex- traneous curative agents introduced into the body shall be able to reach the seat of disease. The parasite, struggling to survive, withdraws, at one time, *A number of diseases of the higher animals, including man, and one disease of plants (the mosaic disease of tobacco) have, within ten years, been traced to submicroscopic parasites. It is indeed not remarkable that the present microscopes should have failed to define the limits of organized nature. Whether we shall ever invent instru- ments capable of resolving and rendering visible these minute particles of living matter is a question impossible to answer. Even doubling the potential power of the microscope by the device of employing, for photographie purposes, the ultraviolet rays of the spectrum has failed to bring them into view. Their place in nature is not accurately established. Some, as the parasite causing yellow fever, that passes a stage of its existence in mosquitoes, probably are protozoal; others, as the parasite of pleuropneumonia of cattle, that can be propagated in artificial cultures, probably are bacterial. It can hardly be doubted that they are living organisms, since they are capable of transmission from animal to animal, in which they produce infection, through an indefinite series. 20 HARVEY SOCIETY into situations to which the curative substances gain access imperfectly and with difficulty, causing thereby local infee- tions more or less cut off from the general circulation and the curative agents purveyed by the blood. This is the condition met with in massive inflanimations, in abscess formation, and in infections of specialized portions of the body—such as the ereat serous cavities—that receive normally a modified and dilute lymph secretion. It is the lymph that carries the protective as it does the nutritive principles for the tissues and organs; and hence this fluid provides the essential safeguard against infection. More- over, the quality of lymph in the several serous cavities is not the same, but is, indeed, peculiar for each cavity, and the lowest limit of strength is reached by the cerebrospinal fluid —regarded as the lymph of the brain and spinal cord, which is almost devoid of protein matter.2 As the protein moiety of the lymph carries the immunity principles, it follows that the serous cavities are really less well supplied with them, and the subarachnoid space of the central nervous system the least well of all. These considerations are not without high im- portance as affecting the provisions for warding off intending infection, and especially for controlling and abating an estab- lished infection. Since the anatomical structure decides the quality of the lymphatic fluid in health, it also determines it *The notion that the cerebrospinal fluid is the lymph of the central nervous system is open to discussion. Mott (The Lancet, 1910) suggests that it “may serve as the ambient fluid of the neurons and play the part of lymph to the central nervous system.” The fluid arises from the choroid plexus and escaping from the foramina of Magendie and Luschka into the subarachnoid spaces occupies them all and communicates, probably, with a “canalicular system surround- ing the cells and vessels of the brain” (Mott). Thus this fluid should provide the most direct path for the penetration of active substances to the nervous tissues; and in fact it has been established by experi- ment that chemical bodies act upon the nerve eells with greater energy and certainty when introduced directly into the cerebrospinal fluid. The hen, indeed, is not subject to the effects of tetanus toxin injected into the blood, while it suffers from tetanus when it is in- jected into the subarachnoid spaces (Behring). LOCAL SPECIFIC THERAPY OF INFECTIONS 21 in disease, and thus by regulating the composition of this fluid commands the issue of the pathological process. Under such circumstances the parasite that becomes localized in these cavities is insured a potential advantage against the host. The parasites possess, moreover, an advantage of regulation within themselves to preserve them from extinction—they are capable of altering rapidly, not their form and external ap- pearances, but their chemical reactions and probably chemical structure when too closely pressed and menaced. The change consists in the development of a state of effective resistance, called ‘‘ fastness,’’ to injurious chemical agents, whether the immunity principles of the blood or other substances. The new qualities acquired have been viewed as the result of muta- tion among the parasites, and the mutants have been observed to transmit the new characters through an indefinite number of generations. It is precisely this property of mutation that we are learning to hold accountable for the troublesome or dangerous relapses that occur in many of the parasitic diseases, commonly for example in malaria, sleeping sickness, spiro- cheetal infection, to mention only a few.* Finally, the so-called chronic carrier of infectious organisms, who is being recognized as a serious menace to the health of society and is sincerely to be pitied, is to be regarded often as the victim of this form of mutation among the micro-organisms which at one time caused him to be ill, but to which he, but not his fellows, has become adapted. In the successful exploitation of specific thera- peutic measures account must obviously be taken of the biologi- *This parasitic mutation or “fastness” is more readily developed against serum immunity principles (antibodies) than against chemical agents of the nature of drugs, but once produced, the latter effect is the more difficult to remove. Serum fastness may be overcome by the superinfection of an animal that has recovered from infection with the corresponding “fast” strain, through which reversion to the normal type may be accomplished; while chemical mutation is over- come solely, apparently, through sexual conjugation of protozoal parasites in the body of an appropriate insect host (Ehrlich, Folia Serologica, 1911, p. 697). 22 HARVEY SOCIETY cal conditions described as well as others that may in time be discovered. Manifestly, therefore, the bringing of the parasitic causes of microbic diseases under the influence of curative agents will be more readily and certainly accomplished when they are widely disseminated throughout the body than when they are hidden away within an organ or in the interior of a serous cavity. Hitherto the most effective agents of specific treat- ment have been just those that operated against the general- ized infections, of which examples are such drugs as quinine in its action against the malarial parasite, and mercury in its effect on the spirochxtal cause of lues. The same result is now being achieved by salvarsan, recently discovered by Ehrlich, in respect to its application to a number of spirochetal affec- tions in man and the domestic animals; while the control of diphtheria by antitoxin, perhaps the most perfect example of all, consists essentially in the neutralization of a universally distributed toxic or poisonous agent that is directly the cause of the serious effects of the disease. When, in generalized infections, the surviving micro-organisms escape from the blood and tissues, as sometimes happens in luetic or other diseases, to aggregate in special situations and local pathological products that are reached imperfectly by the lymph, then the specific drug or other agents assert: their curative powers with far more difficulty and far less certainty. Medicine is now armed with a number of specific remedies for serious diseases, consisting partly of chemical compounds of known composition and partly of more complex serum products of unascertained nature. The number of drugs is potentially greater than the number of sera and is capable of almost unlimited expansion, so that doubtless therapeuties will be greatly enriched by future discovery in this fascinating field. That many immume sera are capable of being prepared artifi- cially is also certain, but the degree of their applicability will need to be worked out in any given instance. It is already clear that the immune sera closely resemble the natural defences against infection and its consequences, so that it follows that LOCAL SPECIFIC THERAPY OF INFECTIONS 23 they are essentially non-foreign bodies, and thus, technically, ideal agents with which to combat disease. They are, in essence, so precisely fashioned as to operate exclusively against the agents of infection, and thus to pass over without molesta- tion the sensitive cells of the organs. In fact, their action is less specific than this statement implies, because, as now manu- factured, they carry with them in the natural serum of animals certain alien substances that do effect, in some degree, the host himself. A factor that bears upon the production of curative immune sera as well as upon specific drugs is that of fastness or mutation of the micro-organisms within the body. Experi- ment has already disclosed the high importance of- this un- expected phenomenon of infection. In the choice of especially fashioned drugs the two properties that now determine avail- ability for practical medical employment are, first, a low degree of toxicity for the organs of the host, and second, absence of the tendency to produce fast strains of the parasite upon which they exert their influence. We have still to learn the extent to which specific drug treatment of the infections is capable of altering the state of the acquired immunity to infectious diseases that protects, in some instances, from second attacks of maladies. Important facts bearing on this subject are already appearing in connec- tion with the more energetic modes of treatment recently intro- duced for the spirochetal infections. It seems that possibly the refractory state in these infections is the result of an enduring sub-infection, the complete removal of which exposes the individual to reinfection.’ In a similar manner it would appear that in the suppression of microbie agents of disease by the body’s forces through a process of immunization, the serum products are more varied and complex than are produced in the *Ehrlich (loe. cit.) explains this phenomenon in a slightly but not fundamentally different manner. He accounts for the decreasing number of spirochete, as the disease advances, by a wiping out of the parasites through the action of the successive specifie antibodies formed. The fresh outbreaks or relapses, then, are caused by mutants or fast strains that are immune to the antibodies thus far elaborated, 24 HARVEY SOCIETY course of artificial immunization of animals that are destined to yield sera to be employed passively, by injection, in the treatment of their corresponding diseases; and that this greater complexity arises from the circumstance that in the suppression of the micro-organisms in the infected body, not only the normal strains but also the mutants are successively overcome, with the result that a series of immune principles, each directed against its particular variety of parasite, is elaborated. Diseases of a relapsing character are accountable for on the basis of the conception that each successive relapse coincides with the appearance of a new mutant of the infecting organism ; and the typical disease of this class, relapsing fever, so-called, is characterized by the ability of its spirochetal cause to under- go at most three or four mutations that in turn lead to an equal number of relapses, which, if survived, are followed by an enduring disappearance of the infection. Hence in the arti- ficial production of curative sera we shall have to take account of the mutants or fast strains of the micro-organisms used for immunization purposes. This result is not necessarily accom- plished, although it may be promoted by selecting cultures from many. different sources. What is required is that we shall learn to distinguish the fast strains or mutants outside the body in cultures and even, indeed, to create them at will so that they may be employed for enriching the sera produced in animals that will thus be better adapted to their purpose of suppressing the parasitic causes of disease. The successful issue of specific therapeutics, toward which goal our hopes have been eagerly turned by the triumph of experimental medicine, will be secured not only by the pro- duction of more perfect instruments for the suppression of the microbie causes of disease, but also through a more effective and the subsidence of the lesions depends on the production of anti- bodies for the new strain. During the actual existence of the syphi- litie infection insusceptibility to reinfection is secured by the presence of antibodies in the blood to which the strain of spirocheetee, intend- ing to infect, is not immune. But once the disease is actually terminated and all the antibodies have been discharged, reinfection with a normal strain becomes possible. LOCAL SPECIFIC THERAPY OF INFECTIONS 25 application of the curative agents themselves to the seat of disease. I have alluded to the circumstance that the infectious agent may be strengthened in its attack by confinement within the organism, through which confinement it is preserved from injury by the defensive principles in the blood and lymph. Now no group of infections is in position better to secure this protection than that located within the membranes surrounding the brain and spinal cord, the fluid contents of which are so poor in defensive principles; and for this reason, and for the reason also that the subarachnoid spaces in these membranes are in such intimate association with the peri-cellular spaces about the sensitive nerve-cells, the consequences of meningeal infections are highly serious. To endeavor to reach the infec- tions seated in the membranes by means of the general blood and lymph circulation is futile because of the established fact that not only are the large protein molecules, which include the immunity principles, not secreted within the membranes, but also because highly diffusible salts tend as well to be excluded. But what cannot be thus accomplished by indirec- tion can, in this important instance, be achieved by direction. No operation is simpler in competent hands than lumbar puncture, so-called, which came into use originally to provide cerebrospinal fiuid for purposes of diagnosis and now promises to be of far greater value in affording the means of local specific treatment of meningeal infections. How valuable this route may be for the introduction of curative agents is illus- trated best at the moment, perhaps, by the convincing results that have been obtained in the treatment of epidemic cerebro- spinal meningitis by the antimeningitis serum. This thera- peutic agent is utterly without effect on the local infection when introduced directly or indirectly into the blood, but it has proven of unmistakable value when injected into the seat of the disease by lumbar puncture. The latest figures relating to its employment are, and should be, the most favorable to its action, since the methods of production and administration have been improved through experience; and, therefore, it is 26 HARVEY SOCIETY a source of gratification that in the recent French epidemic of meningitis the gross mortality among cases treated by serum injections begun in the first three days of illness fell below 10 per cent. The results secured in epidemic meningitis have suggested the extension of the method of direct local specific treatment to still other kinds of infection of the meninges. Meningitis is now known to be caused by a number of micro-organisms, in- eluding the streptococcus, staphylococcus, pneumococcus, the bacillus of tuberculosis and of influenza. Generally speaking, all these inflammations are highly fatal in character, There is still doubt whether recovery from tuberculous meningitis ever takes place; the number of recoveries from pneumococcus meningitis is surely very few; and while we are just learning the extent to which influenzal meningitis prevails, we can already predict that the infection is not only not infrequent, but it is highly fatal in character. Many cultures of influenza bacilli have slight or non-appreciable action on animals, and cannot, therefore, be employed for purposes of artificial immunization; but cultures obtained from cases of influenzal meningitis not only can be used for preparing an immune serum, but also produce, when injected into monkeys, a form of meningitis that in its nature, course, and fatal effects can- not be distinguished from the spontaneous human affection. This experimental fatal disease, like epidemic meningitis, can be controlled by the intraspinal injection of an anti-influenzal serum. The degree of applicability of this serum to the treat- ment of spontaneous disease in human beings is still to be deter- mined; but in view of its highly fatal character it should be tried. Undoubtedly, it will be necessary to apply the serum early and by repeated injection to secure beneficial results; and the early application will be dependent upon prompt bacteriological diagnosis, which can be made by immediate microscopical examination of the cerebrospinal fluid.® Influenzal meningitis, as it oceurs spontaneously or is pro- duced exper imentally, | is attended by an invasion of the blood *See Wollstein: Jour. Exp. Med., nea xiv, p. 73. LOCAL SPECIFIC THERAPY OF INFECTIONS 27 with the influenza bacilli which sometimes appear there in large numbers. It is important, therefore, to consider the conse- quences of the bacteremia, as it is called, upon the local treat- ment of the meningeal infection. Now, fortunately, the diffi- culties surrounding the passage of the antiserum from the blood into the cerebrospinal fluid are sharply contrasted with the ease with which the antiserum escapes from the meninges into the blood. This discrepancy is explained by the fact that while the fluid on entry is in the nature of a secretion from the choroid plexus, the escape is by way of the veins in the membranes themselves. While, therefore, it is impractical to bring the antiserum into the meninges from the blood, the reverse effect is readily accomplished ; and thus it comes about that in such secondary infections of the circulation with bacteria as are being here con- sidered, the suppression of the local development not only stops the eruption of bacilli that causes the blood infection, but the passage of the antiserum from the membranes into the blood arrests their development there. Probably recovery from any local bacterial infection is not wholly accounted for by the several activities of blood-serum and phagocytes that are usually invoked to account for the phenomenon. This restricted view leaves out of consideration certain definite chemical substances that are always present in a focus in which tissues and cells are disintegrating. That some of these substances are injurious to bacteria we now know. While the nature of the so-called stabile bacterial substances yielded by extraction of the somatic cells is still doubtful, it would appear that among them are certain soaps yielded by disintegration of the neutral and higher phosphorized fats con- tained within protoplasm. That soaps are injurious to bacteria has been abundantly proven; so that the view should be enter- tained that the degeneration of leucocytes and tissues which results from a local bacterial infection may not be entirely to the advantage of the parasitic agent, but is also of use to the body in assisting it to overcome the bacteria, since the cells brought to death and disintegration by the parasites yield 28 HARVEY SOCIETY chemical substances that themselves exert a destructive action upon the infecting bacteria. The application of these considerations to the treatment of a typical pneumococcus infection, such as the experimentally produced pneumococcus meningitis in the monkey, has been rewarded with significant results. We are still ill-informed of the factors which control resistance to and recovery from a local pneumococcus infection. The decrease in number of the organisms that takes place as recovery progresses in lobar pneumonia, for example, has not been shown to depend either on phagocytosis or on serum solution of the bacteria. It is a highly suggestive fact that the pneumococcus differs from most bacteria by reason of its solubility in chemical solutions, such as those containing bile-acids and, as has been recently discov- ered, soaps. The effect of soap is peculiar in that exposure of the pneumococci to its weak action merely modifies the texture without altering the growing properties in cultures, so that when the soaped pneumococci are next exposed to blood and serum, and especially to an antipneumococeus serum, they suffer complete dissolution. These conditions are, indeed, present in a local pneumococcus infection since soaps are pro- duced there, and during its progress immunity aa appear in the blood and lymph.’ By employing a suitable combination of sodium oleate and antipneumococeus serum, experimental pneumococcus infections of the meninges can be controlled and abolished. Through this means monkeys that would surely have succumbed have been repeatedly restored to health. But the successful employ- ment of the soap and serum mixture rests upon the overcoming of the property that the soap possesses of uniting with the protein of the antiserum and thus being rendered inert and withheld from acting upon the pneumococeus. This obstacle is the common one on which so many high hopes of the chemical suppression of infections, by. what is termed ‘‘internal anti- sepsis,’’? have been wrecked. Luckily, in this instance, it has been proven that the soap portion can be kept apart from the ie See Lamar: Jour. Exp. Med., 1911, xiii, p. 1. LOCAL SPECIFIC THERAPY OF INFECTIONS 29 protein moiety of the serum by introducing a second protective chemical body, itself innocuous, into the mixture. When minute quantities of boric acid are thus introduced, the soap is isolated and left in condition to exert its injurious action upon the pneumococci, for which organisms it appears to have a greater affinity than for ordinary protein matter. Whether among the products of local tissue disintegration a similar separation of the soap and serum elements is secured has not been ascer- tained; but we should consider factors that possibly suffice to overcome this initial impediment to the bactericidal action of the soaps, among which are the proximity of the bacteria to the nascent fatty acids and soaps and the natural occurrence within the exudate of chemical bodies that have the effect of removing the protein inhibition.® The antisera and the chemical disintegration products of cells do not exhaust the list of defensive agents that operate against infection, for there remain the living leucocytes them- selves. Certain bacterial infections that have not thus far been made to respond to the dissolved immunity principles may still be subject to influence by the white cells of the blood. Hence the effort has been made, and with an encouraging degree of success, to control experimentally produced tuberculous pleurisy in the dog by the repeated injection of living leuco- eytes ;° and the observation made upon this condition has been extended to include experimental tubercular meningitis pro- duced likewise in the dog, the course of which it has also been found possible to affect in a favorable manner.’° In the pneumococeus and tubercular infections just considered, as in the influenzal bacillus affection already mentioned, the general infection of the blood and organs has been suppressed or much reduced by the local specific treatment. *The fatty acids and soaps are yielded by the dissolution of the neutral and the higher phosphorized fats contained within the cellular protoplasm in which other colloidal bodies of a protecting nature may well be stored. *See Opie: Jour. Exp. Med., 1908, x, p. 419. ‘® See Manwaring: idem, 1912, p. 1. 30 HARVEY SOCIETY Although the treatment of these tuberculous affections with leucocytes is still in the experimental stage and is not yet ready for application to medical practice, it has been described in this connection in order that there might be brought under review the diverse means that are at present invocable in the efforts to determine the conditions that underlie the therapeutic control of varied infectious processes. Finally, the application of the principle of the local treat- ment of infections holds out hope of some measure of thera- peutic control, at least, of that serious and menacing disease, now in the foreground of interest for physicians and public alike, namely, epidemic poliomyelitis. The propagation of the disease in monkeys has led to the elucidation of its cause and pathology, while at the same time it has exposed it to thera- peutic experimentation. The cause of the malady is an exceed- ingly minute parasite—submicroscopie and _ filterable—which probably gains access to the spinal cord and brain by way of the meninges and through the lymphatic connections that sur- round the olfactory filaments that terminate in the nasal mucosa and are in direct communication with the subarachnoid spaces. The lesions of the meninges constitute an important effect of the infection, and especially of those prolongations of the meninges about the veins and arteries that enter the spinal cord and bulb and support the perivascular lymphaties. The lymphatics and, indeed, the subarachnoid spaces in general, comprise a system of communicating channels charged with cerebrospinal fluid that extend to the pericellular spaces and therefore penetrate to the nerve-cells. Consequently a para- sitic or toxic agent that gains access to the cerebrospinal fluid is capable of ready transportation to all parts of the nervous system; and by utilizing the same route it is obviously possible to distribute what may prove to be a soluble antagonistic and therapeutie agent. Recent experiments have shown unmistakably that spon- taneous recovery from poliomyelitis is brought about by a set of immunity reactions that involve the formation in the blood of soluble principles or antibodies for the parasitic LOCAL SPECIFIC THERAPY OF INFECTIONS 31 virus. Similar principles are formed in inoculated monkeys; and they can be used successfully, up to a certain point, when injected into the spinal canal by lumbar puncture, in preventing the development, after an intracerebral inoculation of the virus, of experimental poliomyelitis. This effect has not yet been accomplished by the introduction of large quantities of immune blood into the circulation, a result that was predictable in view of the location of the pathological process that leads to the paralysis in the meninges. It is not excluded that epidemic poliomyelitis may be sub- ject to effective treatment by drugs. There is, indeed, one drug—urotropin, or hexamethylenamin—that does exert some action even when administered by the mouth, since it presents the exceptional instance of a chemical body being excreted into the cerebrospinal fiuid.1t But its powers are limited. How- ever, as the drug is constituted in a manner that permits of many modifications of its composition without the sacrifice of its central structure through which formaldehyde may be liberated, it has been found readily possible to prepare a number of derivatives far exceeding urotropin in activity, some of which have been applied to the treatment of experi- mental poliomyelitis with a hopeful measure of success. These new compounds, it should be added, require to be injected into the spinal membranes and act best in conjunction with an immune serum.??. They are subject to rapid dissociation, upon which phenomenon probably their high activity depends; and *See Crowe: Bull. Johns Hopkins Hosp., 1909, xx, p. 102. “The advantage to be secured against the parasites by employing more than one antagonistic agent results, first, from the circumstance that an antibody or drug will operate with greater effect against an already injured than against a normal parasite, and secénd, because mutation in two directions is less readily effected than in one direction. Hence a fortunate combination of serum antibodies and a drug offers, theoretically, a favorable means of overcoming an infecting micro-organism. Ehrlich (loc. cit.) recommends the simultaneous employment of two curative substances, one of which is especially chosen to injure the protoplasm and the other the nuclei of the parasites. 32 HARVEY SOCIETY the dissociation proceeds somewhat more slowly in the presence of the colloidal constituents of the immune serum that itself carries a small amount of healing substances. This is obviously no more than a beginning in the effort to accomplish thera- peutic control of this protean and serious disease, the natural history and significance of which are just beginning to be appreciated ; but the outlook for its conquest is at the moment made hopeful through the utilization of the method of the local specific treatment of infections. The arguments that have been presented and the examples adduced would seem to possess not only theoretical but also established value in justifying the further pursuit of the measure of opposing local infection by local specific remedies. In the effort to combat the infectious processes account will have to be taken, in any given instance, of the peculiarities of the infecting parasite, as well as the particular anatomical and physiological adjustments of the infected parts, that together constitute the foundation upon which effective specific thera- peutic effort must ultimately come to rest. THE CHEMICAL COMPOSITION OF THE CELL* PROFESSOR ALBRECHT KOSSEL Physiological Institute, Heidelberg HEN, in response to your President’s invitation, I at- tempt to put before you a bird’s-eye view of some of the problems which are occupying the attention of biochemists at the present time, I am very cognizant of the difficulties of my task. The anatomist, the pathologist, and the clinician can present his observations to you directly, but this is not possible for the chemist. ‘The phenomena which the chemist studies are only intelligible when considered with the help of a special nomenclature, based upon chemical theories. His results are expressed in a special language in which the letters of the alphabet are represented by elements, the words by chemical formule. He makes use of theoretical conceptions when he as- sumes certain spatial relations for atoms and molecules that we can neither see nor feel. He discusses the arrangement in space of things which are inaccessible to our direct observation. These peculiarities make the presentation of his results specially difficult. When, notwithstanding, I draw your attention to these lines of investigation, it is with the profound conviction of their great importance. It may be truly said that to-day the eyes of the biologist and the pathologist are directed hopefully to- ward chemistry. Everyone who is engaged upon the investiga- tion of the processes of life in the cell, with the problems of fertilization, or of contractility, with the phenomena of nutri- tion, respiration, or growth, comes to the conclusion that all these manifestations of life are ultimately to be referred to chemical changes, and it is chemistry that must bring us the * Delivered October 14, 1911. 3 33 34 HARVEY SOCIETY solution of the most important of the mysteries of life which are accessible to investigation. When we consider the extra- ordinary results of chemistry obtained during the last century, we may well be inclined to expect even more wonderful re- sults in the future, but it is certain that they cannot be obtained at once. It requires long and intensive work to develop from the elementary chemistry of to-day a higher chemical science capable of analyzing those complex chemical processes which to- gether constitute life. To-day we are concerned with the question as to how far chemistry has been of service in promoting our knowledge of the processes of life. How may chemistry concern itself with the fundamental questions of physiology? What are the bio- chemical problems which we may successfully attack in the present state of our knowledge? The medical student begins his studies with anatomy, and the biochemist who investigates the finest details of metabolic changes must begin in a similar fashion. First of all, he must concern himself with questions relating to the presence, distribution, and properties of certain chemical constituents of the animal body. Only when this has been accomplished is it possible for him to approach the chem- ical processes taking place between these different constituents, which together form the basis of metabolic changes. Moreover, the chemical consideration of the various sub- stances present in the body resembles anatomical studies in that both of them are concerned with spatial relationships. I have already referred to the fact that we think of the atoms as ar- ranged in definite positions in space. These arrangements of the atoms, which together make up the ‘‘ formula,’’ give to the chemist a presentation of the properties of a substance. When we have obtained such a formula, we can predict to a certain extent how a substance will behave in certain chemical reac- tions and with certain chemical reagents, and also its behavior toward the chemical actions which are operative in the living organism. If, for example, we find in a chemical formula the group COOH, we infer that the substance possesses the prop- erty of an acid, while the group NH, is indicative of basic qualities. We learn also whether it is attacked by oxygen with CHEMICAL COMPOSITION OF THE CELL — 35 ease or with difficulty, and whether its decomposition by one or other ferment is probable. Thus the foundation for our bio- chemical considerations is derived from chemical formule, just in the same way as physiological and pathological considerations are derived from anatomical representations. I should like to carry the comparison between anatomical and biochemical investigations still further. Laws governing the anatomical relationships of the human body and also the sciences of pathology and physiology have entered upon a new era, since it has been possible to determine certain cellular units in plant and animal tissues which act as centres for de- velopment, for nutrition, and for numerous other special func- tions. Through the determination of these units it has been possible to define more exactly many physiological and patho- logical processes, and also to compare them with one another and so make them more intelligible. Biochemical investigations require the consideration of similar units. So long as one considers the mass of living substance as a whole, an analysis of its activity ean scarcely be undertaken. Such an analysis is only possible through the isolation of certain units capable of chemical investigation and to whose activity the individual functions of living substances may be referred. I wish to speak of these units, which I shall refer to as the ‘‘ Bausteine ’’ or building-stones of protoplasm. The word ‘‘ Baustein ’’ indicates that these units may be united to form larger structures and that their union takes place according to a determined plan or architectural idea. Through the union of these Bausteine larger aggregates are formed which we call either proteins, fats, nucleic acids, phos- phatides, or polysaccharides, as the case may be. On the other hand Bausteine are not the smallest units of the living tissue, for they are themselves composed of a certain number of atoms of different kinds, commonly of carbon, hydro- gen, nitrogen, oxygen, or sulphur. They are, however, not only anatomical or structural units but also physiological units. If we wish to obtain a clear picture of the chemical changes occurring in living substances, we must study the behavior of these Bausteine. It is with them that we must work in our 36 HARVEY SOCIETY studies of physiological combustion and of all the processes bound up with the production and destruction of organic sub- stances in the animal eells. In one relation my choice of the term Baustein is not appli- eable. The Bausteine or building-stones of a house are uni- form, but the Bausteine of living substances possess a great diversity. They differ among themselves as much as the stones of a colored mosaic, and in addition, they are of different sizes. At times, however, we find aggregates which are formed by the repeated combination of a single type of Baustein, but in gen- eral the most varied types of Bausteine are intermingled ac- cording to a definite plan. We may ask ourselves what are the reasons for ascribing to these atomie groups which I term Bausteine a certain indi- viduality, and for singling them out as units from the more complex aggregates of atomic compounds which we find in liv- ing substance. he conception of these atomic groups as Bausteine is due to their internal stability and also to the coherence of the carbon atoms which makes them relatively stable in metabolism. The carbon atoms which go toward the building up of the Bausteine are arranged either in the form of chains or of rings. Where one Baustein is united to another we find another atom such as oxygen, nitrogen, or sulphur taking part in the union. These latter elements may be re- garded in a sense as the mortar of the Bausteine. In the fol- lowing diagram I try to make this clear. TABLE I (1) -C—C—C-—C-—C-—-C-—O-C-—-C-—-C-—-C—-C-C-— (2) C-—-N-—C—-C—C-C-C- | Cc po. | CGC C—C-—-C-—-N-C (3) B | | | ta C Cc ) (4) C-C-C-S~-S-C-C-C CHEMICAL COMPOSITION OF THE CELL 37 The above representation is intended to convey the mode of union of two Bausteine with one another, and the binding atoms are indicated in heavier type. One must remember that the scaffolding or ‘‘ carbon-skeleton ”’ of the Bausteine may greatly vary in size. The union of two Bausteine, each containing six carbon atoms, is shown in the first example, while in the second a Baustein with only one carbon atom is united with one con- taining five carbon atoms, while the third formula represents a Baustein possessing a skeleton of nine carbon atoms partly arranged in the form of a ring united with a side-chain of three carbon atoms. Finally, in the fourth formula, we have two chains each containing three carbon atoms. The union of the Bausteine in the first case is effected by an oxygen atom, in the second and third, by a nitrogen atom, and in the last case by means of two sulphur atoms. We have here four characteristic types of combination such as are to be found in every living part of animal and vegetable organisms. It is possible for a much greater number of Bau- steine to be united in a similar fashion, so that aggregates may be formed containing several hundred carbon atoms. The reso- lution of such large structures can be relatively easily accom- plished at the places indicated in heavy type. This change is brought about especially by the ferments present in the animal and vegetable organisms. Our food contains principally Bausteine united in large aggregates and not in the form of single units. Through the secretion of the salivary glands, stomach, pancreas, and intes- tine, these combinations are to a large extent completely re- solved, and when necessary their disintegration may be made more complete by other ferments present in the tissues. But on the other hand, these large structures may be equally readily built up from the individual Bausteine. The union of Bau- steine, ‘‘ the building-up,’’ requires the expenditure of a very small amount of energy, as is also the case with their decompo- sition, ‘‘ their break-down,’’ which leads to a very slight libera- tion of energy. In addition to these Bausteine, composed of directly united 38 HARVEY SOCIETY carbon atoms, we have a second form in which the carbon atoms are not directly united. This is made clear in the following formule : TaBLeE II I II N-C Avi ZN-G C C-Ny - | ir ee ine? N-C According to what has been previously stated, Formula I shows us three different Bausteine, since the union of the carbon atoms is interrupted at three different places by nitrogen atoms. In Formula II we might assume the presence of two Bausteine. As a matter of fact I prefer in both cases to consider the whole group as a single Baustein, for by the closing of the ring the union of the atoms is made so firm that they possess marked resistance to the decompositions of the organism and the whole system reacts as a unit both within and without the living or- ganism. I found the first grouping as a characteristic constitu- ent of cell nuclei. It is also found, however, in uric acid, and since we find it in the urine, we may regard this as proof of the stability of this ring-system. The substance whose atomic link- ing is represented in Formula II was found by me in the pro- teins and is known as histidine. I have just spoken of the multiplicity of these Bausteine and illustrated it with different formule. The variety is so great that it is necessary for us to limit ourselves for the present to the more important types. Our choice has, however, certain restrictions. We find that certain individual Bausteine are present in all living cells capable of developing, and these re- eur in unchanged or but slightly changed form throughout the animal and vegetable world. We ascribe to these Bausteine a fundamental biological importance, in contrast to others which occur only in certain orders or families, or possibly only in in- dividual species. So far we have only considered the carbon skeleton, which is contained in these substances; their real character is de- CHEMICAL COMPOSITION OF THE CELL 39 _ pendent upon other atoms which are attached to this scaffolding of carbon. In the foregoing tables only the carbon atoms have been inserted, while further on we shall find that the printed formule have their skeletons to a certain extent provided so to say with flesh and blood. By the attachment of oxygen and hydrogen atoms to a chain of three, five, or six carbon atoms, substances are formed which are known as polyatomic alcohols. By the addition of oxygen in a somewhat different manner we obtain saccharides, the biological importance of which is recognized by everyone. By the accumulation of oxy- gen at a particular point in the molecule, the whole complex assumes acid properties, and in this way the organic acids are formed, the higher members of the series being found as Bau- steine of all living cells. As examples of these substances I may mention butyric, palmitic, stearic, and oleic acids. I have already mentioned the fact that the union of nitrogen and hydrogen atoms gives us the amino group, and this, when attached to a carbon scaffolding, confers basic properties upon it. Basic Bausteine of this kind can as a matter of fact be found in all parts of the living organism. As an example we may mention the amidine group which may be converted into urea through the entrance of oxygen and hydrogen. The amino-acids form a group possessing a very wide distribution and apparently concerned with most important biochemical functions. The amino-acids possess at the same time the prop- erties of both acids and bases. A glance at the following table shows us that they contain both the carboxyl and amino groups. The number of amino-acids which are found in protoplasm is very considerable. They form a series constructed according to a common plan, and are known as homologous substances. The simplest member of this group is amino-acetie acid or gly- cocoll. If we replace a hydrogen atom of glycocoll by the group CH,, we obtain another substance which is known as alanine, and this body possesses special interest. There are many Bausteine which may be regarded as ala- nine derivatives. All of these derivatives may be regarded as 40 HARVEY SOCIETY formed by the substitution of hydrogen atoms. Serine for example, by the entrance of (OH), cysteine, by the introduc- tion of (SH). If the group C,H;, the so-called phenyl group, is introduced, we obtain phenylalanine, while the oxyphenyl group leads to tyrosine. Other groups, such as ‘‘ indol’”’ and ‘“iminazol’’ as substituents of alanine, lead to the formation of tryptophane and histidine respectively. Tase III CH, CH,OH CH,SH CH,-CsH; CH,-CsH,OH CHNH, CHNH, CHNH, CHN H, CHNH, Coon Coo COOH COOH COOH Alanine Serine Cysteine Phenyl- Tyrosine alanine CH— NH CH | CH ecaire as TG Nea Chee — 4 | | CHNH,CH C CH CHNH, | CARA | COOH NH CH COOH Tryptophane Histine It is thus seen that we have a large number of Bausteine which resemble each other in general structure but which ap- parently subserve different physiological functions. The two last-mentioned substances, tryptophane and histi- dine, both of which contain five carbon atoms directly united with each other, form a connecting link with those amino-acids containing more than four carbon atoms of which valine is the first representative. Its composition is shown in the fol- lowing table: TaBLe IV CH; GH, CH. (CH: CH, *G.o, L. SO Noes CH CH CH | | | CHNH, CH; CHNH, | | | COOH CHNH, COOH | COOH Valine Leucine Isoleucine CHEMICAL COMPOSITION OF THE CELL 41 Together with the valine we find in the above table two other Bausteine, leucine and isoleucine, which differ from each other by the form of their carbon skeletons. The multiplicity of these chemical forms is increased by the fact that the number of COOH and NH, groups attached to one and the same carbon chain may vary. We find, for ex- ample, in the adjoining table, two amino-acids, one of them glutamic acid containing two COOH groups, the other ormthine containing only one COOH group but two NH, groups. Natur- ally the characters of these two Bausteine are altogether differ- ent. The first is an acid, while in the second substance basic properties predominate. TABLE V CH,-NH, COOH | | CH: CH, | | CH, CH. | | CHNH, CHNH, | | COOH COOH Ornithine Glutamic Acid But I do not wish to weary you with the further enumera- tion and closer characterization of these substances. I will only say that in the amino-acids we have a group of which it may be well said: ‘Alle Gestalten sind ihnlich und keine gleichet der andern Und so deutet das Chor auf ein geheimes Gesetz.’’ In the living cell these substances are found partly in the free state, but chiefly in combination. Under normal econdi- tions they do not accumulate in the free state to any consid- erable extent, but this does frequently happen under pathologi- eal conditions. I need only mention the appearance of cys- tine, glucose, and the higher fatty acids in certain abnormalities of metabolism. It is also well known that these substances are often stored up in considerable amount in ripening seeds. 42 HARVEY SOCIETY Other considerations confirm us in the belief that the Bau- steine of protoplasm play an independent role in the organism. A particularly instructive and well-known example is the for- mation of hippuric acid following the introduction of benzoic acid into the animal body. This change is brought about so that the glycocoll or amido-acetic acid is attached to the benzoic acid administered. Thus we see that the glycocoll not only appears as a chemical unit when we decompose animal tissue by artificial means, but also that it can react as a unit in the processes taking place in the living body. The same thing is true in the case of some other amino- acids, such as ornithine and cystine, and in the case of certain other Bausteine of protoplasm, such as glucose, for example. All these substances may react, at least to some extent, in the free state, as does glycocoll. They may attach themselves to substances which may be introduced into the animal body, and thus it is certain that they may react as independent groups in metabolic processes. As I have previously said, in most cases these Bausteine are found not as chemical individuals but as parts of a larger complex. Thus are formed the most various substances which we know as fats, carbohydrates, phosphatides, and proteins. I have already spoken of their different types of union. In some cases we find the Bausteine united to the larger com- plexes by means of oxygen, in other cases by sulphur or nitro- gen. In those cases where the union is effected by means of nitrogen we find that one of the three valences of nitrogen is united with one of another Bausteine, while the third valence is attached to hydrogen. The linkage is thus effected by an NH group or ‘‘ imino-group.’’ When a large number of amino- acids are joined to each other in this fashion there are formed large aggregates which are known as albumins or proteins. The fats present a very simple form of union in which the triatomie alcohol, glycerin, is united with three fatty acid molecules. The phosphatides form a more complex group and apparently contain combinations of most varied kind, of which some are still unknown to us. In the carbohydrates we also CHEMICAL COMPOSITION OF THE CELL 43 find the linkage brought about by oxygen. These Bausteine have a skeleton containing five or six carbon atoms which are bound together in large or small numbers. The linkage by sulphur is only met with in exceptional cases as in the pro- teins together with the imide forms. These imide linkages are the predominant form present in the proteins. An example is shown in the following formula representing the combination of a glycocoll with an alanine molecule: NH,:CH,:CO NH-CH- COOH CH, Glycylalanine The larger groups formed by the union of many Bausteine are those which the chemist first encounters in his analyses. Thus up to the present it has been customary to consider the proteins, polysaccharides, fats, and phosphatides as the physio- logical units rather than the protoplasmic Bausteine. When, therefore, I regard the smaller protoplasmic fragments as the reacting units, I find myself to a certain extent in opposition to the usual point of view, and this conception of mine should not be generally adopted without further consideration. As a matter of fact, when we consider the physiological réle of the larger aggregates, such as the proteins, it is necessary for us to distinguish between those functions which may be considered as due to the sum of the individual Bausteine and those which depend on the mode of union of these Bau- steine. In the latter case it is the particular formation of the whole molecule which is of importance. This latter is obviously the case where the form of living parts is dependent upon the constituents, as, for example, is the case with cellulose, chitin, and the horny substance of the skin. In other cases it would appear that the function of certain substances is not dependent upon their chemical composition, but it is rather their physical consistence that renders them of value to the organism. In these cases the proteins function as a whole, and probably this is also the case with the muscle proteins con- cerned with the transmission of mechanical and thermal stimuli. 44 HARVEY SOCIETY This is true, too, of the proteins of other parts concerned with the reception and distribution of stimuli. There are many other important functions which are de- pendent upon the chemical peculiarities of the whole molecule. As an example I may mention the taking up cf oxygen by the coloring matter of the red blood-cells. The large protein mole- cules are so arranged that they easily react to feeble chemical influences, and this reactivity is undoubtedly related to their physiological role. The foregoing examples differ from those cases in which we find large molecules, especially in the case of the carbohydrates and proteins, which are to be regarded simply as storage forms of the smaller active components. The proteins, the polysaccha- rides, and other similar aggregates act in this manner when they are employed as foodstuffs. The particular forms of com- bination which are characteristic of the large molecules are de- stroyed in the process of digestion. Specific ferments decom- pose the polysaccharides; others the fats or phosphatides; others the nucleic acid; and still others resolve the proteins into their Bausteine. The individuality of the proteins is completely lost save for the quantitative relations of the Bausteme, which un- dergo absorption and are utilized for the various purposes of the body. We may regard the storage of carbohydrates, fats, and pro- teins in the same way. They form a reserve of nutrient ma- terial which is attacked and utilized according to the neces- sities of the organism. At certain times ferments come into play in the tissues which decompose the larger aggregates into their Bausteine, which then play a part in metabolism as in- dividual units. Glycogen, for example, which is readily stored up as the result of a generous diet, at other times is resolved into glucose molecules, that is to say into its Bausteine. Pro- teins in the same way are decomposed by active tissue ferments into their Bausteine, which are then utilized in the course of metabolism. The importance of this resolution into Bausteine ean only be fully appreciated when one considers that out of these same CHEMICAL COMPOSITION OF THE CELL = § 45 Bausteine entirely new structures may be built up in other parts of the organism. For example, if an animal is fed with fat, the fat is resolved into its Bausteine in the intestinal eanal, but it may be resynthesized, on absorption. Fat in the process of transportation through the intestinal wall may be compared to a portable house which may be taken apart in one place to be reconstructed in another. When the proteins undergo a similar process, involving their decomposition and subsequent re-formation, a change in the character of the synthesized protein may be effected. Thus the body is able to build its own protein substances from foreign proteins. This reconstruction of the proteins is so interesting and so physiologically important that I should like to make further reference to it. I should like to compare this rear- rangement which the proteins undergo in the animal or vege- table organism to the making up of a railroad train. In their passage through the body parts of the whole may be left be- hind, and here and there new parts added on. In order to understand fully the change we must remember that the pro- teins are composed of Bausteine united in very different ways. Some of them contain Bausteine of many kinds. The multi- plicity of the proteins is determined by many causes, first through the differences in the nature of the constituent Bau- steine; and secondly, through differences in the arrangement of them. The number of Bausteine which may take part in the formation of the proteins is about as large as the number of letters in the alphabet. When we consider that through the combination of letters an infinitely large number of thoughts may be expressed, we can understand how vast a number of the properties of the organism may be recorded in the small space which is occupied by the protein molecules. Tt enables us to understand how it is possible for the proteins of the sex-cells to contain, to a certain extent, a complete description of the species and even of the individual. We may also comprehend how great and important the task is to determine the structure of the proteins, and why the biochemist has devoted himself with so much industry to their analysis. 46 HARVEY SOCIETY The first step in these lengthy investigations consists in the determination of the quantitative relations which the Bau- steine in the protein molecules bear to each other—how much of one and how much of another Baustein is present in the large protein molecule. Methods have been worked out for the determination of some of the amino-acids, to estimate the quantity of leucine, alanine, histidine, and lysine in different proteins. The results of these analyses are presented in such a way that one may see the percentage quantity of any par- ticular Baustein in the different proteins. This represents merely the beginning of our investigations, and may be compared to a man attempting to read a book in some foreign language who at first can only determine the numerical relation between the different letters of the alphabet in each section of the book. I should like to illustrate this by an example. It has been possible to remove from proteins some large fragments and successfully investigate their constitution. In this way the relative position of individual Bausteine in the protein mole- cule can be determined, and this again may be compared to the deciphering of separate syllables. Furthermore, it has been possible to reconstruct artificially such compounds and compare the synthetic with the natural products. In this way a knowledge of the chemical make-up of the protein substances may be slowly gained. On the other hand it is possible to find in nature substances which may be regarded as simplified pro- teins, and the constitution of these is more readily investigated than the complex typical proteins. The following is an example of their formation: Observations upon the life-history of the Rhine salmon show that this fish at certain times lives in the sea; at others in fresh water. During the period of life in the sea, he eats freely and devotes himself to the acquisition of a sufficient quantity of protein in his body to serve him for a long time (on an average about ten months) in the river, where the for- mation and storing of the sexual products take place. While in fresh water he takes no food of any kind, and the proteins CHEMICAL COMPOSITION OF THE CELL 47 of the body muscles are used up to a large extent, while the male or female sexual products are being formed. During this time the animal may be compared to a patient in whose body is formed a tumor, the tissue material of which is slowly gathered from the whole body. By the beginning of November the development of the sexual products has reached its high point. If at this time we kill the male animal and compare the protein of the newly-formed male sexual products with the protein which in the course of the development of the testicles has disappeared from the muscles, we find a peculiar relation- ship. Of twenty Bausteine present in the used- -up protein, only four or five kinds are present in the newly-formed proteins. We must conceive of the process as taking place first of all by the resolution of the protein into its individual Bausteine. Some of these Bausteine are completely decomposed during the starvation period of the animal and others of special kinds re- main protected from decomposition and are united to form a new protein substance—the so-called salmine. Similar transformations of proteins into other protein sub- stances possessing totally different characters from the original one take place when foreign proteins are used for food. In the seeds of many plants proteins are contained which differ in their composition from the proteins of the animal organism. This difference is due to the absence of certain Bausteine which are present in the animal protein. Moreover, they possess different solubility relationships. Zein, the protein of maize, is an example of this kind. If a young goose is fed for several months with maize so that its body substance is materially increased, we find on investigation of its or gans that the Bau- steine of the maize have been used for the synthesis of a new animal protein. This process of reconstruction is seen to oc- cur when a mammal such as a dog or mouse is given only Bausteine instead of intact protein substances. In this case it is possible to demonstrate the formation of the proteins charac- teristic of the animal’s own body. Similar phenomena are observed in the ease of other chemi- eal constituents of the tissues, such as carbohydrates and fats. 48 HARVEY SOCIETY It has long been known that glucose when introduced into the body leads to glycogen formation, while fatty acids unite with glycerine and are built up into fats. Thus far we have been considering the Bausteine, the na- ture of their union, and their formation from large groups, without considering the questions of their origin and of their significance in metabolism. I propose to touch on these prob- lems but lightly. When in the seventies the early observations upon the structure of the cell nucleus were made, it was correctly be- lieved that a most important step forward had been taken. The histological structure of the nucleus and its changes in form were rightly considered characteristic of the individuality of the organs. These nuclei are found throughout the whole world of living organisms, and form an ‘‘ Hinheit in der Vielheit’’ of living phenomena. Karyokinesis is brought into relation with the function of cell division and growth of living substance. It is obvious that it would be of even greater im- portance if we could correlate the changes in chemical struc- ture with these histological peculiarities. It would give us a deeper insight into the significance of these parts of the liy- ing substance if we could determine a particular atomic group- ing which would be typical for the cell nucleus or for its functions. It seems to me that such a determination may be derived from investigations upon the chemistry of these elementary parts. If we compare the atomic groupings of the cytoplasm with those of the karyoplasm, we find that long carbon chains either free from or poor in nitrogen predominate in the first. This is also the case with the fatty acids and the carbohydrates. Furthermore, the proteins of the cytoplasm are to a large ex- tent made up of the union of monamino-acids which contain only one nitrogen atom in a large series of carbon atoms. Such is the case, for example, with leucine, valine, tyrosine, or alanine and most of its derivatives. If we now compare the atomic groupings which are char- acteristic of the cell nucleus, and which have already been re- CHEMICAL COMPOSITION OF THE CELL 49 ferred to as constituents of the nucleic acids (Table II) we see, in the first place, an abundance of nitrogen, and secondly a peculiar grouping of this element between the carbon atoms. This is particularly characteristic in the cyclic complexes which are known as pyrimidine and purine derivatives. In many of these compounds, such as adenine for example, we find a nitrogen atom attached to every carbon atom and the arrange- ment is such that C and N alternate with each other in the formula. Similar atomic groupings are found in certain special Bau- steine which make up the protein molecule. It is found that those proteins which occur in the cell nucleus are very rich in these groups. This is particularly true of the so-called amidine group which we find in arginine and which exhibits the accu- mulation of nitrogen shown in the following formula: NH, —C = NH—NH-C:.----:::-- In certain nuclear substances a particularly large amount of histidine is found. This substance belongs to the iminazol group and has the cyclie structure shown in Table III. These observations compel us to assume that these peculiar linkages of the carbon and nitrogen atoms stand in close re- lation to the functions of the cell nucleus and especially that concerned with building up new material. When the proteins of the yolk of insect or hen’s egg are converted into young, growing cells, whose function it is to furnish rapidly new tissue, a rearrangement of the atoms takes place in such a way that these peculiar carbon and nitrogen linkages are stored up in the cell nuclei. The foregoing observations do not exclude the possibility of the same atomic group appearing in other places in the tissues and subserving other physiological functions. Thus for example we find the purine ring in guanine as a constituent of the skin of many organisms in the form of erystals, which apparently influence the color through their optical properties. Or we may find the purine ring among the end products of ani- mal metabolism, since the cyclic grouping is relatively resistant. 4 50 HARVEY SOCIETY Let us now glance once more at the peculiar chemical re- lations of the cell nucleus. Here we find substances of acid property, the nucleic acids which exist in different forms. These substances have acid properties, and long since I have put forward the view that they are to be considered as poly- metaphosphorie acids containing, therefore, a chain of phos- phorus and oxygen atoms to which the previously mentioned pyrimidine and purine derivatives as well as carbohydrates are attached. In the cell nucleus these substances are united only with proteins, and these combinations may be of various kinds. In some cases the combination is quite stable, so that it is impos- sible to resolve it without destruction of the whole chemical structure. In other cases the nucleic acid is united with the protein in a loose salt-like combination which is readily de- composed under the influence of a stronger acid. This is observed in those cases in which the proteins of the cell nucleus are made up of basic molecules such as the histones. It may be said, therefore, that there are two types of nuclear sub- stances occurring in the different cell nuclei. I may refer to these as the dissociated and non-dissociated forms. It would seem likely that microscopical differences between the two forms of cell nuclei may be found. The question presents itself as to whether it is possible to correlate physiological relationships with these two forms of cell nuclei. Up to the present, so far as I know, this has not been possible. In the same organ of one species we find the dissociated, of another species, the non-dissociated forms. For example the nuclei in the heads of the spermatozoa of warm-blooded animals appear to be non-dissociated, so far as my investigations go, while on the other hand they are dis- sociated in the ease of fishes. In the internal organs of higher animals both forms are encountered side by side. These considerations show us how the methods of biochemi- cal analysis may be utilized for the attainment of a knowledge of living processes. CHEMICAL COMPOSITION OF THE CELL 51 While the experimental physiologist approaches the living organs with a definite supposition of hypothesis and plans his experiments with reference to this preconceived idea, the histo- chemist carries on his investigation unhampered by such defi- nite preconceptions, and usually cannot foresee the nature of his results. The descriptive and the experimental method must go hand in hand in the investigation of living function. The ideas derived from the one are carried further by the other. When nowadays we regard it as necessary to separate the experimental and descriptive sciences, to separate anatomy and physiology, and the chemical and physical methods of investigation, it involves the breaking of 2 natural continuity. Such separation is only necessary because of the limitations of individual human endeavor, for it is impossible for a single person to master all the methods and to familiarize himself with so vast a wealth of material. NARCOSIS* PROFESSCR MAX VERWORN University of Bonn WO main reasons induced me to select the subject of nar- cosis for my lecture before your society. On the one hand, I am following herein the suggestion of your honored President; on the other hand, the problem of narcosis has a personal attraction for me, since with my colleagues at Gottin- gen, as well as in Bonn, I have devoted a great deal of attention to its investigation. Furthermore, I believe that this theme, the subject of narcosis, possesses an especial interest for medical men, not only from the theoretical but also from the practical side. From the theoretical side, because the processes of nar- cosis introduce us into the most profound secrets of the mechanism of living matter; from the practical side, because it is incumbent upon the physician to know the actual nature of the condition which he so often induces in man. Practical and theoretical interests have here, once more, the same object. Such union of practical and theoretical interests makes our medical work so fruitful and lends it a special charm among the biological sciences. This is especially manifest in the study of the peculiar phenomena of narcosis, and is also the reason why the subject of narcosis has been so extensively in- vestigated, especially in the latter decades. The knowledge of the use of narcotic substances, especially those from the vegetable kingdom, is ancient. It extends back to prehistoric times, as we may deduce by analogy with primi- tive races living to-day. Man has been, from the first, a stu- dent of nature. He was forced to adapt himself, at every step, - to his environment. This he could do only by very close ob- servation of nature, for there was danger lurking for him “* Delivered October 28, 1911. 52 NARCOSIS 53 wherever, in his wanderings, he was confronted with new con- ditions. ‘Thus, in his quest for food he had to learn to recog- nize the peculiar poisonous effects of plants. All primitive races are familiar with them and employ them for various purposes. The use of nareotizing substances, especially for purposes of enchantment, was well known in the Homeric age. Circe mixed narcotic juices with the food of the companions of Odysseus, making them forget their homes; and Hermes knew already an antidote, which he gave to Odysseus as a protection: pa@iv o8 piv xzaklovot Gent. In Homer we also find, for the first time, although not in connection with poison- ous action, the word from which the modern term ‘‘ narcosis ”’ ig derived. The verb vapxdw, “‘T am paralyzed,’’ appears in Homer as dza& elpnpévov when he deseribes how Hee- tor struck Teukros on the shoulder with a sharp stone, so that his hand, paralyzed, let fall the bow (Iliad VIII, 328). This venerable word serves us to-day to distinguish a special group of paralyses, or depressions, which are induced by chemical substances. The scientific study of narcosis begins, however, only with the time when narcotics came into general use in medical prac- tice for the relief of pain, especially since, in Boston, in 1846, the chemist Jackson and the dentist Morton introduced ether into surgical practice. Soon after this momentous event ex- periments began for the purpose of explaining the striking action of anesthetics. Among the numerous explanatory ef- forts, however, there are only two series of attempts which de- serve scientific consideration. In one series attempts have been made to establish a relation between the depressing action of narcotics and their solubility in certain constituents of the organism. As early as 1847, Bibra and Harless used the fact that cerebral fats are readily soluble in such narcotics as ether and chloroform, as a basis for a hypothesis of the mode of action of narcotics. They assumed that the narcotics act as anesthetics by extracting the brain fats. Hermann indicated later a similar conception, and 54 HARVEY SOCIETY recently Reicher has shown that in deep and long-continued narcosis the fat content of the blood rises indeed quite mark- edly. While already in these assumptions the relations of solubility between fats and narcotics stand in the foreground, Richet has later on called attention to a second relation in regard to solubility. He noticed that many narcotics were distinguished by a very low degree of solubility in water, and believed that, on the basis of his observations, he could make the general statement that a substance acts the more strongly as a narcotic, the less it is soluble in water. The relations be- tween the solubility of narcotics in fats and water and their depressing action, which in the before-mentioned observations and hypotheses were expressed so incompletely and obscurely, were first made clear and formulated according to definite laws by Overton and by Meyer, independently of one another. Hans Meyer and Overton were able to show that the intensity of the narcotic action of any substance is dependent on the proportion in which it is distributed between water and fat when it is shaken with a mixture of fat and water. The co- efficient of distribution, that is, the proportion of solubility of the substance between water and fat, is the greater, the stronger its narcotic action. That is to say, a substance acts the more strongly as a narcotic, the more soluble it is in fats and lipoids and the less soluble it is in water. Meyer and Overton have confirmed this law in the ease of a very large number of narcotics. This interesting fact contains apparently a very important requirement for the production of narcotics, although it does not present a ‘‘theory of narcotics,’’ as has often been incorrectly stated. It shows us one factor that must be realized if the narcotic is to reach its field of action, but it tells us nothing concerning the mechanism of the nar- cotizing action itself. The second series of explanatory attempts ascribes the de- pressing action in narcosis to a change in the state of aggre- gation of certain components of the protoplasm under the in- fluence of the narcotic. Claude Bernard, who noticed the NARCOSIS ; 55 rigidity of muscles which is produced by the influence of chloroform vapor or heat, was the first one to express the view that narcosis consists in a ‘‘ semicoagulation ’’ of the proto- plasm. Binz came to the same conclusion from a microscopic study of ganglion cells and unicellular organisms. He found that the protoplasm of the cells became opaque, granular, and dark under the influence of the narcotic, as is the case in coagulation, and he sees therefore, in narcosis, a depression by coagulation. As a matter of fact, it is easy to observe such changes in unicellular organisms under the influence of large doses of narcotics, but recovery from such a state is no longer possible. In recent times, Hober has expressed similar opinions. Hoéber makes the hypothesis that the process of excitation is associated with a loosening of the protoplasmic colloids, which consist of lipoids and proteids. In connection with this assumption, Hober offers the further hypothesis that nareoties inhibit this loosening of the colloids, especially in the superficial protoplasmic layers of the cell, so that in con- sequence the irritability is reduced or abolished. Thus, we see that widely different hypotheses concerning the nature of narcosis have been expressed, without any of them having as yet achieved general acceptance. Before we attempt to form a conception of the mechanism of narcosis, it appears to me indispensable that we clearly un- derstand what should be required of any theory of narcosis. Narcosis is a state of living matter, in which, under the in- fluence of certain chemical substances, the physiological proc- esses of the cell are altered in a special way. A scientific study of this state can consist only in seeking to determine, as far as possible, the nature of these changes. The more deeply we analyze them, the clearer becomes the theory of narcosis. In order, however, to comprehend the changes in the physiological processes in living matter, it is requisite that we should first know the normal physiological processes themselves, in all their details. In spite of many important and fundamental researches, we are to-day still far from such knowledge. From 56 HARVEY SOCIETY this it is evident that we cannot yet speak of a ‘‘ final ’’ theory of narcosis. But where in our knowledge do we arrive at final results? Wherever we may look, whatever we may achieve, we are always and again confronted with new problems. Is there, anyway, a finality anywhere? Whoever, impatiently rushing forward, looks for a final word in knowledge will, like Goethe’s Faust, only experience grievous disappointment : “Entbehren sollst Du, sollst entbehren! Das ist der ewige Gesang, Der jedem an die Ohren klingt, Den unser ganzes Leben lang Uns heiser jede Stunde singt.” On the other hand, whoever is conscious that all things stand in endless coherence will desist from seeking an imagi- nary goal, and instead will enjoy the inexpressible charm which lies in the unlimited possibilities of finding again and again new links of this coherence. The possibilities of knowledge are endless, because the world is endless. This is true in large as well as in small things, and is true also of our problem. To the extent to which we succeed in discovering new facts which characterize the state of narcosis, to that extent the theory of narcosis develops of itself. Well, then, what do we know of the changes which living matter undergoes during narcosis? Narecosis is a state of depression. Let us understand what this means. All states of depression in living systems are characterized by the fact that all or single partial processes of the normal metabolism undergo a retardation of their course, which may amount to complete standstill. This shows itself in the following symp- tom complex. The specifie manifestations of life of that system are depressed or extinguished. The irritability to ex- ternal stimuli is lowered, so that stimuli which are effective in the normal state show no apparent result. At the same time the power of conductivity, that is, the transmission of the excitation from the point of stimulation to some distant place, is correspondingly restricted, for irritability and conductivity NARCOSIS 57 run always and everywhere along parallel lines. This symp- tom complex occurs in the most diverse living systems and un- der the influence of manifold agencies. We see it as a result of low temperatures in ‘‘frigor depression,’’ or as a result of high temperatures in ‘‘ heat depression ’’; we meet it after ex- treme functional activity, as fatigue; after withdrawal of oxygen, as suffocation; under the influence of chemical sub- stances, as toxic depression; after too low osmotic pressures of the surrounding medium, as ‘‘ water rigor ’’; from stoppage of the blood supply to the tissue cells, as asphyxial depression ; and under many other conditions. The question now arises, whether the mechanism of the de- pressing process is the same under all these widely diverse circumstances. In its generality, we can at once answer this question in the negative. The mechanism of depression in water rigor and in acid intoxication, for instance, is entirely different. Nevertheless, comparative studies of the mechanism of depression under the influence of different factors have shown me that a particular tendency exists toward one etiologic type of depression. In the complex realm of metabolism in all aérobie forms of cell, one part of the many anabolic and catabolic processes is especially sensitive to external influences, and that is the oxygen metabolism. Here is, in a certain sense, the locus minoris resistenti@ of the living matter of all aérobic organisms. In fatigue, it is the relative deficiency of oxygen which produces the depression. The increased demand for oxygen, brought about by the increased functional activity, ean no longer be satisfied by the amount of oxygen present. The same is true of heat depression. The supply of oxygen cannot keep pace with the accelerated catabolism of the living tissue, induced by the temperature. In the asphyxial depres- sion of the tissue cells which occurs as a result of any stoppage of the blood supply, it is not the withdrawal of the organic nutritive materials in the blood, but only the lack of oxygen, which produces the depression. In prussic-acid poisoning, again, it is the suppression of the oxygen metabolism in the 58 HARVEY SOCIETY tissue cells which produces death. Thus we see that oxy- genation is the factor, in the metabolism of aérobic cells, which most easily fails under diverse external influences and so forms the starting-point for the development of depression. The most simple paradigm of this entire group of depres- sions is therefore suffocation of living cells or tissues in indif- ferent media free of oxygen. Fortunately we know to a certain extent the working of the mechanism of suffocation. In normal metabolism during rest the supply of oxygen is always sufficient for the needs of the cells. Molecular oxygen is absorbed by them from the surrounding medium, A certain reserve supply of molecular oxygen, although comparatively small, is always present in the cells themselves, at least in cold- blooded animals not kept at too high a temperature. Many facts force us to this opinion, especially the continuance of normal production of energy and of irritability for a longer or shorter time, under complete exclusion of oxygen supply. The oxygen taken up from the medium is activated by special oxygen carriers and distributed to the oxidizable substances. We know of the existence of such oxygen carriers in the most diverse animal and vegetable cells, and we are accustomed to group them together under the collective name of ‘‘ oxydases,’’ although their chemical constitution is still completely un- known. The oxygen carriers bring activated oxygen, in the manner of inorganic catalysators, to the oxidizable substances, which by the oxidation are split into carbon dioxide and water. One point here remains still undecided, and that is, whether the oxidation attacks the organic fuel directly, such as, for instance, the carbohydrates, which have been synthetically built up by anabolic processes, or whether only the fragments are oxidized to carbon dioxide and water, while the splitting itself is accomplished by enzymatic processes. It is possible that in different forms of living substances the catabolism takes a different course. At any rate, the principal source of energy in all aérobie organisms is to be found in the oxidative splitting-up processes, and not in the non-oxidative part of the NARCOSIS 59 catabolism. These oxidative splitting-up processes represent the principal source of energy production. That is an im- portant fact. It has a special bearing upon the degree of irritability of living matter, for irritability is measured by the amount of energy production which results from a stimulus. What changes does this phase of metabolism undergo, when the external supply of oxygen is withdrawn from a living. system? No more molecular oxygen enters the living matter from the outside. The molecular oxygen, which at the moment of exclusion of oxygen is still present in the living tissue, will, according to its amount, be used up sooner or later. In the same proportion the extent of the oxidative breakdown will decrease. The catabolism will occur more and more in a non-oxidative manner. As soon as all the oxygen is used up, the destructive process will be entirely non-oxidative. This gradual transition from oxidative to exclusively non-oxidative decomposition corresponds in a characteristic way to the development of the depression. The intensity of the sponta- neous vital activities diminishes gradually after the interrup- tion of the external supply of oxygen. Very gradually the irri- tability for external stimuli decreases. Very gradually also the extension of the excitation from the point of stimulation to adjacent parts becomes restricted. Finally no sponta- neous manifestations of life are visible; finally no visible effect is to be obtained from the strongest external stimuli. These are the general consequences which result from an interruption of the oxygen supply and which we observe everywhere in whatever way and at whatever point the oxygen metabolism is disturbed. I have dwelt in some detail on the relations of the metab- olism of oxygen and its disturbances, because our investiga- tions carried out in the laboratories at Go6ttingen and Bonn have shown that in narcosis, also, there is a similar interference with the oxidation process. The fact that the oxygen metab- olism suffers readily under diverse external influences sug- 60 HARVEY SOCIETY gested the question whether also, under the influence of nar- cotics, disturbances of the oxidative processes take place. I had previously studied, by means of an artificial circulation, the réle of oxygen metabolism in fatigue of the spinal cord of the frog, made especially sensitive by mild strychnine poisoning. It seemed to me, from my experience, that this would be a favorable object for the experimental determination of the question whether the oxidative processes are interfered with during narcosis. This question could be particularly well studied on the fatigued spinal cord, because it was found that the fatigue can be completely removed again only by the supply of oxygen. If the spinal cord is fatigued and oxygen is not supplied, as can easily be arranged with an artificial cir- culation, and if now the completely fatigued and oxygen-greedy spinal cord is narcotized, it can be determined whether, with a free supply of oxygen, the spinal cord can take it up, and thus recover during narcosis. If the fatigued cord is irrigated during narcosis with arterial ox blood or with an oxygen containing saline solution, and later, while the narcosis still continues, the blood is removed again by oxygen-free salt solution, and if then the narcosis is stopped, it must become manifest whether the centres of the cord have taken up the abundantly supplied oxygen during narcosis, and recovered. Winterstein has performed this experiment at Gdéttingen, using various narcotics, such as ether, alcohol, chloroform, and carbon dioxide. All the experiments agreed in showing that not the least trace of recuperation occurred; while, after the end of the experiment, the cord was completely restored in a few minutes by perfusion with oxygenated ox blood with- out narcosis. Herewith the first proof was given that, during narcosis, living tissues are unable to utilize the oxygen offered to them. Nerves offered a second favorable object for testing our question. We had succeeded, after many vain attempts, in perfecting a method by which it was possible to show that nerves died of suffocation when eut off from all possible supply NARCOSIS 61 of oxygen. This fact, established by H. von Baeyer, placed us in a position to make on the nerve, which proved to be an exceedingly favorable object, experiments on the question of oxygen metabolism during narcosis analogous to those made on the cord. The sciatic nerve of the frog was asphyxiated, and thus made oxygen greedy. When its conductivity was lost and its irritability reduced to a very low level, it was nareotized with ether. Then, during narcosis, oxygen was supplied to it for a long time. After the oxygen had been finally removed by pure nitrogen, the narcosis was stopped. In these experiments, which were first made by myself, after- wards by Frohlich, and later on by Heaton, there was never any trace of recovery. When the nitrogen was replaced by air, the nerve recovered in one minute and showed normal irrita- bility and restoration of conductivity. Finally, in a series of experiments which have not yet been published, Ischikawa proved that amcebe, also, which had been asphyxiated in a gas chamber in pure nitrogen and had become motionless, did not take up oxygen which was supplied to them during narcosis, while after stopping the narcosis and replacing nitrogen by air they rapidly resumed their amceboid motion. These experiments show unequivocally that living tissues, even when their demand for oxygen has been raised to an extreme degree by fatigue or asphyxia, cannot, during narcosis, make use of oxygen, even when offered to them abundantly. This conclusion caused us to advance one step further. If living tissue, during narcosis, cannot use the oxygen which is supplied to it, this inability might be produced in several ways. Either narcosis depresses the entire phase of catabolism, with all its partial processes, perhaps by paralyzing the first step, or it hinders especially only the oxidation processes. In the former case, we should expect that a narcosis of a cer- tain depth, in which the destructive processes were completely abrogated, could continue for an indefinite time. In the second alternative, that is, if only the oxidation is prevented, 62 HARVEY SOCIETY destruction must proceed in non-oxidative form, just as in the absence of external oxygen supply, and the living tissue under narcosis must eventually die of asphyxia, even though suffi- cient oxygen is constantly at its disposal. We can decide between these two possibilities. On the one hand, experience shows that no narcosis, whatever its depth, can continue indefi- nitely without the tissue losing its viability. On the other hand, we can demonstrate experimentally that during narcosis catabolism proceeds in non-oxidative manner and that as- phyxia gradually supervenes. Here again the nerve proved to be a favorable object for experiment. Heaton has used the two sciatic nerves of the same frog for the following parallel experiment: One nerve was drawn through a gas chamber which contained pure nitrogen; the other was narcotized in a similar gas chamber filled with air. The experiments began simultaneously in the two nerves. In the asphyxiated nerve the irritability sank very gradually lower and lower. When it had fallen to a certain level, the conductivity for an excita- tion coming from the part of the nerve outside of the gas chamber vanished also. The time at which this degree of depression is reached depends on the length of the asphyxiated portion of the nerve, on the condition of the frog, and on the temperature. At room temperature it requires, on the average, from two to three hours. At the time that the conductivity of the asphyxiated nerve was abolished, the air surrounding the narcotized nerve was replaced by pure nitrogen, and the narcosis interrupted, so that the nerve, after the narcosis was stopped, had no more oxygen at its disposal. If the whole destructive. phase of metabolism had been brought to a stop, the nerve should, after stopping the narcosis, be in about the same condition as before it. This was, however, not the ease. All the experiments, rather, agreed that during narcosis this nerve was also asphyxiated like the nerve in pure nitro- gen, in spite of the fact that the former always had air at its disposal. Its irritability had been greatly reduced and its conductivity was abolished. That it was actually asphyxi- NARCOSIS 63 ated was shown by the control experiment, in which both nerves recovered completely as soon as air was conducted over them. The irritability increased rapidly as the conductivity returned. Ischikawa has recently performed similar experiments on ameebe. Ameebe gradually lose, in nitrogen, their amcboid motions. They regain them only when oxygen is supplied. If amcebe are narcotized with ether, they are also asphyxiated; for after the narcosis, in the absence of oxygen, they do not regain their ameboid motions. These only return after oxy- gen is supplied. It is thus evident that living tissue is asphyxiated during narcosis; that is, that the destructive phase of metabolism proceeds in a non-oxidative manner. We can add yet another fact. Even during narcosis the destructive processes can be increased, that is, accelerated, by exciting stimuli. Teaton has narcotized the two sciatic nerves of a frog in a double chamber under absolutely identical con- ditions. While one of them remained at rest, the other was continually stimulated by a faradic current applied to the end beyond the chamber. After discontinuing the narcosis in pure nitrogen it was always found that the irritability of the stimulated nerve had fallen to a lower level than that of the other. Placed in air, both recovered to an equal degree. The results of this experiment entirely agree with the phenom- ena of fatigue, which were found by Thoérner in his researches on the fatigue of nerves in nitrogen. On the basis of all these experiments, we may make the following statement: Living tissue becomes asphyxiated during narcosis. The catabolic phase of metabolism continues in the form of a non-oxidative destruction, just as in asphyxia, and can also, as in asphyzia, be accelerated by exciting stimuli. Recovery from this asphyxia is, as in every asphyxia, only to be attained by sup- plying oxygen. Under these circumstances the idea naturally presents itself, that the entire symptom complex of narcosis is only a mani- festation of asphyxia, which the narcotic induces by inhibi- 64 HARVEY SOCIETY tion of the oxidative processes. Before we accept this idea, however, we must assure ourselves that there is no fact which stands in the way of its acceptance. It goes without saying, that if asphyxia occurs in narcosis, the general picture of asphyxia must be present. This is actually the case. The cessation of spontaneous evidences of life, the reduction of irritability, the decreased power of conductivity—all the typi- cal symptoms are identical in narcosis and in asphyxia in an oxygen-free medium. In only one point is there a noteworthy difference. That is in the time relations of the depression symptoms. In narcosis of nerves, for instance, irritability sinks in a few minutes to a point which in pure nitrogen is only reached in two or three hours. The question therefore arises, whether we have not here a fact which must inevitably eliminate the idea that narcosis is nothing more than asphyxia. A more careful consideration shows, however, that this is not the case. The experiments which have already been described contain the explanation of this difference in the rapidity of onset of the depression. The fact that living cells, during narcosis, can make no use of molecular oxygen, even when it is freely offered to them, shows that the narcotic renders the living tissue incapable of undergoing oxidations. It cannot, therefore, utilize for its oxidation processes the oxygen present in itself. The con- ditions during asphyxia in an oxygen-free medium are, how- ever, quite different, as for instance in asphyxia of nerves in nitrogen. Here the power to carry on oxidations is not inter- fered with in the least. As long as any trace of molecular oxygen is present, it can be used for oxidation. Now it is of course impossible that, at the moment that the air in a gas chamber is replaced by nitrogen, every trace of oxygen should disappear from the nerve in the chamber. The nerve, there- fore, with its small oxygen requirement, can, even in pure nitrogen, carry on its oxidation processes in a more or less decreasing degree, according to the temperature and to the amount of oxygen contained in the nerve itself. Accordingly, NARCOSIS 65 the irritability decreases only gradually, and in proportion to the extent of the decrease of the oxidative processes. In the depression of nerves in an oxygen-free medium we deal with a slow, while in narcosis we deal with an acute, asphyxia. That is the factor which produces the difference in time. We have also, therefore, the power of eliminating this difference completely. We may do this, in one way, by those measures which hasten asphyxia in an oxygen-free medium. Such a measure is the increase of the demand for oxygen by raising the temperature. In this case heat depression occurs. Of heat depression we know that it is an asphyxia which results from a relative lack of oxygen, because the supply of oxygen cannot keep pace with the markedly increased demands of the living tissue, just as in fatigue. As H. von Baeyer has shown, complete loss of irritability in nerves may be attained by keep- ing them for 20 minutes in a gas chamber at a temperature of 42° to 47° C. The lost irritability cannot be restored by reduction of temperature alone; while, after supplying the nerve with fresh air, recovery results in a few minutes. At higher temperatures asphyxia occurs still more rapidly. In the ganglion cells of the cerebral cortex of mammals, asphyxia results in a few seconds when the air supply is cut off. On the other hand, the narcosis of the nerves can be greatly delayed if the narcotic is administered only in small amounts. In short, the more rapid or slow onset of depression ts solely dependent on the rapidity with which the oxidation processes are abolished. In narcosis this occurs very rapidly, because the narcotic renders the cells incapable of carrying on oxida- tions; in asphyxia in oxygen-free media, it occurs only very slowly, because the living tissue retains its power to carry on oxidation and continues to do so until the last trace of oxy- gen present in the tissues is used up. The difference in the time of development of the depression in the two cases is solely dependent on the different way in which the oxidation proc- esses are brought to a standstill. The symptom complex of 5 66 HARVEY SOCIETY narcosis, therefore, not only is comprehensible, but on the basis of the ascertained facts it is inevitable. It seems to me that, after these considerations, it is no longer possible to doubt, not only that narcosis is accompanied by asphyxia, but that the acute asphyxia is the deciding factor which produces the depression. This does not exclude the possibility that the narcotic may also produce other changes in the living matter, for instance changes in the state of ag- gregation of certain substances. Whatever other changes may occur, the factor which produces the characteristic symptom complex of narcosis 1s under all circumstances the suppression of the power to carry on oxidations. The conclusions which may be drawn directly from the facts bring us as far as this; but the problems are by no means finished. At this juncture the new question arises: In what way does the narcotic, by entering the cell, inhibit the power of the latter to carry on oxidations? Here the facts leave us still in the dark. If we wish to answer this question, it can only be done in the form of a hypothesis. I wish to empha- size this point particularly. But ‘‘ no true scientist fails to realize that the essential factor of progress les in a hypoth- esis which agrees with the facts.’’ These words of one of the greatest physiologists, who was also my predecessor in Bonn, shall serve as my excuse if I attempt now, with the assistance of a working hypothesis, to go a step further in the direction indicated. When we recall the fate of molecular oxygen in the normal metabolism of the cells, from the moment at which it enters the living substance to the moment at which it decomposes the oxidizable materials into carbon dioxide and water, we find that the narcotic, which overflows the cell, could establish its inhibitory action upon the oxidation at various stages of this process. In the first place we might conceive that the narcotic, when it has penetrated into the living substance, prevents in some way the entrance of molecular oxygen from the surrounding NARCOSIS 67 medium into the cell. This assumption, however, may be dis- missed at once. If the depression of narcosis were produced by the fact that oxygen could not penetrate into the cells, then we could expect a course of depression with exactly the same time relations as in complete withdrawal of external oxygen ; the cell would be in exactly the same position as it is, for instance, in pure nitrogen. The difference in the time relations between the two cases, for instance in the nerves, shows us, however, that this is not the case. Next we must consider the possibility that narcotics ap- propriate the oxygen which enters the cells, and use it for their own oxidation. The narcotics are, it is true, generally looked upon as chemically indifferent substances, but Biirker has recently published experiments which show that, under certain conditions, narcotics may be oxidized, at least by nascent oxygen. Biirker performed the following interesting experiment: He placed two identical voltameters in the same electric circuit. One of them was filled with acidulated water; the other had in addition a small percentage of ether. Then he decomposed the fiuids electrolytically by means of a galvanic current. In the voltameter which contained no ether, the gas collected at the two poles in the usual relation, the volume of hydrogen at the cathode being to the volume of oxygen at the anode as 2 to 1. The relationship was, how- ever, entirely different in the voltameter which contained ether. Here only a very small amount of oxygen collected at the anode; while the analysis of the gas from the anode showed that carbon dioxide, acetaldehyde and acetic acid had also been formed, as oxidation products of ether. Based on this result, Biirker put forward the hypothesis that narecoties had the same effect in living substance as in the voltameter, and that the depression of the oxidation process in narcosis depends on the fact that the narcotie itself appropriates the oxygen. As, in living tissue, oxygen is activated by oxygen earriers, the possibility of oxidation of ether even in the cells is not, indeed, excluded. But under the conditions which obtain in 68 HARVEY SOCIETY living tissue, it is doubtful whether it really occurs to such a degree as to reduce the oxidation of respiratory materials to a noticeable extent. For many of the narcotics, oxidation in the cells in very unlikely, and in the case of carbon dioxide it is absolutely excluded. A third possibility of the interference with oxidation is, that the narcotic in some way blocks the molecules of oxidiz- able material, perhaps by a loose chemical fixation, and thus renders them inaccessible to oxidation, and the oxidation will thus cease. However, this view also has very little likelihood. According to this view, we would have to presuppose that the narcotics, which in themselves present substances with very heterogeneous chemical properties, were also able to block very diversified substances; for in non-oxidative catabolism, such as occurs in narcosis, manifold products arise with very different chemical properties. We would have to assume that all these different substances can be prevented from oxidation by all the different narcotics. We cannot readily have recourse to such an assumption. Finally, there remains one more possibility to be considered. It might be assumed that the narcotic renders the oxygen carriers incapable of activating the oxygen, so that the ox- dizable materials could no longer be oxidized and decompo- sition would proceed only in non-oxidative form. This view seems to me the most probable, as we have inorganic analogies for it. The colloidal solutions of metals, for instance platinum solution, can, as Bredig has shown, be prevented from acting as oxygen carriers by diverse chemical substances, such as cor- rosive sublimate, hydrogen sulphide, hydrocyanic acid, ete. ‘‘Paralyses,’’ or depressions, are produced in this way, which correspond to a great extent with the depressions of living cells. If I therefore form the hypothesis that narcotics, in an analogous way, render the oxygen carriers in living tissues incapable of carrying oxygen, all the facts of narcosis find a simple mechanical explanation. But still more, the possibility is also given here to combine NARCOSIS 69 the relation between the solubility in lipoids and narcotic action, discovered by Overton and Meyer, with the facts already given concerning the influence of narcotics on ox1- dation processes. The fact that the lipoid solubility of a sub- stance primarily determines the degree of its narcotic action, shows us that the mechanism which lies at the base of the symptom complex of narcosis must be associated in some way with lipoids. We have seen that this mechanism consists in an inhibition of oxidations, and it is highly probable that this comes about through a paralysis of the oxygen carriers. It is quite natural to assume that the oxygen carriers, whose chemi- cal nature is still entirely unknown to us, stand in some close relation to the lipoids, that they are perhaps themselves of lipoid nature, or that they are attached as specific atom groups to lipoid molecules. By this assumption the relations dis- covered by Hang Meyer and Overton and the facts shown by us, that narcosis depends on acute asphyxia, would be com- bined in a natural manner. Both facts would mutually com- plete each other, and the result would be a further elucidation of the mechanism of narcosis. However, I wish to emphasize, again, that the conception regarding the nature of inhibition of oxygen metabolism in narcosis is of a purely hypothetical character. It is only an established fact that narcotics induce an acute asphyxia of the cells. Herein is the essence of narcosis. If we are satisfied, for the present, with this knowledge and put the question of the particular mechanism of the asphyxia to one side, the mere fact that narcotics inhibit oxidation processes will in itself guard us from many false conceptions in regard to narcosis. The knowledge of this fact has some significance also for the practical use of narcosis. Let us ask, first, what we narcotize when we induce narcosis in man by inhalation of ether or chloroform. All tissues of the body are not affected equally by any means. Even if it is assumed that the blood carries the narcotic to all the tissues in nearly the same concentration, the different tis- 70 HARVEY SOCIETY sues are influenced to a very different extent by the narcotic. When the ganglion cells are already completely depressed, the nerve fibres and muscles still show no sign of narcosis. The ganglion ceils of the brain, and especially those of the cere- bral cortex, are most readily affected in their specific functions by narcotics. Thus, if we induce so-called ‘‘ general ’’ anes- thesia by ether or chloroform narcosis for any operative pur- pose, we deal in reality only with narcosis of the cerebral cortex. In this lies the great value of narcosis; for we desire in narcosis to eliminate conscious sensation, and the acts of con- sciousness are, as is well known, due to excitation of the ganglion cells of the cerebral cortex. The ganglion cells of the cerebral cortex, with their functions intact, are the most valu- able asset that man possesses. Therefore it is particularly important to us that nothing shall happen which might injure them permanently, and we must therefore know the possible dangers of narcosis, in order to avoid them. The fact that the ganglion cells of the cerebral cortex lose their specific functional activity, under the influence of narcotics, sooner than any other body cells, must, on the basis of our new data in regard to the relationship of narcosis and asphyxia, naturally give rise to the idea that they are more sensitive to asphyxia than any other body eells. That is actually the fact to a striking extent. Mosso has demonstrated this in a classic way on man, in whom alone direct studies of the conditions of the processes of consciousness can be made. In his experiments on Bertino, he found that a few seconds’ interruption of the supply of oxygen sufficed to produce loss of consciousness. Bertino had a large defect in his skull over the frontal lobe, and the cerebral pulsation could be graph- ically recorded there. The frontal lobe receives its blood supply from branches of the carotid arteries. When Mosso compressed these arteries in the neck, so that the cerebral pul- sation ceased, Bertino lost consciousness in five seconds with- out having had any premonitory disagreeable sensations. After releasing the pressure upon the carotid arteries, con- NARCOSIS 71 sciousness returned at once. This experiment shows how de- pendent the cells of the cerebral cortex are on their supply of oxygen, and in how short a time unconsciousness occurs after complete interruption of this supply. Here we have an example of a depression rapidly following the withdrawal of oxygen. The associative workings of our ideas and sensa- tions, thoughts and feelings can proceed in an undisturbed manner only when there is complete integrity of the specific irritability of all the ganglion cells concerned. The slightest loss of irritability interrupts the orderly play of excitations and inhibits the activity of consciousness. From this peculiarity of the cortical cells is the important requirement derived, long known empirically, that in man we should employ a light degree of narcosis, just sufficient to paralyze consciousness. Under such circumstances the de- pression of the oxidative processes is undoubtedly of very limited extent, and there is no demonstrable danger of per- manent injury to the normal brain. When we employ a deeper narcosis, the danger of rapid and complete asphyxia of the ganglion cells increases with the depth of the narcosis. At any rate it ought to be always present in our mind that the deeper the narcosis the more it inhibits oxidation processes, and that the ganglion cells of the cerebral cortex are exceed- ingly sensitive to lack of oxygen. Here we deal with the most tender and perishable cells of our body. In this connection I wish, before concluding, to point out an error that has been handed down from olden times, and even at present has not been corrected everywhere. It is the identification of narcosis with sleep. The origin of this confusion is evident. It is based on the entirely superficial analogy that both states are characterized by loss of consciousness. But not every loss of consciousness is sleep. This confusion, which may have been justified in earlier times, when both conditions were known only by their external symptoms, is to-day, when we have penetrated some- what more deeply into the inner processes of the cells of the 72 HARVEY SOCIETY cerebral cortex, a grave mistake. Closer consideration will show this plainly. What occurs in the neurons of the cerebral cortex during an act of consciousness? I am far from intending to give here a detailed analysis of these processes. I wish to emphasize only a single general fact. Let us conceive a condition of the cerebral cortex in which the neurons are in metabolic equilib- rium; that is, in which the two phases of metabolism, the ana- bolic and catabolic phases, balance each other. We should have then a state of complete rest, in which no act of con- sciousness takes place. An act of consciousness ensues only when the metabolic equilibrium in a chain of associated neurons is disturbed by an exciting stimulus which causes a sudden increase of the catabolic phase. Every act of con- sciousness is the expression of a catabolic disturbance in the cortical neurons. This is not merely an assumption; it is shown, among other things, by the fact that even the simplest conscious process requires the associated co-operation of sev- eral ganglion-cell stations, and that on the other hand the nerve fibres which provide for this associated co-operation conduct no other impulses than catabolic excitation proc- esses. On this general basis, for all processes of consciousness there are two possible origins of unconsciousness. Loss of consciousness will occur either because the ganglion cells are depressed, so that the external stimuli produce no excitation, or because exciting stimuli are absent. As we have seen, the first condition prevails in narcosis; the irritability is so much depressed that stimulation is ineffective. In sleep, the second alternative is predominant; the first plays at most the réle of a predisposing part for the induction of sleep. We sleep, and determine the moment of going to sleep, by limiting as far as possible the sensory stimuli, especially the optical. This state of the utmost exclusion of external stimuli lasts through- out the entire period of sleep. This is supported to a certain extent by fatigue, that is, the decrease of irritability, which the ganglion cells have sustained by the constant action of NARCOSIS 73 sensory stimuli while awake during the day. A comparison of the processes which occur in the ganglion cells of the cere- bral cortex during sleep and during narcosis will show us plainly how diametrically opposite these are. During sleep, restitution occurs. The irritability, which becomes reduced in the course of the day as a result of the fatiguing action of sensory stimuli, gradually rises again. The fatigue of the ganglion cells, which, as we know, depends only on a relative lack of oxygen, becomes completely dispelled. The supply of oxygen, which during constant activity was not quite sufficient to keep irritability at its maximum, is, after the cessation of functional demands, fully sufficient to banish the fatigue. In short, during sleep, restoration occurs princi- pally by the action of oxygen. In the morning the ganglion cells are refreshed and possess their full capacity for work. How different is narcosis! In narcosis there is, on the con- trary, as we have seen, a depression of the oxidation processes. The experiments showed that even with a free supply of oxygen a fatigued ganglion cell did not recover at all during narcosis. There occurs, rather, a gradual asphyxia, and, al- though this process is only developed to a small extent in light narcosis, still it presents just the reverse of that which sleep brings to the ganglion cells. In the one case, recovery from fatigue by oxidation; in the other, prevention of restitution by inhibition of the oxidation process. There can be no con- fusion between sleep and narcosis. If we use narcotics to induce sleep, we must always bear in mind that no true sleep occurs as long as the narcosis of the cortex lasts. We can speak of ‘‘ hypnotics,’’ or ‘‘ remedies for sleep’’ (Schlafmittel), only in the sense that, when there is constant excitation of the ganglion cells, they reduce irrita- bility and induce a greater degree of depression, so that true sleep may take place as the narcosis passes off. In that sense a hypnotic may prove beneficial in the hands of the physician, and when used sparingly. The physician must, however, never forget that not the entire period of unconsciousness which fol- 74 HARVEY SOCIETY lows the use of the hypnotic is true sleep, but that at first it is, rather, a depression, the injurious effects of which will mani- fest themselves when the hypnotic is used for a longer period. Ladies and Gentlemen: I am at the end of my lecture. The facts which I have stated take us, I believe, a step forward in the analysis of narcosis. They show us the general nature of the process, which is merely one of the great group of depres- sive actions which depend on a disturbance of the oxygen metabolism. They open, however, at the same time, a number of new questions. The previously mentioned hypothesis con- cerning the method by which narcotics inhibit the process of oxidation shows us the direction in which these questions lie. It may serve us as a guide for the present. The further analysis of the process will principally have to determine the nature of the transmission of oxygen and in what way this is affected by the narcotic. The experiences of modern physical chemistry will be of great help to us in the study of this ques- tion. I may, however, take this opportunity of warning against the misuse of physical chemistry in the explanation of biological facts; and this the more, since this misuse, which has grown with the development of that science, is already beginning to arouse in the minds of many biologists a strong distrust of the value of physical chemistry in the analysis of biological processes. It is frequently believed that a biological process is explained when the terminology and certain catch- words, I might almost say the scientific ‘‘ jargon,’’ of physical chemistry have been applied to biological relations. There has been recently, for example, a great misuse of the word ‘‘eolloidal process.’? There is positively nothing gained by it when a biological phenomenon (for instance, excitation or depression) is designated as colloidal process. This is neither correct nor incorrect; it says nothing. That the living tissues contain various colloid substances, and that these colloids un- dergo alterations in the course of the vital processes, has long been known. We wish, however, to know what it is that happens to the colloids, which of their properties are altered NARCOSIS 75 and how these changes are incorporated into the machinery of the cell. For this purpose patient and careful analysis is required, and not the introduction of mere catch-words. The methods and results of physical chemistry give us very valu- able material for such analysis; but it would be very one-sided to consider the methods of physical chemistry only. The methods and results of chemistry, physics, and microscopical research must be employed, as well as those of physical chem- istry. In short, every method must be employed which will bring us a step further. That alone can be the general prin- ciple of all physiological research, and this principle will also lead up to new knowledge in the investigation of narcosis. ON FREUD’S PSYCHO-ANALYTIC METHOD AND ITS EVOLUTION * PROF. JAMES J. PUTNAM Harvard University HE subject of psycho-analysis, on which your long-hon- ored president has invited me to speak, is one that deals with serious and difficult problems. I shall be glad if I can throw a flashlight on them here and there, and in so doimg I shall try to answer some of the questions which have most frequently been asked me concerning the subjects in hand. Do not suppose that I shall pretend to give directions such as could enable any physician to put this method into prac- tice. On the contrary, I beg you to regard it as a matter for congratulation that the leaders in this movement have a strong sense of the need of careful training and high stand- ards on the part of those who desire to join their ranks. I have recently returned from a trip abroad, where I made the per- sonal acquaintance of quite a number of the more prominent psycho-analysts, attended their congress, and was able to learn a great deal about the details of their mode of work. I came away strongly impressed with the fact of the recognition on their part of the importance of their task and that this recog- nition had had a good effect on the mental attitude of the workers, many of whom are still young and full of promise. These men seemed to me, for the most part, strikingly eager, earnest, and sincere. ‘‘ Sie haben gelernt ein Stick Wahrheit zu ertragen,’’ said Freud to some of us when these facts were under comment. I learned to my surprise and interest that the greater number of the investigators had subjected themselves, more or less systematically, to the same sort of searching character-analysis to which their patients * Delivered November 11, 1911. 76 FREUD’S PSYCHO-ANALYTIC METHOD ve were being subjected at their hands. It is fast getting to be felt that an initiation of this sort is an almost indispensable condition of good work; and for this important reason: The main thesis of the supporters of these new doctrines—which are at bottom old doctrines, rearranged and re-emphasized, for psycho-analysis is largely an accentuated phase of education— is that most of the emotional disorders to which we give the name of psychoneuroses arise largely from an instinctive self- concealment, and concealment of one’s self from others; that is, from an unwillingness or an inability to see or look at all the facts that should be seen, respecting one’s own ten- dencies and motives, as the basis for the control of feeling, thought, and action. Recognizing this principle, these physi- cians have seen that so long as their own lives, too, are par- tially on a false basis, so long as they also are self-concealed, they cannot do justice to their patients, either in the way of appreciation or of criticism. Obviously, a person ridden by prejudices that he does not recognize cannot do justice to another person in a like state; one is reminded of the simile of the ‘‘ beam ’’ and the ‘‘ mote.’’ It is, therefore, I repeat, a matter for congratulation that the need of preparation for these tasks is being taken seriously, and the assertion is justi- fiable that the introduction of this specialty is likely to make better men, in every sense, as well of the physicians who prac- tise it as of the patients whom they treat. But while no man, however able, can without long study master the details of this method, every man who would be liberal or scientific can and should master its principles and give the movement his generous sympathy and support. What is psycho-analysis, and what, in general, are its aims? Psycho-analysis is a method of investigating and treating ner- vous invalidism and (incidentally) faults of character, which owes its strength to the fact that it searches and studies in de- tail, so far as this is practicable, all the significant experiences through which the patient to be treated has passed, and the motives and impulses which have animated him at psychologic- 78 HARVEY SOCIETY ally important moments of his life, even since his earliest child- hood. In doing this it discovers, not, indeed, all the causes of the disorder from which he suffers, but a large number of important partial causes, and thus prepares the way for the influences tending toward recovery. This definition is, I think, substantially correct, but it needs some explanation, amplifica- tion, and qualification. First, it is not strictly true to say that the attempt is made, during a psycho-analytic treatment, to pass in review all of the important motives and impulses, or even all of the kinds of motives and impulses, which had animated the mind of the person who subjects himself to this treatment, but, strictly speaking, only a certain class of them,—those, namely, that were originally based on emotions which had been repressed because they were painful or seemed out of harmony with the chosen plan of life, but which, in spite of all repression, had remained as active causes of serious mischief. It does not systematically deal with those motives and impulses which may be designated as aspirations and ideals, derived, as I believe, from the essential endowment of the spiritual nature by which every man is animated and which is to be regarded as an independent, primary, creative force. Psycho-analysis does not, in other words, pretend to take the place of philo- sophic teaching; but it does help, even without claiming to do so, to give such teaching a better chance to make itself effective. On the other hand, it is not just to characterize psycho- analysis solely as a therapeutic measure. In proportion as the psycho-analytic movement has developed toward maturity, it has shown itself able to make scientific contributions of great value to psychiatry,t psychology, mythology, philology, so- ciology, as well as to education and to prophylaxis. In other *The value of Jung’s argument for ranging Kripelin’s dementia precox, together with many symptom-complexes classified by Janet as psychasthenia, under the psychological category of the introver- sions, is now generally conceded. FREUD’S PSYCHO-ANALYTIC METHOD 79 words, these investigations bring support to every research which deals with the inward and the outward manifestations of human effort and mental evolution, while at the same time they draw important aid from all these inquiries into the psychology of the human race, for the benefit of the single human life. The practical aim of this method is to enable persons who are hampered by nervous symptoms and faults of character to make themselves more efficient members of society, by teaching them to shake themselves free from the subtle web of delusive, misleading, half-unconscious ideas and feelings by which they are bound and blinded as if through the influ- ence of an evil spell. Such persons—and in some measure the statement is true of all persons—have to learn that they are responsible, not only for the visible, but also for the hidden portions of themselves, and that, hard as the task may be, they should learn to know themselves thoroughly in this sense. For it is the whole of ourselves that acts, and we are responsi- ble for the supervision of the unseen as well as for the obvious factors that are at work. The moon may be only half illumi- nated and half visible, but the invisible half goes on, none the less, exerting its full share of influence on the motion of the tides and earth. Some patients may learn to override or sidetrack their troubles and can be helped by various means to do so. These other means are, however, not to be compared, for power of accomplishment or permanency of result, with that of which I now speak to you. It is difficult to see why any broad-minded person should refuse to recognize, on theoretic grounds at least, the value of the self-knowledge here alluded to, especially when the treat- ment of the more serious forms of psychoneurotic illnesses is at stake. These more serious forms are very numerous and the causes of enormous suffering. Difficult and doubtful of issue as the treatment of them is, the method here discussed holds out a new and vital hope. 80 HARVEY SOCIETY It would obviously be impossible to offer you anything ap- proaching to an adequate account of the means by which it is sought to discover, for each individual case, the particular facts and tendencies from which the particular symptoms * that are present may have sprung. It must be enough to assert the fact which Freud established, that each person’s memory, if allowed and encouraged to wander, uninhibited by resistances and repressions, may usually be counted upon to furnish the information that is needed. Where this is insufficient, two other plans may be adopted, one of which, indeed, comes largely into play in every case. These two methods are, first, the use of word-associations, the value of which Dr. Jung, of Zurich, has done so much to establish, and, next, the study of dreams. The significance of the word-association method, stated in briefest terms, is that it serves as a sort of concentrated con- versation. The patient, answering at random as he should do, instinetively lets go,* for the time being, of the reins which he ordinarily holds tight over his inmost thoughts, and allows glimpses into the mental processes which it is of the utmost importance that he should know yet which constantly tend to elude his attempt to seize them. Further inquiries and associa- tions may, then, if necessary, proceed from such beginnings. The elucidation of the means by which the interpretation of dreams may be successfully carried on, and a path thereby opened into the inner chambers of the mental life, is one of Freud’s contributions which well deserves being designated as a mark of genius. Whatever differences there may be between the conscious lives of different individuals, in our repressed and unconscious lives we are all very much alike—not, indeed, * Such symptoms are not to be regarded as haphazard and unlucky but meaningless signs of breaking down on the part of the nervous system; they are, rather, real and significant reactions, dumb ex- pressions of both terms of very deep and vital inner conflicts, but under the form of compromises between instinetive desire or eravings and instinetive denials of these cravings. °Tf the reins of thought and emotion are not relaxed this fact too will become evident. FREUD’S PSYCHO-ANALYTIC METHOD 81 in detail, but as regards the principles in accordance with which we are constructed. Just as we speak the same verbal language, so we speak, at bottom, the same dream language, and can learn to make the meaning of our dreams clear to others and to ourselves. It eannot be too often represented that the disharmony between the conscious and the unconscious portions of our lives, which is sometimes productive of so much misery, ought not to exist. Every one recognizes this after a fashion, and tries, instinct- ively, but, as a rule, without success, to overcome the dishar- mony by finding some sort of outlet for the repressed—and usually childish—feelings which his conscious intelligence will not tolerate. But this is not enough. If he would really overcome the disharmony, he must meet the situation face to face, and the study of his dreams, in which his repressed thoughts are represented in caricature and in picture lan- guage, is perhaps the best means of obtaining clues to the in- formation which he seeks. These hidden portions of our lives must be thought of as seeking to make themselves felt in action though not in words. Ordinarily, we keep them, like the evil spirits in Pandora’s box, under pretty strong lock and key. At night, however, the locks are loosened, and our repressed emotions succeed in finding their way to the theatre-stage of consciousness. Even then, the thoughts which arise are not allowed to become too evident, but are concealed beneath picturesque symbolisms and disguises. It is a very interesting fact that, as each new person comes into the world and begins his life of dreams, he adopts forms of symbolism analogous to those which have been in use since even semi-civilized life began. The various animals with which our childhood was familiar come forward to play the role of animal-passions; the rapidly moving trains typify our hurrying emotions. And so, too, still or moving water, the rooms or buildings in. which we like to place ourselves, the bare or varied landscapes, and many a symbol more, are all 6 82 HARVEY SOCIETY utilized as elements of a picture-language which is almost as well defined as that indicated by the rebuses of the child, or the hieroglyphs of the Egyptians, or the mythology of the ancient Greeks. So full of meaning are these signs that no dream carries its true, much less its whole, significance on its face; no item, no obvious omission even, is without its bearing; hardly a feature or character is to be found that is not of even multiple value. The general proposition has been laid down—and certainly with good reason—that every dream represents the fulfilment of an unconscious wish. No one would doubt that this state- ment is true of the day-dreams of childhood, and when for ‘* wishes’? we read ‘‘ partial ’’ or ‘‘ temporary ’’ wishes, and learn by self-study what these partial wishes are, it is found in the dreams which appear so terrifying, the wish is con- cealed behind an attempt to repress it, just as the partial wishes of our waking moments are often concealed behind the disguise of fears, a phenomenon very characteristic of the phobias of neurotic patients. Persons unfamiliar with the in- terpretation of dreams often deny this tendency, and point out that their dreams are nothing but jumbled representa- tions of some trivial happenings of the day before. It is true that every dream takes the happenings of the day before as materials out of which to construct its apparent story. These trivial experiences are utilizable, partly because of their ana- logical bearings, partly because they are still conveniently available for the memory and yet not fully woven into any other of the various complexes which our emotions tend to man- ufacture. In utilizing these experiences the dreamer does what any person might do who wished to tell a story while sitting at the dinner-table with his friends. Assuming that he desired to describe a journey he had taken, he might select a salt-cellar to stand for a castle that he had seen, a fork for one road, a spoon for another road, a plate for a pond or lake, ete. But behind these hastily chosen symbols, there would be a connected story; and in the same way, behind FREUD’S PSYCHO-ANALYTIC METHOD 83 the trivial details which make the outward framework of the dream there is a connected story, which, indeed, reaches, in layer after layer, back into the dreamer’s earlier life and even into his childhood. For in every mental act the whole personality of the individual comes into play, although in each act certain elements of the personality are illustrated far more than all the rest. Of course, it need hardly be said that the analogy between the forks and spoons and the apparently trivial incidents of the day previous to the dream-night is by no means a complete one. Unimportant as the real incidents may seem, they are often full of meaning, which, however, only an expert analysis can reveal. Each dream, then, furnishes, to the expert, and to the patient, a path into the inmost recesses of the patient’s life, better than any other means could furnish. As regards the therapeutic value of the psycho-analytic method, it is almost needless to say that there are many cases that baffle every treatment, not excepting that by psycho-analy- sis, and that this method has its special limitations. The pa- tient, to be treated with success, must be reasonably young, reasonably intelligent, and able to give a large amount of continuous time to the investigation. His outlook as regards conditions of life must be reasonably favorable, or else he must have the capacity for idealization such as will enable him to override outward misfortunes, and to face existing condi- tions cheerfully. He must want to get well, and not count on his illness as giving him gratifications or advantages which he is unwilling to sacrifice, even for better health. Then, ‘Perhaps the two most important sets of facts to look for in the interpretation of a dream are: (1) the multiple and multiform special reminiscences suggested or symbolized by each thing, circumstance, or relation; (2) the various “ movements” or “ tendencies” hinted at. Somebody (the dreamer) is doing or experiencing something or having something done to him. That something is of deeply personal, perhaps infantile significance. Knowledge and keen in- sight must see through all disguises and determine what that something is. Not infrequently the apparent data must be absolutely reversed in order to be rightly understood. 84 HARVEY SOCIETY of course, some sorts of symptoms are less curable than others, The length of time sometimes required for successful treat- ments has often been the subject of comment. But in fact it is a great gain to have a method capable, even in a long time, of producing fairly good results. Any one who thinks about the matter must realize that it is extremely difficult to make any considerable change in one’s own character or habits. Our good qualities, as well as our faults, are deeply founded. Both have their roots in the experiences of infancy or in the reactions of childhood, and if we would help our- selves to the best purpose we must get back, in knowledge, feeling and imagination, to the conditions under which the deviations from the normal first began. To accomplish this takes time and patience, though the task is full of interest. It would not be justifiable to assert that the psycho-analytic treatment can accomplish such results as are claimed for it if we could not assert at the same time that the investigations based on psycho-analytie studies have thrown new and im- portant light on the nature of the disorders with which the method deals. Without this light, a rational, causal treat- ment of these affections would be as far out of our reach to- day as it was in the last century, and we should still be throw- ing ourselves against the rocks and reefs of this great prob- lem, chipping off a bit of stone here and there, but making no consistent progress. The splendid insights of Charcot, and the remarkable re- searches of Pierre Janet with regard to the phenomena of automatism and the mental state of hysterical patients, brought the first real illumination into this obscurity,—an obscurity greater than we then could realize. The lines on which Freud began to work were somewhat parallel to Janet’s in that both of these great leaders quickly learned to recognize the im- portance of the apparently forgotten and seemingly dead ex- periences of the invalid, and showed that they might still be acting as motive forces in the affairs of the present mo- ment. Freud soon arrived, however, at the important con- FREUD’S PSYCHO-ANALYTIC METHOD 85 clusion that it is not enough to know single incidents of the past life, let them be never so grave, but that the whole life must be drawn upon and made to yield its entire history, and he proved that when the whole life is exhaustively studied on this plan it is possible to explain the symptoms of illness as largely referable to demonstrable influences operating since birth, and thus to get on without making such large drafts on ‘‘ inherited tendencies,’’ of which we know so little, as the principal causal factor. Then it gradually became clearer that the gaze of the investigator must be directed with ever greater insistence towards the very earliest years of life as the time when the seeds of mischief are sown—that marvellous period when tendencies are established and paths of least resistance are laid down, which may give a set or bias to all the years to come, and cause the child’s mind to become sensitized, as if through a process of anaphylaxis, to special influences which may be brought to bear later, though perhaps not strongly until a much later period. The life-history of the normal child became, naturally, the next object of these ever-widening studies, and then the attention of a special group of investi- gators was turned upon the childhood-history of the races of men, as described in sagas and in myths. Even the his- tory of criminology and of sexual perversion—already mapped out in part through the studies of many men, but now for the first time made to yield its true lessons—has been largely drawn upon, for the sake of discovering and illustrating the nature of the dangers with which the early years of every child are more or less beset. One instructive method of getting an idea of what passes in the child’s mind, of the difficulties which he encounters and the means that he takes to meet them, is to observe carefully how we ourselves deal with corresponding situations: Every one who is accustomed to scrutinize his own thoughts and conduct must realize that he is often tempted to put out of sight what he does not like to think of; to seek enjoyment 86 HARVEY SOCIETY instead of doing work, and, in general terms, to live on a mental plane lower than his best. Most of the temptations by which we are beset might be classified under one or the other of two headings; namely, the desire for gratifications or undue self-indulgences of a relatively personal sort, and the desire for gratifications im- plying the approbation, admiration or the attention of others, if only through subserviency or domination. I am not now concerned to prove the prevalence of these temptations or to deny that we may utilize them to our profit, but only to call attention to the fact that a more or less universal and some- times irresistible tendency exists, which impels us, on the one hand, to secure these gratifications, and, on the other hand, to protect ourselves from self-reproach for so doing. In the interest of these two motives, which are, of course, comparatively rarely conscious motives, we cloak our cravings under forms which tend to make them seem justifiable and even admirable. Every thoughtful person is more or less aware,—though it is only the well-trained or unusually discriminating ob- server who can thoroughly appreciate the fact,—that an ele- ment of craving for self-gratification may lie hidden under the guise of anger, prejudice, fear, jealousy, depression, de- sire for self-destruction, ‘‘ over-conscientiousness,’’? and the wish to inflict or to suffer pain. It is equally true that un- der the form of restlessness, or that of a sense of incom- petency, we symbolize the hidden conflicts which cover our desire to escape from ourselves, or our incapacity to under- stand or unwillingness to face the full meaning of our emo- tional desires. Those of us who eall ourselves ‘‘ well ’’ owe it to those who are forced to call themselves ‘‘ sick ’’ to study the true nature of these innumerable faults of character. When this is done, it is discovered that these faults deserve the name of ‘* symp- toms,’’ and that, like symptoms, they are disguises and com- FREUD’S PSYCHO-ANALYTIC METHOD 87 promises, concealing painful conflicts that may date back to the experiences of infancy. It must be remembered that between the period of birth and the later years of childhood each individual recapitulates in a measure the history of civilization. The parent and the community who see in the infant not so much what he is as the promise of what he is to be, make little of those qualities in him which would be considered as intolerable if judged by our adult standards. But these qualities exist, neverthe- less, and the growing child to whom they are transmitted must deal with them as he is best able, whether by gradually modi- fying them for the better, or by shrinking from them in dis- gust, or by continuing to indulge himself in them in con- cealed forms. One fact must never be forgotten, namely, that each child comes into the world with one mission which he can- not overlook or delegate and which he shares in common with every living thing,—the mission of preparing to do his part in the perpetuation of his race. For the sake of the establish- ment of the great function on which this depends, he is pro- vided, in infancy, with a considerable number of capacities in the way of sense-gratification and with ample means of indulging them, which, however, he must eliminate as he grows older or preserve at his risk. But this risk the infant does not see, and before the time comes when he can see it he may have found himself drawn into paths of least resistance, lead- ing both to pleasure and to pain, from which it will be diffi- cult for him to escape. There is, then, no easy course left open for him but to repress his desires for these indulgences, just so far as may be necessary for concealing them from him- self, while at the same time he invents substitutes and com- promises in which the indulgences are continued under a new form. Yet, unfortunately, the adoption of such compromises is equivalent to laying a foundation for defects of character or for symptoms of obstinate forms of nervous illness, as the case may be. Clear memories of these earliest years of childhood rarely 88 HARVEY SOCIETY are retained. Yet some individuals retain very much more than others, and this fact, taken in connection with the evi- dence furnished by dreams, by a few careful observations of young children, and by the memories of patients trained under the psycho-analytic treatment, leads to the conclusion that a large part of the apparent forgetting is based really on repression. From the standpoint of the next later period many of the details of infancy are unpleasant to recall. One is reminded of the Mohammedan cadi who, when asked about the early (Christian) history of his town, replied: ‘‘ God only knows the amount of dirt and confusion that the infidels may have eaten before the coming of the sword of Islam. It were un- profitable for us to inquire into it.’’> The period of childhood, though it contains many elements of happiness, which are usually accentuated and continued by the child’s delightful power of grief-compensating fancy as exhibited in day-dreams, contains also many elements of suffering. The child’s fears—of the dark, of storms, of mys- tery and power in a thousand forms—have been explained ° as due to the organic memories of his pre-human ancestry; to the recognition of the contrast between his weakness and the bigness and strength of those about him or (in a religious and philosophic sense) the vastness of his own inexhaustible possibilities. There is nothing to urge against these explana- tions, but they cannot be regarded as covering the ground. The young child is at least partly like the older child and the adult, and fear, with them, cannot be studied as apart from the desire which so often underlies it. Like Scott’s aged harper, we all ‘‘wish, yet fear,’? and frequently the wish becomes gradually repressed, and the fear alone remains. We all ‘‘ fear ’’ those most whose approbation we most ‘‘ wish,”’ and fear the tests in which we most long to succeed. The * Cited in James’s “ Psychology,” vol. ii. °Of. Pres. G. Stanley Hall’s paper: Study of Fears. Am. Jour. Psychol., January, 1897, vol. viii, pp. 147-249. FREUD’S PSYCHO-ANALYTIC METHOD 89 child, with his splendid fancy and his intensified training in the symbolism of fairy-tales, loves to play with these fears and wishes. The dark stands for delicious, as well as alarming, mysteries, and beyond these there is also always the longed- for chance of the pleasure of re-discovering himself in his mother’s arms." The strength of the child’s tendency to follow pleasurable paths of least resistance may be vastly diminished, or, on the other hand, vastly increased, by the fact that the immense forces of social custom, by prescribing what should be done, help to deprive the child of his own sense of responsibility, while at the same time they seem to relieve the parent from the necessity of seeking to discover what is really passing in the child’s mind. We talk of independence, but, in fact, the community is almost fanatic in its demand for conformity. The key to the solution of these difficulties must be sought, not primarily in the education of the younger generation, but in that of the older. Jt is with the lack of knowledge on the part of the parents, and the disregard by physicians of the need of acquiring and imparting adequate information on these subjects, that the reform must deal. There can be no doubt but that our social and ethical customs, which rep- resent the filtered experience and wisdom of the race, are of immense value. But the ends which they mainly seek and the methods which they follow are not chosen with reference to the needs of the neurotic child. These points are of such importance that an attempt must be made to state them some- what more fully, even at the risk of exciting misunderstand- ings. The family influences under which most healthy-minded children grow up are, of course, eminently beneficial, and this is no place for discussing their shortcomings. But the fact remains that nervous invalidism is extremely common; that it is closely bound up with social relationships "This pleasure has a philosophie bearing to which I cannot here allude. 90 HARVEY SOCIETY of varied sorts; and that the school in which the child gets his first introduction to these relationships is the home. One cause of unhappiness in married life, for example, is the inability on the part of the husband or the wife to adopt the new duties with a whole heart. This inhibition is often due, in part, to the craving, established in childhood, for an undue continuance of the parental ties, with all that they imply; an unconquerable homesickness, which often cannot be put into words or recognized in its own form, overrules the new interests which ought to be supreme. These are facts of common knowledge, but under the light of this new movement they have been studied with a thor- oughness previously impossible, and have been correlated with others of a kindred sort, with the result of immensely increas- ing their significance. It should not be forgotten that father and mother are not only objects of admiration, imitation and veneration to the growing child, but that they stand likewise to him as man and woman, and that, as such, they are in a position of peculiar responsibility and may be centres of peculiar harm. I am not undertaking here to lay down rules for conduct, nor even to assert that although, on the whole, frankness and a well-guarded, thoroughly wholesome intimacy between pa- rents and children is eminently desirable, it is very undesirable to break down all barriers of restraint between them. The evolution of modesty and of a certain amount of personal re- serve needs to be safeguarded, even at some risk. Real knowledge with respect to these complex matters should be sought, but it is hard to get and its advent is not to be awaited with impatience, or its acquisition as the basis of judgment and conduct assumed on insufficient grounds. Another point of importance is that the dawning self- consciousness of the infant represents him to himself, not definitely and distinctively as ‘‘ boy ’’ or ‘‘ girl,’’? but as a being standing in relations of dependence to other and more powerful beings, whose characteristics he does not differentiate FREUD’S PSYCHO-ANALYTIC METHOD 91 from the sex-standpoint. The significance of this statement will be understood without difficulty by any one who will con- sult carefully even his own experience and observation. Every one must be aware that we all have some traits which are com- monly designated as masculine, and others designated as feminine, and that the evolution which best marks social prog- ress is based on the working out, in the case of each person, of capacities related to both of these sorts of traits. The at- traction which persons of our own sex have for us is of great value as leading to friendships which may become exceedingly warm without ceasing to be eminently desirable. It is, how- ever, well known that such friendships may develop into rela- tionships which are eminently undesirable and a-social, and even, in the case of men, of a kind that would be called criminal. Between these two extremes, tendencies are to be observed, or are to be detected through careful study in a given case, which may lead to hidden conflicts and to distress- ing nervous symptoms. Good observers have shown it to be true that just as, to a certain degree, many men prefer the society of their fellows at the club to that of their wives and families at home, so, in a much deeper sense, nervous invalids often waver between attractions which would lead them in the direction of the most wholesome and useful relationships, either of marriage or friendship, and those which have an un- wholesome tendency. The objectionable forms of these ten- dencies, if not created, are, at least, accentuated, by the over- strong, or, rather, by the slightly abnormal attachment of the infant to the father on the one hand or to the mother on the other. It is true, at the same time, that there are probably also deeper influences at work, dependent on some tendency which each person brings into the world, but of the exact na- ture of these latter influences it would be premature to speak. The subtlety of the danger here noted is what gives it its effective power, for what could seem to be freer from danger than parental love? Obviously nothing, when this love is fortified by wisdom and knowledge. In fact, however, it hap- 92 HARVEY SOCIETY pens but too often that, either because the child is too imma- ture in his manifestations of affection or because the parents retain too much of their own childishness, that which should be a source of infinite happiness and should lead the child towards independence and self-reliance becomes, instead, an opportunity for the growth of unwise emotion and a weaken- ing tendency to imitation and dependence. A careful study of the child’s personal gratifications has shown that a portion of the earliest and strongest of them, which, for the most part, have to be repressed later, are re- lated, first, to the satisfying of hunger, then to the securing of certain specific pleasures, such as the massive feelings of warm contact (during the diaper period), and those due to the excitation of the orifices of the body, especially the mouth, the urethra and the anus. To the child these sources of gratification stand at first, both morally and from the social standpoint, on an equal footing. He is unaware that he is likely to be subjected to serious temptations with reference to some of them; he does not know that his reaction to them may decide whether he is to become a being capable of recog- nizing that his best freedom is to be found in a willingness to devote himself to the welfare of the social whole, or whether self-indulgence is to be his ruling motive. The child who con- tinues too long to suck his thumb, or wet his bed, or who finds undue fascination in the emptying of the bladder and the rectum, or detects a mysterious significance in these events, may be acquiring a tendency to prolong bodily indulgences which ought to be outgrown, and laying the foundations for other personal gratifications of more subtle, more distinct- ively mental, and, socially, of more disastrous sorts. Mastur- bation, of course, although accused of dangers which do not belong to it, stands high among these over-indulgences of a purely personal, auto-erotie sort. Freud has been criticised for making too much of the sexual element in these problems; for seeing sexuality where it does not exist. But is this eriticism just? The number of FREUD’S PSYCHO-ANALYTIC METHOD 93 those who think so is growing daily less, as sober judgment and knowledge of the facts come better into play. Think with what inconceivable, with what seemingly unwarrantable te- nacity, nature, bent on the perpetuation of the life, both of the individual and the race, has safeguarded the function on which this depends. Many plants if starving will flower all the more abundantly, as if in order that their descendants at least may live. Think how every novel, every drama, is founded on some aspect of the sex problem. Is not the truth rather that these problems are felt to be of such enormous importance that we ought perhaps to shrink from touching them just as we might shrink from handling bombs charged with dynamite of high explosive power? And yet, is this true? Is not the dynamite to a great extent the figment of our imaginations, filled with repressed memories which we have not known how to study, but whose rumblings we have all vaguely felt within us? This, or something like it, was, at any rate, the feeling which led Professor Freud long ago to enlist for his campaign, and determined him to risk everything for the laying bare of these long-neglected facts. He might have said to himself, whether he did or not, that he would take the great studies of human character, like those by George Eliot, or by Meredith, and would go on where these writers stopped, striving, in the spirit of the novelist turned man of science, to discover the processes of childhood through which the strong, deep tendencies which they describe came into being. Those who oppose this move- ment out of unwillingness to discuss the sexual life, are not only declining to be scientific and impartial (since to the scien- - tific person nothing is in itself disgusting or unworthy of con- sideration), but also are rendering it harder for patients to get well, by stamping as indecent their attempts to gain a true knowledge of themselves. I should like to eall your attention to the fact that in the beginning it may be only a slight over-accentuation of an infan- tile tendency that makes the difference between the promise 94 HARVEY SOCIETY of health and the promise of invalidism. But when the lines which enclose the angle of deviation have become extended, as the child grows up to manhood, the actual distance becomes immense. One is reminded, here, of Jean Ingelow’s poem, ‘* Divided,’’ and, still more, of George Eliot’s great study of Tito, in ‘‘ Romola.’’ Charming, handsome, kindly, scholarly, Tito seemed, as a youth, to have all possible good qualities, save that he possessed, or was possessed by, an apparently trifling tendency to self-indulgence, or selfishness, of the concealed, insistent, infantile type. This was never very prominent, but it was always present and always irresistible, and it made him in the end a fiend. And yet, from the psycho-analytic standpoint, Tito’s was a curable case. At any moment, up to the very last, if he could have been aided to penetrate the history of his own life, and thereby to see at one glance the system of interlocking forces representing his still active ten- dencies of childhood and their logical outcome in his present acts,—as one looks through a transparent model of the brain- tracts,—he might perhaps have undone the mischief. For a man’s emotional and mental past, even if of his infancy, never dies; it is always present and active, and represents a force which is always susceptible, theoretically at least, of modifica- tion or neutralization, in the interest of progress.® There are several advantages in classifying, as Freud has been criticised for doing, the many and varied tendencies of which novelists write, as sex-tendencies. But perhaps the most important advantage is the practical one that it enables the physician, on suitable occasions, to point out the direction in which a given act or thought, conceivably innocent in itself, may lead. “Strictly speaking, we never obliterate the memories of our past experiences, and even to wish to do so would be in accord with the spirit of an Oriental rather than of a Christian philosophy. The new growth to which we should aspire diverges at a certain point from the old but gains a certain richness from the memories of the latter, and these memories cease to be painful, in the old sense at least. FREUD’S PSYCHO-ANALYTIC METHOD 95 It would be worth while to know whether, when you lay your hand on a man’s shoulder, you are to be taken for a friend or arrested for assault and battery. The strongest term which points to the possible practical outcome of your act is oftentimes the best. A bit of self-indulgence, if it rep- resented a force which had its rise in infaney, may not be as harmless as it seems. The child must, at every cross-road, se- lect and accentuate on the one hand, repress on the other. But this power of selection and repression, which stands so high among our attributes, is itself a source of danger. The adop- tion of this or that principle of accentuation or repression may become habitual, and some of them are harmful. The child is like a merchant who cannot oversee all his affairs in detail and so indicates to his subordinates the general trend of his policy and then lets them work it out alone. But let him look out lest he become narrow-visioned and get hoodwinked. The really wise merchant does not often leave his subordinates to work out his plans indefinitely by themselves, whereas the indication of policy made in early childhood is often a de- cision, in one or another particular, made once for all and for a lifetime. Truly, the child is the father,—indeed, the mas- ter,—of the man, to a degree hard to appreciate except for those who have taken the great amount of pains required for following the literature of these researches of which I speak to-night.° Not only is the policy of the lifetime often dictated onee for all in childhood, but this fact itself is often erased from memory, that is, it is repressed, and the results of an early misjudgment are then accepted as if assumed to be gov- erned by an intelligence cognizant of facts and tendencies of which in reality it knows nothing. To summarize once more what I have said: Nervous in- validism, in the sense in which I now mean that term, is not *It would be obviously impossible even to indicate here the mis- chances which often come with the later years of childhood, when curiosity and fantasy become active; still less those which attend the oncoming and course of adolescence. 96 HARVEY SOCIETY only a source of suffering: it is also a sign that those who suf- fer from it cling—unwittingly but under the pressure of strong instincts—to modes of thought and feeling which should be recognized as belonging to childish stages of development. The mode of action of this tendency is subtle, but a crude illus- tration of the principle indicated is given in the obvious fact that depression and feelings of weakness and incapacity, painful though they are, are often made to serve as self-indul- gent and childish self-excuses from effort, and as means of ex- citing self-pity and the attention from others which almost all children so much erave. The simple recognition of this tendeney is, however, not competent to banish it from the mental life of the adult; the whole chain of experiences and shifting emotions which led to the habit must be laid bare and scrutinized. It is, then, found that men sometimes allow themselves even to fall sick, or to suffer pain, or to adopt some species of asceticism or of morbid self-depreciation, for the reason that behind these symptoms and tendencies there lurks often a desire for self-gratification of a childish type the real roct of which can usually be revealed in detail, and must be revealed if a radical cure is to be obtained. In the case of neurotic phobias, it is, essentially, himself, not -the supposed source of terror, that the patient mainly fears. So, too, morbid introspection is largely a search for emotional excitement, the desire for which only disappears when its true nature is clearly exhibited by the aid of a deep-going introspec- tion of a totally different, a more wholesome and more rational sort, through which we see ourselves, no longer as unfortunate individuals, but as companions in arms in the great march of social progress; as akin, perhaps, with those whom we had called sinners, and had pitied at long range, but akin also with men of devotion and force, whose characteristics we can dis- cover to have been won by conflicts like our own. Broadly speaking, it may be said that every man has had, theoretically, at his birth, the capacity of developing, under favorable conditions, in such a way that he would have become FREUD’S PSYCHO-ANALYTIC METHOD 97 possessed of a fairly well-balanced character, and that this capacity was the best element of his birthright. The condi- tions required for this development may have been such as it would have been extremely hard, even impossible, to secure at the outset, but in the psycho-analytic method we have a means of readjustment, difficult of application, it is true, but through the aid of which at least a certain number of those who have gone seriously astray may be restored to reasonable health. But for this purpose they must teach themselves to review their adolescence, their childhood, and their infancy, and thereby strip off the veils by means of which their ease and pleasure-seeking instincts had sought to conceal them from themselves. The game is worth the candle, for, in my estimation, no disease from which men suffer causes, in the aggregate, so much misery as the fears, the obsessions, the compulsions, the need- less weaknesses, the innumerable faults and vices of character, by which we see ourselves surrounded. All these ills spring virtually from three sources,—inherited tendencies, the fail- ure duly to recognize our spiritual origin and destiny and the obligations which this recognition should impose on us, and the absence, during our development, of the conditions neces- sary for the successful making of the journey from infancy to adult life. It is very important to note that the infant starts on his - journey of life with a series of instincts, motives and inhibi- tions which are less strongly unified than are those of the adult. He does not at once feel the intense repression and directive force of public opinion which is to be reflected later by his mother and his nurse. Each sensation, each inclination to seek the renewal of a gratification once felt, he must take at first, at least relatively, in or for itself and at its face value. Until the necessity is felt for the subordination of some im- pulses and the emphasis of others (those which are necessary for reproduction) as entitled to a relative primacy, the in- fant’s tendencies might be compared to a set of loose threads 7 98 HARVEY SOCIETY of differently colored wersteds, lying side by side or crossing each other more or less at random, but not yet woven into a chosen, much less a beautiful pattern. The accomplishment of this latter task would mean health. Nervous illnesses and faults of character arise largely as the primary or secondary results of the failure on the part of the forees of civilization, brought to bear on this or that individual child, to set the intricate machinery in action which should weave his threads into a good pattern. We need not now in- quire where the fault lies; the main question is as to the ef- fect. Let it be assumed that some special sort of gratification is too strong to be lightly abandoned in the child’s mind in favor of the sort of subordination and co-operation offered by the oncoming years; or, to make the facts and argument seem more familiar, let it be assumed that the individual is drawn by some instinct to remain a child, with a child’s egotism, longings, whims, propensities, and a child’s world of dreams and fancies. I hardly know, though I might guess, how strongly this audience feels sympathetic to these Freudian doctrines. I do know, however, how I once felt myself. I well remember my own first attempt and failure—perhaps fifteen years ago—to grasp the real thought of Sigmund Freud, then a little-known physician, now deserving to be ranked as a great leader, and honored as we honor such men as Charcot, Hughlings Jackson and Pierre Janet. I was glancing over a copy of the Newrologisches Central- blatt at a friend’s house, when my eye was attracted by a bold claim concerning an asserted common origin for all the psycho- neuroses. The paragraph stated that these neuroses never arose except on the (partial) basis of some disturbance of the sexual life and that the differences in the character of the symptoms, as, for example, between hysteria and neurasthenia, were determined largely by the period of life at which this or that disorder of the sexual life set in. I was impressed by the boldness and confidence of the statements, but rashly FREUD’S PSYCHO-ANALYTIC METHOD 99 attributed these qualities to eccentricity and perhaps notoriety- seeking on the part of the writer, and laid the paper down with a distinct feeling of disgust: the reasoning, I thought, could not be correct. How different are my sentiments at present, now that through three years’ hard work I have learned what these state- ments really mean; have made the personal acquaintance of the author of them and his supporters, and have discovered what a treasure-house of facts respecting the deep currents of human life they have amassed. I have come to believe that if we had the power and the will to turn inward the search- light of self-knowledge on a large scale, there would be far less prejudice and cruelty in the world than there is at pres- ent; far less envy, jealousy and suspicion; far less terror, disappointment, depression of spirits and suicide; far less disorders of the nervous system; far less inability to realize our best destinies. The whole great drama of life is played— in embryo as one might say—within the mind and heart of each and every individual, before he sees it played,—for the first time as he thinks,—on the larger stage of the social world around him; and this fact is worth our knowing. To bring about an advance in these directions, an advance in the prophylactic education of the child, an advance in the better understanding and treatment of neurotic invalids, would be well worth all the vast labor expended, or to be expended, on these investigations. It is not for the purpose of humbling ourselves that we need to scrutinize our repressed thoughts. There is little need of final judgments, but much need of free- ing ourselves through wider knowledge from the unseen chains that restrain the freedom of the reason and the will, ILLUMINATING GAS AND THE PUBLIC HEALTH * PROF. WILLIAM T. SEDGWICK Massachusetts Institute of Technology N the days of William Harvey there was no such thing as illuminating gas. One of the most striking passages in the ‘‘ Intellectual Development of Europe,’’ by Dr. John W. Draper—a New York medical man, who was also a brilliant historical writer—contrasts unfavorably the unlighted streets of Harvey’s London with those of Moorish Cordova, which, six hundred years earlier, were well illuminated: ‘‘ Cordova [about the tenth century] boasted of more than two hundred thousand houses and more than a million of inhabitants. After sunset a man might walk through it in a straight line for ten miles by the light of the public lamps. Seven hundred years after this time there was not so much as one public lamp in London.’’ Illuminating gas derived from the distillation of bitumi- nous coal was first used in a few private houses and factories at the end of the eighteenth century and for cities early in the nineteenth century. A centennial celebration of this latter event was held in Philadelphia in March, 1912. In the cities of the United States gas did not become a common illuminant until about 1850, but by 1855, according to Dr. Samuel Eliot, the father of President Eliot, there were several hundred gas companies in successful operation in America. The revolution wrought by the substitution of gas for oil for lighting purposes and the reluctance of some to exchange gas for electricity are pleasantly touched upon by Stevenson in his well-known sketch in ‘‘ Virginibus Puerisque’’ entitled ‘‘A Plea for Gas Lamps.”’ * Delivered November 25, 1911. 100 ILLUMINATING GAS AND PUBLIC HEALTH 101 From the beginning until about 1880 there was only one principal kind of illuminating gas for cities and towns, namely, that made by distilling bituminous coal and hence properly called ‘‘ coal-gas.’’ But about 1880 a new kind, _ known as “‘ water-gas,’’ was invented, which has since, to a large extent, displaced coal-gas for illuminating purposes. Water-gas is not made from bituminous but from an- thracite coal, and not by distillation, but by passing steam (the vapor of water) upward through retorts filled with glow- ing coal (carbon). The hot carbon (C) decomposes the water (H,O) and combines with its oxygen (O), setting free its hydro- gen. But since there is an excess of carbon in the retort and a limited supply of oxygen in the water vapor much carbonic monoxide (CO) and but little carbonie dioxide or carbonie acid -(CO,) results. The gaseous output of the retort is thus largely hydrogen and carbonic monoxide, a mixture of gases excellent for fuel, but burning with a blue flame poor for illuminating purposes. This ‘‘water’’-gas must therefore be ‘‘enriched’’ with other gases, and for this purpose such gases are added to it by further treatment of no special interest to sanitarians. The end result is a gas of fair illuminating and heating qual- ity, containing a large percentage of the well-known and highly poisonous carbonic monoxide (CO). At least three times as much of this deadly poison is usually present in the water-gas as in the coal-gas sold in Massachusetts, but there is reason to believe that the water-gas is far more than three times as dangerous as the coal-gas—very much as a grain of morphine is far more dangerous than a third of a grain. As soon as the new water-gas began to be introduced, in the early 80’s, long-established and prosperous gas companies in Massachusetts, threatened by the innovation and looking about for weapons of defence, seized upon and exploited the fact that water-gas was rich in poisonous gases and hence dan- gerous to the public health; and from that time forward, for this and other reasons, the illuminating gas question has be- come a public health question. 102 HARVEY SOCIETY In 1885 an article bearing the same title as the present paper appeared in the Annual Report of the State Board of Health, Lunacy, and Charity of Massachusetts. It was care- fully prepared by the able Secretary of the Board, the late Dr. Samuel W. Abbott, and the reason for its appearance at that time was the recent perfection of a simple and con- venient patented process for the manufacture of the new kind of illuminating gas, then and since known as ‘“‘water’’- gas. This was placing upon the market an illuminating gas easier and often somewhat cheaper to make, and ranking higher in candle power, than the ordinary coal-gas derived by the distillation of bituminous coal, but a gas also much more heavily charged with carbonic oxide (CO). Promoters of the new process naturally urged its adoption upon the old and established gas companies, which in some cases began to make use of it, especially for supplementary supplies, but in other cases, particularly if they were already prosperous, refused to have anything to do with it. Advantage was also taken of the water-gas process to form new and competing com- panies, charters being sought on the promise of lower prices and higher candle power for gas. Attempts were likewise made to buy out at low prices long-established and prosperous companies occupying inviting territory, by threats of invasion and competition with gas of lower price and higher candle power. In Massachusetts, a comparatively thickly settled and there- fore attractive territory for the manufacture and sale of gas, there were in the early 80’s many and prosperous gas com- panies, and these for the most part, under the leadership of the largest—the Boston Gas Company—refused to adopt the new process or to be frightened by threats of competition into selling out at low prices. But when the water-gas interests undertook to obtain charters in Massachusetts for new and competing companies, they encountered a formidable obstacle in a statute (enacted in 1880) forbidding the distribution and sale of illuminating gas containing 10 per cent. or more of ILLUMINATING GAS AND PUBLIC HEALTH 103 CO. This law it was therefore necessary to have annulled before the new process could be introduced into that State. A battle royal for the repeal of the law now began be- tween the older coal-gas companies on the one side, who did not eare to pay for or use the new process, or did not desire to sell out to the new companies, or did not want competition, and those newer companies which for one reason or another wished to enter Massachusetts territory and sell and distribute water-gas containing more than 10 and often as much as 30 per cent. of carbonic oxide. Popular attention was drawn by the old gas companies to the sanitary aspects of the ques- tion, and the battle before long raged fiercely around the ques- tion of the public health. Meantime the State Board of Health, Lunacy, and Charity referred the mooted question of the rela- tive poisonous properties of the two gases, coal-gas and water- gas, for investigation to two professors of the Massachusetts Institute of Technology—one, the eminent sanitary chemist,. the late William Ripley Nichols, and the other, then a physiolo- gist, the present author. These investigators soon after made a report, based upon extensive experiments upon animals, showing, as might have been expected, that much greater dan- ger exists in water-gas than in the ordinary coal-gas (Report of Massachusetts State Board of Health, Lunacy, and Charity, for 1885, p. 275). In the same report Dr. S. W. Abbott, then Secretary of the Board and an excellent statistician, published the paper already referred to above, in which he showed that for the preceding 20 years there had been but four deaths from gas poisoning in Massachusetts and predicted many more if the 10 per cent. limit should be abandoned. Victory in the Legislature rested for a time with the older companies. But in 1888 the Gas Commissioners (who had been created in 1885) were empowered to license certain companies to make and sell water-gas for illuminating purposes; and in 1890 the 10 per cent. statute was repealed, because meantime the opposition of the older companies was for one reason or another relaxed, while the State Board of Health (as it was 104 HARVEY SOCIETY now and had since 1886 been called) made no effective ob- jection. Commercial conditions had changed, and many of the coal-gas companies now wanted the privilege of making water- gas if it suited their convenience. Moreover, water-gas was being widely used in other States without public protest, and when the commissioners recommended the change it was speedily made by the Legislature—with what obviously dis- astrous consequences to the public health we shall learn in the present paper. Of the unobserved and perhaps imperceptible consequences, such as diminution of vital resistance and in- creased susceptibility to disease either constitutional or in- fectious, we have, and in the nature of the case can have, no exact knowledge. There is reason to believe, however, that here also the consequences, if less disastrous, have been no less real. MORTALITY FROM ILLUMINATING GAS POISONING IN MASSACHU- SETTS: MORE THAN 1200 DEATHS IN THE LAST 20 YEARS It was predicted by the investigators employed by the State Board in 1884 and reaffirmed by Dr. Abbott in 1885, that if water-gas should replace coal-gas in Massachusetts the conse- quences to the public health would probably be dangerous if not disastrous. Other experts of equal or greater eminence took precisely the opposite ground and even ridiculed the possibility of any such consequences. Among these were Pro- fessor C. F. Chandler, of Columbia University, and the dis- tinguished English chemist, Dr. E. Frankland, who stated in a letter read during these hearings: ‘‘ I have no hesitation in saying that it (water-gas) may be used with safety both in public buildings and private houses. I should be delighted to substitute this pure and powerful illuminating agent for the gas with which my house in London is at present supplied, although it is used in all the bedrooms.”’ More than a quarter of a century has since gone by and there are now available for study the results of a considerable, though by no means total, replacement of coal-gas by water- ILLUMINATING GAS AND PUBLIC HEALTH 105 gas during a period of about 20 years (1890-1909). The author of the present paper and one of his associates, Mr. Franz Schneider, Jr., have accordingly undertaken a careful inquiry to see how far the predictions referred to have come true. The problem is of course complicated by the fact that in spite of the legislative permission to manufacture and dis- tribute water-gas, this has by no means wholly displaced coal-gas. The results at hand, originally published in the Journal of Infectious Diseases, vol. ix, No. 3, 1911, are there- fore not such as we might have obtained if the replacement had been complete. Since 1890 some companies have made only water-gas; others, only coal-gas; many have made a mixture of the two, and some have made each intermittently. Still, the broad fact remains that an increasingly larger amount of the poisonous gas, CO, has been distributed since 1890 than before that date and not only absolutely but relatively to the population. The matter is further complicated by the use of illuminating gas for suicide, a subject which requires, and in the present paper will receive, special consideration and discussion. One good result of the long and active agitation in Massa- chusetts was that a State Gas Commission had been provided for in 1885. Another was that in 1888 the Gas Commissioners were required to investigate, keep a record of, and report all deaths (or injuries to health) from gas poisoning within the State. From 1888 onward, therefore, we have for Massa- chusetts a fairly complete report of fatalities and other con- sequences of gas poisoning, and one probably far better than any possessed by any other State. It is perhaps the only record of the kind existing anywhere. Fortunately we have also, for the same period, the returns of the Medical Examiners concerning deaths from illuminating gas—a body of experts whose opinions possess expert value. We have taken for study the fatalities, only, from gas poisoning. Of the numerous injuries which do not result fatally we have, and can have, no complete record. Some are 106 HARVEY SOCIETY reported by the Gas Commissioners, but many are never reported at all and many less striking and seemingly transient effects, such as headache or malaise, are neither heard nor even thought of as due to gas poisoning. As stated above, we have obtained the records of death from gas poisoning in Massachusetts from two sources, namely, TABLE A. DeEatTHS FROM ILLUMINATING GAs POISONING IN MASSACHUSETTS. (1886-1909.) Years Ending Dee. 31. Eee Pia Retaeag: SES yey ae eee tes pete asus, Le SMs became. Noy iy iu 5 0 LTE Ce x AAP oUF gern ERENCE Atak 6 9 ES SS eee eee Manta? ce SEAL STN AO Go ce) Dy 6 0 Th STOAU NES ops (2 cuenta een RENN Pe ME SAR a Me OM Ma A 5 2 SOO ae ee ce ert en Piece rence eee ee eres 12 10 BS I ei: SYS RIAy Sey AAR Oe REL CE IS 2 WP a Di tees ane 16 14 TSO PAA ARGU hs SOT oF REIL SY SURED yO SG Bh 28 18 1 foto BS Bence Bh cl Ais ACH emer tine tals hummel Abie 27 25 1 ofO Ye Dae eats CNTY APPR ies DHT e a a anes Cas Boat MBS 43 33 POO Sie neiere ples eae ee Tea doy ae hae bola NN a 31 26 Tey ea ede pee eelat toate hah A eli tbs SV ale otad 2 Retake 52 51 1 eo eae ANS Mh ae plan a Ah eA Cd ey Ae 63 58 MBO Sk eos em ale det ee mea eno cod abt h a Ca 78 be 1 oko) Oi STs oe rite ited 1 Ri hy itd or las Se 65 65 GOO ire ee PEAS AV ares Rie Fh Sy Se Sas 45 46 1 RTD Resta Oe TE MITA Day ESN PN ate Su aE 37 37 TOA thar ins epee A a dee nee in Annet, BiB RS gad a 63 62 OOS ee eaee te rela Oe ete ers eee 71 (P: 5 S(O ES OR ANE I RIAL OS ARENA Caled Je enya 61 59 HAC8 OSS et Rik aie aa we ica Bd Pe EEG a al mk ERO 77 72 TOO Gi Bees eee br ee ee sy ea eae 68 71 TOO Fess ha Fee a cacteus clothes cierto ee 147 145 ge SPER Sd ALE UE AA Ra PURI SPAS ot kbd 123 115 EGO OI a TER Ree OI i ln ei deh 102 99 POGUES SPs Masia eae ee wees 1,231 1,157 the reports of the Gas Commissioners, and the returns of the Medical Examiners. The former are published in the Com- missioners’ Annual Reports, the latter in the State Registration Reports. The Gas Commissioners’ records we owe to a pro- vision of the law already referred to, permitting the use of water-gas, but at the same time requiring all gas companies to ILLUMINATING GAS AND PUBLIC HEALTH 107 return to the Commissioners a written report of any death or injury due to gas distributed by the company in question. On the whole this arrangement has worked out fairly well, al- though in the early years the Commissioners complained with reason that some deaths were not reported. The Commis- sioners’ records begin with the year 1886 and it is interesting to note that poisoning by illuminating gas did not earn itself Cuart [. Seen a Ea | lscduef eter} | dosdei| | rebishel | [DE ee See D CO aN J Metsret | \ ea ae selene lead a separate place in the classification of deaths reported by the Medical Examiners until that same year. The figures of the latter are also available, therefore, since 1886. For data pre- vious to 1886 we have only Dr. Abbott’s valuable paper of 1885. The table now given (Table A) shows side by side the fig- ures derived from the two independent sources mentioned. 108 HARVEY SOCIETY These data are for the calendar year indicated, and include only deaths from poisoning by illuminating coal-gas and water- gas. Deaths from oil gas or acetylene gas and deaths caused by gas explosions, or from burning by gas, have been excluded. The table shows substantial agreement in the two sets of data, especially in the later years. The Medical Examiners’ figures are probably the more accurate. Some of the salient features of this table are the sharp rise beginning in 1890 from a very low previous level and con- tinuing to a high maximum in 1898, with a fall to a lower level in 1901, followed by a rebound which in 1907 reached the highest point in the entire table. From five or six deaths each year before 1890, the number rose to 147 deaths from poisoning by illuminating gas in 1907. Previous to 1885, ac- cording to Dr. Abbott, there had been only four deaths dur- ing 20 years. The same fluctuations which appear in this table may be seen in more graphic form, but as death rates, in the lowest curve—the heavy black line marked ‘‘ Gas Poisoning, Mass.’’— on Chart I. Variations corresponding more closely to those in Table A may also be seen upon Chart II in the heavy black line marked ‘‘ Deaths by Gas Poisoning.’’ It should be noted, however, that the correspondence of these data is not exact in all cases, since the figures in the table above and the curve on Chart I represent calendar years and rates, while the heavy black line on Chart IT represents actual deaths and years ending June 30. The highest point of the line on Chart II thus falls in 1908 and not as on Table A and Chart I, in 1907. SOME DEATH RATES FROM SCARLET FEVER, FROM MEASLES AND FROM ILLUMINATING GAS IN MASSACHUSETTS AND IN RHODE ISLAND We can best realize the growing importance of illuminating gas as a cause of death by comparing its mortality rate for a period of years with the death rates from such familiar dis- ILLUMINATING GAS AND PUBLIC HEALTH 109 eases as scarlet fever and measles in States having trustworthy vital statistics. For this purpose we have computed the fol- lowing statistics for two such States, namely, Massachusetts and Rhode Island: TABLE 1. DeatH RATES FROM SCARLET FEVER, FROM MEASLES AND FROM ILLUMI- NATING GAs IN MASSACHUSETTS AND IN RHODE ISLAND. (Per 100,000.) Illuminating | Illuminati Calendar Years. Pea Olas) oo | “Gey LES ie oe ere 28.80 22.08 | 0.29 LS OE ee Zone 10.33 0.29 ISS Se Ne 8.49 7.85 0.23 fee os Se 8.76 5.09 0.54 Lilo -e ee 10.74 LOLS 0.70 WLS 28 .56 S78 1.19 Doh Sin. + oe eae 33.80 2 eS MOA eee ose base 26.51 4.00 1.76 OE Einar rn 19.31 4.63 1.24 LEM AL a 9.73 5.35 2.03 Uo Tie 13.05 6.03 2.40 ESO SMT PLS ss a'si5-s! g 5.25 2.05 2.91 LON AL led er 8.56 8.78 AER Y/ LOTS J ee 13.94 LG RE7 (Ff 1.60 1.63 LST Lue See 13252 6.03 ico 3.42 DLs 2 a 10.84 11.53 2.18 4.01 Ll 2) 6 17.42 8.44 2.43 6.10 LT. os ee 4.65 5.39 2.06 4.69 ieee 3.90 5.89 2.56 1.92 Ly | hve ae ee 4.39 6.76 APA 7.50 LSU 2 i re 9.04 5.18 4.67 eas TES Ws ee eR 11.46 10.27 3.82 L415 eae ee, Se 7.86 4.77 3.10 Table 1 shows strikingly how important poisoning by illu- minating gas has recently become as a cause of death in Massa- chusetts and in Rhode Island; and the same facts are dis- played graphically by the diagrams on Chart I (p. 107). The death rate from the two contagious diseases (scarlet fever and measles) has evidently greatly declined, while that from illu- HARVEY SOCIETY The death rate from poisoning by illuminating gas was minating gas poisoning has greatly increased, so much so that higher in Massachusetts in 1907 than from scarlet fever in the latter bids fair soon to exceed the former. 1905 and 1906, while in Rhode Island the death rate from illuminating gas from 1903 to 1907 was at times higher than 110 a Sa 2 aS a ee eS ee RRR ee ese eee eRe eeea ees eese Ete Skst: Bees neias Bee Seneaeee ShaBeS Se eae Reet eeSeerekhees EAS sE 2aeMeeaee ee Ses sessear (222 sce ae aes eae ae Vee Sa JGGebe = he es seas oe aa ae See Sk SS eenhse te aS hs Ree eo eet Bis se ees ese oe olan eee gt eget Ps a a a 9 at a SRR ESS eae kkia===SS SS Seah ar £12 eee Nee ee eC ee Cart II. SaPEPHRE EEE EEE pape : SCARE ECACC PS Roe pp 2 Poisoning by illuminating gas has evidently become in Massa- chusetts and in Rhode Island a cause of death nearly as ef- fective as is scarlet fever or measles. It has of late years claimed that in Massachusetts from either scarlet fever or measles. as many victims as has typhoid fever in some American and many German cities. ILLUMINATING GAS AND PUBLIC HEALTH 111 AMOUNTS AND KINDS OF ILLUMINATING GAS MANUFACTURED IN MASSACHUSETTS (1886-1909) The following table (Table 2), the main features of which appear also on Chart II, p. 110, shows the amounts of total il- luminating gas (coal-gas and water-gas) and of water-gas manufactured in each year in Massachusetts. The data are de- rived from the Annual Reports of the Gas Commissioners. TABLE 2. Amounts oF ILLUMINATING Gas MaprE AND OF WATER-GAS, AND DEATHS FROM ILLUMINATING Gas IN MASSACHUSETTS. (1886-1909.) Total Coal- and ; ¥ Water-Gas Made Deaths from Years Ending June 30. ae Ge Mees (Million Cu. Ft.) | Illuminating Gas. ls oS pele Aer 2,625 12 a ne 2765 28 5 a ae 3,010 47 8 ve ae 3,156 78 4 are 3,346 212 7 er. 3,300 777 19 0 ae 3,370 1,231 21 a 3,594 1,467 26 ee ee 3.671 2,022 29 i. ces a 3,955 2,413 45 2 a ea 4,639 2,876 33 ee 4,731 3,090 63 Be es secs. 4,901 3,167 77 NP eee in. 5,120 3,265 70 ee 5,608 2,881 50 ea Sian 6,059 1,961 37

| | | | | | | AL TT TT __ J TNE eR RRS RANA _ SSR RRR RRR eee EET GHGnEGRGnann | (SRR RRREEP SRR ERRARS SUees LAAN AL iE _. _S DERE SE sei Ge heehee meee ea Nee eee | _ SERRE RaSh Te eee Ae _ 4 SQRC UREN ENY eee PE Nae PT Tt Tt TT VIET TY TW AAT AI ZY | Nash ort _| CEU RERD2ZP VAR Awe A EEL PECTIN SNe ACEC Beye eee Examiners’ returns are correct. If any reasonable doubt could exist as to the fact that many accidental deaths do oceur from poisoning by illuminating gas it would be dissipated by an examination of the data shown on the following table (Table 5) and its corresponding chart (Chart V), on pp. 120-121. This table and its corresponding plate show how sudden was the increase in 1891 of deaths from illuminating gas, an increase much more reasonably explained by increase in acci- dents than by increase in suicidal use of the new and as yet 120 - HARVEY SOCIETY generally unknown poison, especially when we observe that this increase was accompanied by a decrease in the whole num- ber of suicides for the year. Again, in 1895, with no increase in the whole number of suicides, there was a very large in- crease in the number of deaths from poisoning by illuminating TABLE 5. DEATHS FROM SUICIDE BY ALL Mertuops, DEATHS FROM ILLUMINATING Gas, AND PopuLATION (MASSACHUSETTS, 1887-1909). (Medical Examiners’ Returns.) : 7 ne 7 Years Ending Junsgo | Suigiteeby All | Desthe tom || Mamuaieaaes PSS 7iecearnacihorae aren 152 5 SSS Otel n ne cite oe adres yea 8 1 ooh) Eis euch ert Meh Otel eae 196 4 TSO evs matrens ie oaks emieus Tora 202 7 2,238,943 TST Seis s actin 194 19 SOD eae er ecanae heres 2 231 21 Ufo U By ue) Cree ate acne MER IEEE 270 26 DS area tcacin staph statthones 284 29 PSO Deas ete a cigaae 282 45 2,500,183 SOG Siac lsasnteyeteo eee 269 33 ESO ehyenenestete win eretake 304 63 US OS eters chee: Geaeiocte oh ie 321 Ga ASO OE on sroyais ists eerie eons 323 70 DOQQ Ea ceo ntarerna siento 312 50 2,805,343 OOM oe Acr overs oie re hers 347 37 OOS aia ceds eh ila ghcieretecte 350 48 VOUS aie Je erat cele sastas) as eereae 358 aire NOOSE. Houten ek One 369 64 UGOS weeks eh cine SOK 366 64 3,003,680 SOG. cys leet macro 338 74 ISO. Shen cok oe oe 390 92 OOS tales cts ahaha 494 148 LOO GS a ike Broce coor teteiats 476 114 gas; in 1904, while the whole number of suicides was increas- ing, deaths from illuminating gas decreased; while in 1906 the reverse was the case. Undoubtedly, there is on the whole a striking correspondence in the forms of the two curves, such as ought to exist when we remember that (as shown in Table B) about one-half of all the deaths in the lower line are an important factor in the upper. ILLUMINATING GAS AND PUBLIC HEALTH 121 A STUDY OF THE SEASONAL DISTRIBUTION OF DEATHS FROM ILLUMINATING GAS IN MASSACHUSETTS We had not been studying the general subject of illuminat- ing gas poisoning very long before it became plain that such poisoning bears a close relation to the seasons. And this re- CHART V. DEATHS FROM GAS Poisoning, DEATHS FROM SUICIDE BY ALL METHODS, AND POPULATION. MASSACHUSETTS 1887-!907 “ABse ae, ABSC-” YEARS Enbing June 30. FW a i ee sa ee Se Suiciwwes 20 40 60 60 ee Ao Sor LinE - DEATHS BY GAS POISONING. DASH LINE -SviciDES BY ALL METHODS. Dot % DASH LINE ~ POPULATION, 1887 88 89 1890 9) 92 93 94 95 96 97 98 99 1900 01 OAR O35 OF O5 O lation proved to be almost precisely what might have been an- ticipated. Deaths from illuminating gas are comparatively few in summer and comparatively many in winter, as is shown 122 HARVEY SOCIETY by the first column in the following table, and by the heavy black line on the corresponding chart (Chart VI) based upon it. The reason is, of course, because in summer, with open windows, short nights, and outdoor life, people in Massachu- setts are much less exposed to gas poisoning than in winter, when they are housed most of the time, often in apartments piped for gas and having little or no ventilation. Similar considerations probably make gas poisoning also largely a mat- ter of latitude—northern cities suffering more from gas poison- TABLE 6. SEASONAL DiIsTRIBUTION OF DEATHS FROM ILLUMINATING Gas, OF DEATHS By ACCIDENT FROM ILLUMINATING Gas, OF DEATHS BY SUICIDE FROM ILLUMINATING GAS, AND OF SuricipEs By ALL METHODS (Massacuusetts, 1886-1909). (Medical Examiners’ Returns.) Total Deaths |} Accidental Deaths} Suicidal Deaths Suicides by All Month r rom "i lheninative Gas illuminating Gas ilustunune Gas Methods January.....- 106 73 33 568 February..... 97 49 48 462 Marcha sng. 106 59 47 597 ATT ne ean: 116 51 65 749 ORs LG Ses eee 90 36 54 686 June eae 67 30 37 647 DY ics ats ievetens 57 20 37 634 INOP UA Gaal 64 23 41 603 September. ... 92 34 58 611 October... ... 144 77 67 655 November... .. 143 80 63 594 December. .... 149 92 57 541 ing than southern cities—and likewise produce annual varia- tions according as the winters are mild or severe. This table and the corresponding chart (Chart VI) disclose many interesting and important details. December stands out as the month of most deaths, and December is one of the months of shortest days and longest nights as well as of lowest aver- age temperature. It is therefore one of the times of greatest use of gas, of most indoor life, and of least ventilation by open doors and windows. It is not surprising that these condi- ILLUMINATING GAS AND PUBLIC HEALTH 123 tions are correlated with the highest mortality from poisoning by illuminating gas. What is remarkable is that the deaths from this source were almost equally numerous in October and November, although the days are then longer, the average temperature considerably higher, and the possibility of com- fortable sleeping with more open windows is much greater; Cuart VI. TTL I [etadodad obrpigution oF | [ | | | I | [| [DEATHS FROM GAS RoIBoNINGIMaisachusetiTs] | | | tit segueeeeeceee= as aS a nae cian ES Res p | | HEE ie ss Me SOAR Ee GS RAGE e Ee ae. Be ae oe teal PEPER Eee Cees BEee Sraaas aH | A pa A y mo ae January, which in mex of day and temperature closely resembles December, shows fewer deaths than does December from illuminating gas. July, as might be expected, shows the smallest number of deaths (57), June (67) and August (64) more, and each about the same number, while September yields an increase of more than 40 per cent. over June and over August. These facts are not surprising when we reflect upon the cooler and longer 124 HARVEY SOCIETY nights of June and August over those of July, and the much cooler nights—often with frosts—of September over those of June and of August. But beginning with October there is no great difference in the deaths by months until we come to January, when in spite of very cold weather and very short days we find a marked decrease of deaths from poisoning by illuminating gas, the deaths for January, February, March, April, and May differing astonishingly Little. We are aided in explaining these various figures by the fact that April and October are the months of most numerous suicides, not only by all methods (as shown by the last column in Table 6 and by the corresponding thin, solid line, without legend, on Chart VI), but also by illuminating gas; so that the curve of total deaths by illuminating gas is necessarily quite different from what it would be if it represented only those deaths due to accident, and if accidents were solely due to considerations correlated with the movement of the sea- sons—such as temperature and length of days—and effective ventilation. We find here, readily enough, a satisfactory ex- planation of the large number of total deaths in October (144) and November (143) as compared with December (149) when the deaths from suicide (both by all methods and by gas) were passing during these months from a maximum to a much lower level. The fact appears to be that while the accidental gas deaths were increasing during this quarter (as appears in Table 6 and Chart VI and as would be required by theory) the suicidal gas deaths were declining almost pari passu; so that a remarkably even and high total of deaths from illuminat- ing gas was maintained during this last quarter of the year. In the next quarter (January-March) the gas suicides were considerably fewer, as were also the deaths from acci- dental gas poisoning, and very likely the same explanation holds good of both these causes of death; namely, that condi- tions had now become comparatively endurable, those that were absolutely intolerable having already destroyed their victims or having been changed for the better. The high number of ILLUMINATING GAS AND PUBLIC HEALTH 125 total deaths in April appears to be chiefly due to the excess of suicides in general characteristic of that month, as does also the lower but still large number in May, when, as required by theory, the seasonal conditions do not greatly favor acci- dental gas poisonings and when, in fact—as shown by our fig- ures—such poisonings are comparatively few. It is also interesting to note, in passing, that upon Table 6, and excepting in the first quarter, a close correspondence is shown between the frequency of suicides by all methods and those by illuminating gas. THE RELATION OF CERTAIN COMBUSTION PRODUCTS OF ILLUMINAT- ING GAS TO THE PUBLIC HEALTH The principal combustion products of illuminating gas are carbonic acid (CO,), water (H,O), light, and heat. Small, but not insignificant amounts of ammonia, sulphurous acid, soot, and other substances are also produced. Carbonic acid, an inevitable product of all complete com- bustion of carbon compounds, while not a desirable addition to the atmosphere of a dwelling, a store, or a workshop, is probably, unless present in very large quantities, of but little consequence from the stand-point of health or comfort. Water vapor, which is also copiously and inevitably pro- duced in the ordinary combustion of illuminating gas, is prob- ably of more importance than is carbonic acid to health and comfort. Evidence of its abundant presence may often be seen in the water upon the windows of shops, of stores, or of living rooms, upon which it condenses freely and runs down, sometimes almost in streams. The high humidity to which this testifies is often prejudicial to the comfort, and probably also to the health or working capacity, of the inmates. The light produced by illuminating gas varies widely in amount and composition. The old-fashioned coal-gas gave an agreeable and apparently powerful yellowish light, and when those who were accustomed to it began to be served with water-gas, many found the latter bluish and less efficiently luminous. Much here depends, no doubt, upon the special 126 HARVEY SOCIETY form of burner, or ‘‘ tip ’’ employed, but after all is said and done there are many—of whom the author is one—who, hay- ing lived with both kinds of gas (and with many kinds of mix- tures of the two) would gladly go back to the old-fashioned coal-gas at double the present cost of gas, not only because of its greater safety, but also because of its greater and more agreeable illuminating effects. As to the question of heat produced by combustion—a ques- tion of great economic importance for those using gas as a source of power, or for cooking or heating purposes, and of much hygienic significance for persons occupying rooms lighted by gas, it should be said that water-gas is not greatly superior to coal-gas, while, since much heat is produced by the com- bustion of either gas, their hygienic effects in this particular are probably not very different. Electric lighting (although open to other objections) is vastly preferable to gas lighting on the score of heat production and that of objectionable chemi- eal products. Among the less abundant products of the combustion of illuminating gas is sulphurous acid. Most coals used in the manufacture of gas—and hence known as “‘ gas coals ’’—con- tain a small percentage of sulphur, some of which appears in illuminating gas as hydrogen sulphide and some as bisul- phide of carbon, or other sulphur compounds. These, when burned, formed sulphurous acid, an irritating and poison- ous gas. Most of the sulphur compounds in illuminating gas are, however, removed by processes of purification during manufacture, but owing to the difficulty of complete removal, 20 grains of sulphur in every hundred cubic feet have gen- erally been allowed by law to remain in the gas distributed to the public. The 20-grain limit has prevailed in Great Bri- tain for about half a century, and was apparently copied into American statutes when legal regulation of the quality of il- luminating gas was first undertaken—in Massachusetts, for example, in 1861. And until quite recently no objection to this legal limit has been raised by the gas manufacturers or ILLUMINATING GAS AND PUBLIC HEALTH 127 by anyone else. A few years ago, however, the London gas companies sought to have this sulphur regulation removed, claiming that because the best gas coals are now scarce, it is much more difficult than formerly to procure coals low in sulphur, so that processes for the removal of sulphur have become more costly and really burdensome to the industry of gas manufacture. And after protracted hearings with the taking of much testimony the sulphur restrictions were, in fact, removed in England. A little later gas manufacturers in the United States and in Canada came forward with a simi- lar demand, and in Massachusetts the legal limit for sulphur has now been raised from 20 grains to 30 grains per 100 cubic feet of gas. A complete discussion of the whole subject of the relation of the combustion products of sulphur compounds in illuminating gas to the public health would require a mono- graph. Suffice it to say that the testimony taken by the Brit- ish Commission having the matter in charge, and by the Gas Commissioners of Massachusetts (not to mention other authori- ties) was voluminous, instructive, and important, and deserv- ing of careful attention. It is the opinion of the author of the present paper that the British authorities were not sufficiently considerate of the public health aspects of the subject when they allowed all restrictions upon the sulphur content of illu- minating gas to be removed, and that the Massachusetts Gas and Electric Light Commissioners acted more wisely when they declined to follow the British example, and merely relaxed somewhat the severity of the legal requirements regarding sulphur. Illuminating gas is required by law in Massachusetts (and in many other places) to be free from ammonia as well as from sulphuretted hydrogen, but this is more because of in- jury to fixtures than because of danger to health. THE PREVENTION OF POISONING BY ILLUMINATING GAS The question naturally arises, What can be done for the protection of the public health against poisoning by illuminat- ing gas, which as a cause of sickness and death now almost 128 HARVEY SOCIETY equals in Massachusetts and Rhode Island some of the dreaded infectious and contagious diseases? We must admit at the outset that about one-half of the recorded deaths from this source are voluntary or suicidal, but while recognizing this fact we have no right to dismiss it as irrelevant to the present discussion. The State seeks, as far as possible, to prevent suicide, by laws, for example, regulating the sale of other poisons and of firearms, and may well regard with concern the general distribution to the public of a dangerous gas readily available for self-destruction. Even more serious are the public consequences of the wide- spread distribution to sick and well for industrial and do- mestic purposes of a dangerous and highly poisonous sub- stance, insidious in its mode of operation, quickly harmful in its effects, and delivered under such pressure that leaks are frequent. Those who have read and retlected upon the facts given in the preceding sections will hardly need to be told how prejudicial to the public health even small leaks of illuminat- ing gas must be, especially if long continued, while the leakage or escape of larger amounts is well known to be often fatal to those exposed. The simplest and most natural remedy for these evils would be, of course, to return to the former prac- tice of making and distributing only coal-gas instead of water- gas or a mixture of the two. But here, as so often in public health problems, a balance must be struck between industrial advantages accruing to the public in less cost, and some sav- ing of life and health. If the industrial, economic, or efficiency gain is very great, it may justify some increase of danger to life and health. But if it is not very great, then life and health have the prior claim. In the present case it is not claimed that water-gas in Massachusetts or Rhode Island is, as a rule, much if any cheaper to manufacture than is coal- gas, but that it is very convenient to produce because more quickly made when needed. The claims of the advocates of water-gas in 1884 that this gas would furnish 24 candles of light against the 16 candles of the old-fashioned ecoal-gas do ILLUMINATING GAS AND PUBLIC HEALTH 129 not appear to have been substantiated, since most of the gas now distributed in Massachusetts equals—according to the State Inspector—only about 18 candles. The price of gas to the consumer has, however, fallen greatly since 1884, and this decrease in cost, as far as it is due to the use of water-gas, must be balanced against the damage done to the public health by the loss of more than 1200 lives and an unknown amount of less obvious injury to life and health. Undoubtedly a mixture of coal-gas and water-gas, such as is often distributed to-day, is less dangerous than is water- gas alone, but this appears to be merely because the dangerous constituent, carbonic oxide, so abundant in water-gas, is diluted by the process of mixture; and up to a certain point, the greater the dilution, the less the danger. We know from ex- perience that when carbonic oxide forms only about 6 per cent. of illuminating gas very little danger exists. We also know from experience that 20-30 per cent. of carbonic oxide means danger. But whether 10 per cent. or perhaps 12 per cent. might be allowed without much danger, we do not yet know. It should, however, be possible to determine by experi- ment the minimum amount safely allowable. Meantime, in view of the appalling loss of more than 1200 lives which has occurred in Massachusetts since the 10 per cent. restriction upon carbonic monoxide was removed, it seems not unfair or unreasonable to demand a return to the 10 per cent. limit until such time as evidence shall be forthcoming that a higher percentage will properly safeguard the public health. A CONSIDERATION OF THE NATURE OF HUNGER* PROF. WALTER B. CANNON Harvard University LABORATORY OF PHYSIOLOGY IN THE HARVARD MEDICAL SCHOOL HY do we eat?’’ This question, presented to a group of educated people, is likely to bring forth the answer, ‘‘We eat to compensate for body waste, or to supply the body with fuel for its labors.’’ Although the body is in fact losing weight continuously and drawing continuously on its store of energy, and although the body must periodically be supplied with fresh material and energy in order to keep a more or less even balance between the income and the outgo, this mainten- ance of weight and strength is not the motive for taking food. Primitive man, and the lower animals, may be regarded as quite unacquainted with notions of the equilibrium of matter and energy in the body, and yet they take food and have an efficient existence, in spite of this ignorance. In nature, gen- erally, important processes, such as the preservation of the individual and the continuance of the race, are not left to be determined by intellectual considerations, but are provided for in automatic devices. Natural desires and impulses arise in consciousness, driving us to action; and only by analysis do we learn their origin or divine their significance. Thus our primary reasons for eating are to be found, not in convictions about metabolism, but in the experiences of appetite and hunger. APPETITE AND HUNGER The sensations of appetite and hunger are so complex and so intimately interrelated that any discussion is sure to go * Delivered December 16, 1911. The results here stated were pub- lished in the American Journal of Physiology, 1912, xxix, 441-454. 130 CONSIDERATION OF NATURE OF HUNGER 131 astray unless at the start there is clear understanding of the meanings of the terms. ‘The view has been propounded that appetite is the first degree of hunger, the mild and pleasant stage, agreeable in character; and that hunger itself is a more advanced condition, disagreeable and even painful—the un- pleasant result of not satisfying the appetite.t On this basis appetite and hunger would differ only quantitatively. Another view, which seems more justifiable, is that the two experiences are fundamentally different. Careful observation indicates that appetite is related to previous sensations of taste and smell of food. Delightful or disgusting tastes and odors, associated with this or that edible substance, determine the appetite. It has therefore important psychic elements in its composition, as the studies by Pawlow and his collaborators have so clearly shown. Thus, by taking thought, we can anticipate the odor of a delicious beefsteak or the taste of peaches and cream, and in that imagination we can find pleasure. In the realization, direct effects in the senses of taste and smell give still further delight. We now know from observations on experimental animals and on human beings, that the pleasures of both anticipation and. realization, by stimulating the flow of saliva and gastric juice, play a highly significant rdle in the initiation of digestive processes.” Among prosperous people, supplied with abundance of food, the appetite seems sufficient to ensure for bodily needs a proper supply of nutriment. We eat because dinner is announced, because by eating we avoid unpleasant consequences, and because food is placed before us in delectable form and with tempting tastes and odors. Under less easy cireum- tances, however, the body needs are supplied through the much stronger and more insistent demands of hunger. The sensation of hunger is difficult to describe, but almost every one from childhood has felt at times that dull ache or gnawing pain referred to the lower mid-chest region and the epigastrium, which may take imperious control of human actions. As Sternberg has pointed out, hunger may be suffi- ciently insistent to force the taking of food which is so dis- 132 HARVEY SOCIETY tasteful that it not only fails to rouse appetite, but may even produce nausea. The hungry being gulps his food with a rush. The pleasures of appetite are not for him—he wants quantity rather than quality, and he wants it at once. Hunger and appetite are, therefore, widely different—in physiological basis, in localization, and in psychic elements. Hunger may be satisfied while the appetite still calls. Who is still hungry when the tempting dessert is served, and yet are there any who refuse it, pleading they no longer need it? On the other hand, appetite may be in abeyance while hunger is goading.2 What ravenous boy is critical of his food? Do we not all know that ‘‘hunger is the best sauce’’? Although the two sensations may thus exist separately, they nevertheless have the same function of leading to the intake of food, and they usually appear together. Indeed the co-operation of hun- ger and appetite is probably the reason for their being so frequently confused. THE SENSATION OF HUNGER In the present paper we shall deal only with hunger. The sensation may be described as having a central core and certain more or less variable accessories. The peculiar dull ache of hungriness, referred to the epigastrium, is usually the organ- ism’s first strong demand for food; and when the initial order is not obeyed, the sensation is likely to grow into a highly uncomfortable pang or gnawing, less definitely localized as it becomes more intense. This may be regarded as the essential feature of hunger, Besides the dull ache, however, lassitude and drowsiness may appear, or faintness, or violent headache, or irritability and restlessness such that continuous effort in ordinary affairs becomes increasingly difficult. That these states differ much with individuals—headache in one, and faintness in another, for example—indicates that they do not constitute the central fact of hunger, but are more or less inconstant accompaniments, and need not for the present engage our attention. The ‘‘feeling of emptiness,’’? which has been mentioned as an important element of the experience,* is an CONSIDERATION OF NATURE OF HUNGER 133 inference rather than a distinct datum of consciousness, and ean likewise be eliminated from further consideration. The dull pressing sensation is left, therefore, as the constant char- acteristic, the central fact, to be examined in detail. Hunger can evidently be regarded from the psychological point of view, and discussed solely on the basis of introspec- tion; or it can be studied with reference to its antecedents and to the physiological conditions which accompany it—a con- sideration which requires the use of both objective methods and subjective observation. This psy chophysiological treatment of the subject will be deferred till the last. Certain theories which have been advanced with regard to hunger and which have been given more or less eredit must first be examined. Two main theories have been advocated. The first is sup- ported by evidence that hunger is a general sensation, arising at no special region of the body, but having a local reference. This theory has been more widely credited by physiologists and psychologists than the other. The other is supported by evidence that hunger has a local source and therefore a local reference. In the course of our examination of these views we shall have opportunity to consider some pertinent new observations. THE THEORY THAT HUNGER IS A GENERAL SENSATION The conception that hunger arises from a general condition of the body rests in turn on the notion that, as the body uses up material, the blood becomes impoverished. Schiff advocated this notion, and suggested that poverty of the blood in food substance affects the tissues in such manner that they demand a new supply. The nerve-cells of the brain share in this general shortage of provisions, and because of internal changes give rise to the sensation.» Thus is hunger explained as an experience dependent on the body as a whole. Three classes of evidence are cited in support of this view: 1. ‘‘Hunger Increases as Time Passes’’—A Partial State- ment.—The development of hunger as time passes is a common observation which quite accords with the assumption that the 134 HARVEY SOCIETY condition of the body and the state of the blood are becoming constantly worse, so long as the need, once established, is not satisfied. While it is true that with the lapse of time hunger increases as the supply of body nutriment decreases, this concomitance is not proof that the sensation arises directly from a serious encroachment on the store of food materials. If this argument were valid we should expect hunger to become more and more distressing until death. There is abundant evidence that the sensation is not thus intensified; on the contrary, during con- tinued fasting hunger wholly disappears after the first few days. Luciani, who carefully recorded the experience of the faster Succi, states that after a certain time the hunger feelings vanish and do not return.®. And he tells of two dogs that showed no signs of hunger after the third or fourth day of fast- ing; thereafter they remained quite passive in the presence of food. Tigerstedt, who also has studied the metabolism of starvation, declares that although the desire to eat is very great during the first day of the ordeal, the unpleasant sensations disappear early, and at the end of the fast the subject may have to force himself to take nourishment.‘ The subject, ‘‘J. A.,’’ studied by Tigerstedt and his co-workers, reported that after the fourth day of fasting, he had no disagreeable feelings. Carrington, after examining many persons who, to better their health, abstained from eating for different periods, records that ‘‘habit-hunger’’ usually lasts only. two or three days and, if plenty of water is drunk, does not last longer than three days.® Viterbi, a Corsician lawyer, condemned to death for political causes, determined to escape execution by de- priving his body of food and drink. During the eighteen days that he lived, he kept careful notes. On the third day the sensation of hunger departed, and although thereafter thirst came and went, hunger never returned.'® Still further evidence of the same character could be cited, but enough has already been given to show that, after the first few days of fasting, the hunger-feelings cease. On the theory that hunger is a manifestation of bodily need, are we to suppose that, in the CONSIDERATION OF NATURE OF HUNGER = 135 course of starvation, the body is mysteriously not in need after the third day, and that therefore the sensation of hunger disappears? The absurdity of such a view is obvious. 2. ‘“Hunger May be Felt Though the Stomach be Full’’— A Selected Alternative-—Instances of duodenal fistula in man have been carefully studied, which have shown that a modified sensation of hunger may be felt when the stomach is full. A famous case described by Busch has been repeatedly used as evidence. His patient, who lost nutriment through the fistula, was hungry soon after eating, and felt satisfied only when the chyme was restored to the intestine through the distal fistulous opening. As food is absorbed mainly through the intestinal wall, the inference is direct that the general bodily state, and not the local conditions of the alimentary canal, must account for the patient’s feelings. A full consideration of the evidence from cases of duodenal fistula cannot so effectively be presented now as later. That in Busch’s case hunger disappeared while food was being taken is, as we shall see, quite significant. It may be that the restora- tion of chyme to the intestine quieted hunger, not because nutriment was thus introduced into the body, but because the presence of material altered the nature of intestinal activity. The basis for this suggestion will be given in due course. 3. ‘Animals May Eat Eagerly After Section of Their Vagus and Splanchnic Nerves’’—A Fallacious Argument.— The third support for the view that hunger has a general origin in the body is derived from observations on experimental animals. By severance of the vagus and splanchnic nerves, the lower cesophagus, the stomach, and the small intestine can be wholly separated from the central nervous system. Animals thus operated upon nevertheless eat food placed before them, and may indeed manifest some eagerness for it.1? How is this behavior to be accounted for—when the possibility of local peripheral stimulation has been eliminated—save by assuming a central origin of the impulse to eat? The fallacy of this evidence, though repeatedly overlooked, is easily shown. We have already seen that appetite as well as 136 HARVEY SOCIETY hunger may lead to the taking of food. Indeed the animal with all gastro-intestinal nerves cut may have the same incentive to eat that a well-fed man may have, who delights in the pleas- urable taste and smell of food and knows nothing of hunger pangs. Even when the nerves of taste are cut, as in Longet’s experiments,'* sensations of smell are still possible, as well as agreeable associations which can be roused by sight. More than fifty years ago Ludwig pointed out that, even if all the nerves were severed, psychic reasons could be given for the taking of food,'* and yet because animals eat after one or another set of nerves is eliminated, the conclusion has been drawn by various writers that the nerves in question are thereby proved to be not concerned in the sensation of hunger. Evidently since hunger is not required for eating, the fact that an animal eats is no testimony whatever that the animal is hungry, and therefore, after nerves have been severed, is no proof that hunger is of central origin. Weakness of the Assumptions Underlying the Theory that Hunger is a General Sensation.—The evidence thus far exam- ined has been shown to afford only shaky support for the theory that hunger is a general sensation. The theory further- more is weak in its fundamental assumptions. There is no clear indication, for example, that the blood undergoes, or has undergone, any marked change, chemical or physical, when the first stages of hunger appear. There is no evidence of any direct chemical stimulation of the gray matter of the cerebral cortex. Indeed attempts to excite the gray matter artificially by chemical agents have been without results;'® and even electrical stimulation, which is effective, must, in order to pro- duce movements, be so powerful that the movements have been attributed to excitation of underlying white matter rather than cells in the gray. This insensitivity of cortical cells to direct stimulation is not at all favorable to the notion that they are sentinels set to warn against too great diminution of bodily supplies. Body Need May Exist Without Hunger—Still further evidence opposed to the theory that hunger results directly CONSIDERATION OF NATURE OF HUNGER 137 from the using up of organic stores is found in patients suf- fermg from fever. Metabolism in fever patients is augmented, body substance is destroyed to such a degree that the weight of the patient may be greatly reduced, and yet the sensation of hunger under these conditions of increased need is wholly lacking, Again if a person is hungry and takes food, the sensation is suppressed soon afterward, long before any considerable amount of nutriment could be digested and absorbed, and therefore long before the blood and the general bodily condition, if previously altered, could be restored to normal. Furthermore, persons exposed to privation have testified that hunger can be temporarily suppressed by swallowing in- digestible materials. Certainly scraps of leather and bits of moss, not to mention clay eaten by the Otomacs, would not materially compensate for large organic losses. In rebuttal to this argument the comment has been made that central states as a rule can be readily overwhelmed by peripheral stimulation, and just as sleep, for example, can be abolished by bathing the temples, so hunger can be abolished by irritating the gastric walls.1° That comment is beside the point, for it meets the issue by merely assuming as true the condition under discussion. The absence of hunger during the ravages of fever, and its quick abolition after food or even indigestible stuff is swallowed, still further weakens the argument, therefore, that the sensa- tion arises directly from lack of nutriment in the body. The Theory that Hunger is of General Origin Does Not Explain the Quick Onset and the Periodicity of the Sensation. —Many persons have noted that hunger has a sharp onset. A person may be tramping in the woods or working in the fields, where fixed attention is not demanded, and without premoni- tion may feel the abrupt arrival of the characteristic ache. The expression ‘‘grub-struck’’ is a picturesque description of this experience. If this sudden arrival of the sensation corre- sponds to the general bodily state, the change in the general bodily state must oceur with like suddenness or have a critical point at which the sensation is instantly precipitated. There 138 HARVEY SOCIETY is no evidence whatever that either of these conditions occurs in the course of metabolism. Another peculiarity of hunger which I have noticed in my own person, is its intermittency. It may come and go several times in the course of a few hours. Furthermore, while the sensation is prevailing, its intensity is not uniform, but marked by ups and downs. In some instances the ups and downs change to a periodic presence and absence without change of rate. In making the above statements I do not depend on my own intro- spection alone; psychologists trained in this method of observa- tion have reported that in their experience the temporal course gf the sensation is distinctly intermittent.* In my own experi- ence the hunger pangs came and went on one occasion as follows: Came Went 12-37-20 38-30 40-45 41-10 41-45 42-25 43-20 43-35 44-40 45-55 46-15 46-30 and so on, for ten minutes longer. Again in this relation, the intermittent and periodic character of hunger would require, on the theory under examination, that the bodily supplies be intermittently and periodically insufficient. Durimg one moment the absence of hunger would imply an abundance of nutriment in the organism, ten seconds later the presence of hunger would imply that the stores had been suddenly reduced, ten seconds later still the absence of hunger would imply a sudden renewal of plenty. Such zig-zag shifts of the general bodily state may not be impossible, but from all that is known of the course of metabolism, such quick changes are highly improbable. The periodicity of hunger, therefore, is further evidence against the theory that the sensation has a general basis in the body. *T am indebted to Professor J. W. Baird, of Clark University, and his collaborators, for this corroborative testimony. CONSIDERATION OF NATURE OF HUNGER 139 The Theory that Hunger is of General Origin Does Not Explain the Local Reference.—The last objection to this theory is that it does not account for the most common feature of hunger, namely, the reference of the sensation to the region of the stomach. Schiff and others who have supported the theory ** have met this objection by two contentions: First they have pointed out that the sensation is not always referred to the stomach. Schiff interrogated ignorant soldiers regard- ing the local reference; several indicated the neck or chest, 23 the sternum, 4 were uncertain of any region, and 2 only designated the stomach, In other words the stomach region was most rarely mentioned. The second contention against the importance of local reference is that such evidence is fallacious. An armless man may feel tinglings which seem to arise in fingers which have long since ceased to be a portion of his body. The fact that he experiences such tinglings and ascribes them to dissevered parts does not prove that the sensation originates in those parts. And similarly the assignment of the ache of hunger to any special region of the body does not demonstrate that the ache arises from that region. Such are the arguments against a loeal origin of hunger. Concerning these arguments we may recall, first, Schiff’s admission that the soldiers he questioned were too few to give conclusive evidence. Further, the testimony of most of them that hunger seemed to originate in the chest or region of the sternum cannot be claimed as unfavorable to a peripheral source of the sensation. The description of feelings which develop from disturbances within the body is almost always indefinite. As Head and others have shown, conditions in a viseus which give rise to sensation are likely not to be attributed to the viscus, but to related skin areas.1* Under such cireum- stances we do not dismiss the testimony as worthless merely because it may not point precisely to the source of the trouble. On the contrary, we use such testimony constantly as a basis for judging internal disorders. With regard to the contention that reference to the peri- 140 HARVEY SOCIETY phery is not proof of the peripheral origin of a sensation, we may answer that the force of that contention depends on the amount of accessory evidence which is available. Thus if we see an object come into contact with a finger, we are justified in assuming that the simultaneous sensation of touch which we refer to that finger has resulted from the contact, and is not a purely central experience accidently attributed to an outlying member. Similarly in the case of hunger—all that we need as support for the peripheral reference of the sensation is proof that conditions occur there, simultaneously with hunger pangs, which might reasonably be regarded as giving rise to those pangs. OBJECTIONS TO SOME THEORIES THAT HUNGER IS OF LOCAL ORIGIN With the requirement in mind that peripheral conditions be adequate, let us examine the state of the fasting stomach to see whether indeed conditions may be present in times of hunger which would sustain the theory that hunger has a local out- lying source. Hunger Not Due to Emptiness of the Stomach—Among the suggestions which have been offered to account for a peripheral origin of the sensation is that of attributing it to emptiness of the stomach. By use of the stomach tube Nicholai found that when his subjects had their first intimation of hunger the stomach was quite empty. But, in other instances, after lavage of the stomach, the sensation did not appear for intervals vary- ing between one and a half and three and a half hours.*® Dur- ing these intervals the stomach must have been empty, and yet no sensation was experienced. The same testimony was given long before by Beaumont, who, from his observations on Alexis St. Martin, declared that hunger arises some time after the stomach is normally evacuated.” Mere emptiness of the organ, therefore, does not explain the phenomenon. Hunger not Due to Hydrochloric Acid in the Empty Stomach.—A second theory, apparently suggested by observa- tions on cases of hyperacidity, is that the ache or pang is due to hydrochloric acid secreted into the stomach while empty. Again CONSIDERATION OF NATURE OF HUNGER 141 the facts are hostile. Nicolai reported that the gastric wash- water from his hungry subjects was neutral or only slightly acid.2t. This testimony confirms Beaumont’s statement, and is in complete agreement with the results of gastric examination of fasting animals reported by numerous experimenters, There is no secretion into the empty stomach during the first days of starvation. Furthermore, persons suffering from absence of hydrochlorie acid (achylia gastrica) declare that they have normal feelings of hunger. Hydrochloric acid cannot therefore be called upon to account for the sensation. Hunger Not Due to Turgescence of the Gastric Mucosa.— Another theory, which was first advanced by Beaumont, is that hunger arises from turgescence of the gastric glands.”? The disappearance of the pangs as fasting continues has been accounted for by supposing that the gastric glands share in the general depletion of the body, and that thus the turgescence is relieved.* This turgescence theory has commended itself to several recent writers. Thus Luciani has accepted it, and by adding the idea that nerves distributed to the mucosa are spe- cially sensitive to deprivation of food he accounts for the hunger pangs.t Also Valenti declared two years ago that the turgescence theory of Beaumont is the only one with a semblance of truth in it.2* The experimental work reported by these two investigators, however, does not necessarily sustain the turgescence theory. Luciani severed the previously ex- posed vagi after cocainizing them, and Valenti merely cocain- ized the nerves; the fasting dogs, eager to eat a few minutes previous to this operation, now ran about as before, but when offered food, licked and smelled it, but did not take it. This total neglect of the food lasted varying periods up to two *A better explanation perhaps is afforded by Boldireff’s discovery that at the end of two or three days the stomachs of fasting dogs begin to secrete gastric juice and continue the secretion indefinitely. (Boldireff: Archives biologiques de St. Petersburg, 1905, xi, p. 98.) + Luciani: Archivio di fisiologia, 1906, iii, p. 54. Tiedemann long ago suggested that gastrie nerves become increasingly sensitive as fasting progresses. (Physiologie des Menschen. Darmstadt, 1836, iil, p. 22.) 142 HARVEY SOCIETY hours. The vagus nerves seem, indeed, to convey impulses which affect the procedure of eating, but there is no clear evidence that those impulses arise from distention of the gland cells. The turgescence theory, moreover, does not explain the effect of taking indigestible material into the stomach. Accord- ing to Pawlow, and to others who have observed human beings, the chewing and swallowing of unappetizing stuff does not cause any secretion of gastric juice.** Yet such stuff when swallowed will cause the disappearance of hunger, and Nicholai found that the sensation could be abolished by simply intro- ducing a stomach sound. It is highly improbable that the turgescence of the gastric glands can be reduced by either of these procedures. The turgescence theory, furthermore, does not explain the quick onset of hunger, or its intermittent and periodic character. That the cells are repeatedly swollen and contracted within periods a few seconds in duration is almost inconceivable. For these reasons, therefore, the theory that hunger results from turgescence of the gastric mucosa can reasonably be rejected. HUNGER THE RESULT OF CONTRACTIONS There remain to be considered, as a possible cause of hunger- pangs, contractions of the stomach and other parts of the alimentary canal. This suggestion is not new. Sixty-six years ago Weber declared his belief that ‘‘strong contraction of the muscle fibers of the wholly empty stomach, whereby its cavity disappears, makes a part of the sensation which we call hun- ger.2> Vierordt drew the same inference twenty-five years later (in 1871),?° and since then Ewald, Knapp, and Hertz have declared their adherence to this view. These writers have not brought forward any direct evidence for their conclusion, though Hertz has cited Boldireff’s observations on fasting dogs as probably accounting for what he terms ‘‘the gastrie con- stituent of the sensation.’’ 27 The Empty Stomach and Intestine Contract.—The argument commonly used against the gastric contraction theory is that the stomach is not energetically active when empty. Thus Schiff CONSIDERATION OF NATURE OF HUNGER 143 stated ‘‘the movements of the empty stomach are rare and much less energetic than during digestion.’’** Luciani expressed his disbelief by asserting that gastric movements are much more active during gastric digestion than at other times, and cease almost entirely when the stomach has discharged its contents.” And Valenti stated only year before last, ‘‘we know very well that gastric movements are exaggerated while digestion is pro- ceeding in the stomach, but when the organ is empty they are more rare and much less pronouneed,’’ and therefore they can- not account for hunger.*° Evidence opposed to these suppositions has been in exist- ence for many years. In 1899, Bettmann called attention to the contracted condition of the stomach after several days’ fast.** In 1902, Wolff reported that after forty-eight hours without food the stomach of the cat may be so small as to look like a slightly enlarged duodenum.*? In a similar circumstance I have noticed the same extraordinary smallness of the organ, especially in the pyloric half. The anatomist His also recorded his observation of the phenomenon.*® Six years ago Boldireff demonstrated that the whole gastro-intestinal tract has a peri- odie activity while not digesting.** Each period of activity lasts from 20 to 30 minutes, and is characterized in the stomach by rhythmic contractions 10 to 20 in number. These contrac- tions, Boldireff reports, may be stronger than during digestion, and his published records clearly support this statement. The intervals of repose between periodic recurrences of the con- tractions lasted from one and a half to two and a half hours. Especially noteworthy is Boldireft’s observation that if fasting in continued for two or three days, the groups of contractions appear at gradually longer intervals and last for gradually shorter periods, and thereupon, as the gastric glands begin continuous secretion, all movements cease. Observations Suggesting a Relation Between Contractions and Hunger.—When Boldireft’s paper first appeared I was studying auscultation of abdominal sounds, Repeatedly there was occasion to note that the sensation of hunger was, as already stated, not constant but recurrent, and that its momen- 144 HARVEY SOCIETY tary disappearance was often associated with a rather loud gurgling sound, as heard through the stethoscope. That con- tractions of the alimentary canal on a gaseous content might explain the hunger pangs seemed probable at that time, espe- cially in the light of Boldireff’s observations. Indeed Boldi- reff himself had considered hunger in relation to the activities he described, but solely with the idea that hunger might pro- voke them; and since the activities dwindled in force and frequence as time passed, whereas, in his belief they should have become more pronounced, he abandoned the notion of any relation between the phenomena.*® Did not Boldireff misinterpret his own observations? When he was considering whether hunger might cause the contractions, did he not over- look the possibility that the contractions might cause hunger? A number of experiences have led to the conviction that Boldi- reff did, indeed, fail to perceive part of the significance of his results. For example, I have noticed the disappearance of a hunger pang as gas was heard gurgling upward through the eardia. That the gas was rising rather than being foreed down- ward was proved by its regurgitation immediately after the sound was heard. In all probability the pressure that forced the gas from the stomach was the cause of the preceding sensa- sion of hunger. Again the sensation can be momentarily abol- ished a few seconds after swallowing a small accumulation of saliva or a teaspoonful of water. If the stomach is in strong contraction in hunger, this result can be accounted for as due to the inhibition of the contraction by swallowing.*® Thus also could be explained the prompt vanishing of the ache soon after we begin to eat, for repeated swallowing results in continued inhibition.* Furthermore, Ducceschi’s discovery that hydro- chlorie acid diminishes the tonus of the pyloric portion of the stomach *? may have its application here; the acid would be secreted as food is taken and would then cause relaxation of the very region which is most strongly contracted. *The absence of hunger in Busch’s patient while food was being eaten (see p. 135) can also be accounted for in this manner. CONSIDERATION OF NATURE OF HUNGER 145 The Concomitance of Contractions and Hunger in Man.— Although the evidence above outlined had led me to the con- viction that hunger results from contractions of the alimentary canal, direct proof was still lacking. In order to learn whether such proof might be secured, one of my students, Mr. A. L. Washburn, determined to become accustomed to the presence of a rubber tube in the csophagus.* Almost every day for several weeks Mr. Washburn introduced as far as the stomach a small tube, to the lower end of which was attached a soft rubber balloon about 8 em. in diameter. The tube was thus carried about each time for two or three hours. After this preliminary experience the introduction of the tube and its presence in the gullet and stomach were not at all disturbing. When a record was to be taken, the balloon, placed just below the cardia, was moderately distended with air, and was con- nected with a water manometer ending in a cylindrical chamber 3.5 em. wide. A float recorder resting on the water in the chamber permitted registering any contractions of the fundus of the stomach. On the days of observation Mr. Washburn would abstain from breakfast, or eat sparingly; and without taking any luncheon would appear in the laboratory about two o’clock. The recording apparatus was arranged as above de- scribed. In order to avoid the possibility of an artifact, a pneumograph, fastened below the ribs, was made to record the movements of the abdominal wall. Between the records of gastric pressure and abdominal movement, time was marked in minutes, and an electromagnetic signal traced a line which could be altered by pressing a key. All these recording arrangements were out of Mr. Washburn’s sight; he sat with one hand at the key, ready whenever the sensation of hunger was experienced to make the current which moved the signal. Sometimes the observations were started before any hunger was noted; at other times the sensation, after running a course, gave way to a feeling of fatigue, Under either of these cir- * Nicolai (loe. cit.) reported that although the introduction of a stomach tube at first abolished hunger in his subjects, with repeated use the effects became insignificant. 10 146 HARVEY SOCIETY cumstances there were no contracticns of the stomach. When Mr. Washburn stated that he was hungry, however, powerful contractions of the stomach were invariably being registered. As in the experience of the psychologists, the sensations were characterized by periodic recurrences with free intervals, or by periodic accesses of an uninterrupted ache. The record of Mr. Washburn’s introspection of his hunger pangs agreed closely with the record of his gastric contractions. Almost dalla ai LA isla a Fra. 1. One-half the original size. The top record represents intragastric pressure (the small oscillations due to respiration, the large to contractions of the stomach); the second record is time in minutes (ten seconds); the third record is Mr. Washburn’s report of hunger pangs; the lowest record is respiration registered by means of a pneumograph about the abdomen. invariably, however, the contraction nearly reached its maxi- mum before the record of the sensation was started (see Fig. 1). This fact may be regarded as evidence that the contraction pre- cedes the sensation, and not vice versa, as Boldireff considered it. The contractions were about a half minute in duration and the intervals between varied from 30 to 90 seconds, with an average of about one minute. The augmentations of intra- gastric pressure in Mr. Washburn ranged between 11 and 13 in CONSIDERATION OF NATURE OF HUNGER 147 twenty minutes; I had previously counted in myself eleven hunger pangs in the same time. The rate in each of us was, therefore, approximately the same. This rate is slightly slower than that found in dogs by Boldireff; the difference is perhaps correlated with the slower rhythm of gastric peristalsis in man compared with that in the dog.** Before hunger was experienced by Mr. Washburn the re- ‘cording apparatus revealed no signs of gastric activity. Some- times a rather tedious period of waiting had to be endured before contractions occurred. And after they began they con- tinued for a while, then ceased (see Fig. 2). The feeling of hunger, which was reported while the contractions were recur- x y * z Fig. 2. One-half the original size. The same conditions asin Fig. 1. (Fifteen min- utes.) There was a long wait for hunger todisappear. After z, Mr. Washburn reported himself ‘‘tired but not hungry.”’ The record from y to z was the continuance on a second drum of z to y. ring, disappeared as the waves stopped. The inability of the subject to control the contractions eliminated the possibility of their being artifacts, perhaps induced by suggestion. The close concomitance of the contractions with hunger pangs, therefore, clearly indicates that they are the real source of those pangs. Boldireff’s studies proved that when the empty stomach is manifesting periodic contractions, the intestines also are active. Conceivably all parts of the alimentary canal composed of smooth muscle share in these movements. The lower cesophagus in man is provided with smooth muscle. It was possible to 148 HARVEY SOCIETY determine whether this region in Mr. Washburn was active during hunger. To the csophageal tube a thin rubber finger-cot (2 em. in length) was attached and lowered into the stomach. The little rubber bag was distended with air, and the tube, pinched to keep the bag inflated, was gently withdrawn until resistance was felt. The air was now released from the bag, and the tube further withdrawn about 3 cm. The bag was again distended Fic. 3. One-half the original size. The top record represents compression of a thin rubber bag in the lower esophagus. The pressure in the bag varied between 9 and 13 cm. of water, The cylinder of the recorder was of smaller diameter than that used in the gastric records, The cesophageal contractions compressed the bag so completely that, at the summits of the large oscillations, the respirations were not registered. When the oscillations dropped to the time line, the bag was about halfénflated. The middle line registers time in minutes (ten seconds). The bottom record is Mr. Washburn’s report of hunger pangs. with air at a manometric pressure of 10 em. of water. Inspira- tion now caused the writing lever, which recorded the pressure changes, to rise; and a slightly further withdrawal of the tube changed the rise, on inspiration, to a fall. The former position of the tube, therefore, was above the gastric cavity and below the diaphragm. In this position the bag, attached to a float- recorder (with chamber 2.3 em. in diameter), registered the periodic oscillations shown in Fig. 3. Though individually more prolonged than those of the stomach, these contractions, it will be noted, occur at about the same rate. It is probable that the CONSIDERATION OF NATURE OF HUNGER 149 periodic activity of the two regions is simultaneous, for other- wise the stomach would force its gaseous content into the esophagus with the rise of intragastric pressure. What causes the contractions to occur has not been deter- mined. From evidence already given they do not seem to be directly related to bodily need. Habit no doubt plays an im- portant role. For present considerations, however, it is enough that they do occur, and that they are abolished when food, which satisfies bodily need, is taken into the stomach. By such indirection, as already stated, are performed some of the most fundamental of the bodily functions. Peculiarities of Hunger Explained by Contractions.—lf these contractions are admitted as the cause of hunger, most of the difficulties confronting other explanations are readily obviated. Thus the occurrence of hunger at meal times is most natural, for, as the regularity of defecation indicates, the alimentary canal has habits. Activity returns at the usual meal time as the result of custom. By taking food regularly at a definite hour in the evening for several days, a new hunger period can be established. Since at these times the cesophagus and the empty stomach strongly contract, hunger is aroused. The contractions furthermore explain the sudden onset of hunger and its peculiar periodicity—phenomena which no other explanation of hunger can account for. The quick develop- ment of the sensation after taking a cold drink is possibly associated with the well-known power of cold to induce con- traction in smooth muscle. The great intensity of hunger during the first day of starvation, and its gradual disappearance till it vanishes on the third or fourth day, are made quite clear, for Boldireff observed that the gastric contractions in his fasting dogs went through precisely such alterations of intensity, and were not seen after the third day. In fever, when bodily material is being most rapidly used, hunger is absent. Its absence is understood from an observa- tion reported four years ago, that infection, with systemic involvement, is accompanied by a total cessation of all move- 150 HARVEY SOCIETY ments of the alimentary canal.*® Beldireff observed that when his dogs were fatigued the rhythmic contractions failed to appear. Being ‘‘too tired to eat’’ is thereby given a rational explanation. Another pathological form of the sensation—the inordinate hunger (bulimia) of certain neurotics—is in accordance with the well-known disturbances of the tonic imnervation of the alimentary canal in such individuals. Since the lower end of the cesophagus, as well as the stomach, contracts periodically in hunger, the reference of the sensation to the sternum by the ignorant persons questioned by Schiff was wholly natural. The activity of the lower esophagus also explains why, after the stomach has been removed, or in some eases when the stomach is distended with food, hunger can still be experienced. Conceivably the intestines also originate vague sensations by their contractions. Indeed the final banishment of the modified hunger sensation in the patient with duodenal fistula, described by Busch, may have been due to the lessened activity of the intestines when chyme was injected into them. The observations recorded in this paper have, as already noted, numerous points of similarity to Boldireff’s observations on the periodic activity of the alimentary canal in fasting dogs. Each period of activity, he found, comprised not only wide- spread contractions of the digestive canal, but also the pouring out of bile, and of pancreatic and intestinal juices rich in ferments. Gastric juice was not secreted at these times; when it was secreted and reached the intestine, the periodic activity ceased.*? What is the significance of this extensive disturb- ance? Recently evidence has been presented that gastric peri- stalsis is dependent on the stretching of gastric muscle when tonically contracted.41 The evidence that the stomach is in fact strongly contracted in hunger—.e., in a state of high tone —has been presented above.* Thus the very condition which *The “empty” stomach and csophagus contain gas (see Hertz: Quarterly Journal of Medicine, 1910, iii, p. 378; Mikuliez: Mittheil- ungen aus dem Grenzgebieten der Medicin und Chirurgie, 1903, xii, p. 596). They would naturally manifest rhythmic contractions on shortening tonically on their content. CONSIDERATION OF NATURE OF HUNGER 151 eauses hunger and leads to the taking of food is the condition, when the swallowed food stretches the shortened muscles, for immediate starting of gastric peristalsis. In this connection the recent observations of Haudek and Stigler are probably significant. They found that the stomach discharges its con- tents more rapidly if food is eaten in hunger than if not so eaten.*? Hunger, in other words, is normally the signal that the stomach is contracted for action; the unpleasantness of hunger leads to eating; eating starts gastric secretion, distends the contracted organ, initiates the movements of gastric diges- tion, and abolishes the sensation. Meanwhile pancreatic and intestinal juices, as well as bile, have been prepared in the duo- denum to receive the oncoming chyme. The periodic activity of the alimentary canal in fasting, therefore, is not solely the source of hunger pangs, but is at the same time an exhibition in the digestive organs of readiness for prompt attack on the food swallowed by the hungry animal. BIBLIOGRAPHY *Bardier: Richet’s Dictionnaire de Physiologie, article Faim, 1904, vi, p- 1. See also, Howell: Text-book of Physiology, fourth edition, Philadelphia and London, 1911, p. 285. *Pawlow: The Work of the Digestive Glands, London, 1902, pp. a0; 71. * Sternberg: Zentralblatt fiir Physiologie, 1909, xxii, p. 653. Similar views were expressed by Bayle in a thesis presented to the Faculty of Medicine in Paris in 1816. *Hertz: The Sensibility of the Alimentary Canal, London, 1911, p. 38. * Schiff: Physiologie de la Digestion, Florence and Turin, 1867, p. 40. *Luciani: Das Hungern, Hamburg and Leipzig, 1890, p. 113. "Tigerstedt: Nagel’s Handbuch der Physiologie, Berlin, 1909, i, ps 376: * Johanson, Landergren, Sonden and Tigerstedt: Skandinaviseches Archiv fiir Physiologie, 1897, vii, p. 33. *Carrington: Vitality, Fasting and Nutrition, New York, 1908, p. 555. *® Viterbi: Quoted by Bardier, loe. cit., p. 7. “Busch: Archiy fiir pathologische Anatomie und Physiologie und fiir klinische Medicin, 1858, xiv, p. 147. 152 HARVEY SOCIETY * Schiff: loe. cit., p. 37. Also Ducceschi: Archivio di Fisiologia, 1910, viii, p. 579. *Longet: Traité de Physiologie, Paris, 1868, i, p. 23. “Ludwig: Lehrbuch der Physiologie des Menschen, Leipzig and Heidelberg, 1858, 11, p. 584. * Maxwell: Journal of Biological Chemistry, 1906-7, ii, p. 194. * Schiff: loe. cit., p. 49. * Schiff: loc. cit., p. 31. Bardier: loc. cit., p. 16. * Head: Brain, 1893, xvi, p. 1; 1901, xxiv, p. 345. * Nicolai: Ueber die Entstehung des Hungergefiihls. Inaugural- Dissertation, Berlin, 1892, p. 17. * Beaumont: The Physiology of Digestion, second edition, Burling- ton, 1847, p. 51. “Nicolai: loc. cit., p. 15. “Beaumont: loe. cit., p. 55. Valenti: Archives italiennes de Biologie, 1910, lu, p. 94. * Pawlow: loc. cit., p. 70. Hornborg: Skandinavisches Archiv fiir Physiologie, 1904, xv, p. 248. * Weber: Wagner’s Handwérterbuch der Physiologie, 1846, iii’, p. 580. *° Vierordt: Grundriss der Physiologie, Tiibingen, 1871, p. 433. * Knapp: American Medicine, 1905, x, p. 358. Hertz: loc. cit., p- 37. ** Schiff: loc. cit., p.. 33. *® Luciani: loe. cit., p. 542. * Valenti: loe. cit., p. 95. * Bettmann: Philadelphia Monthly Medical Journal, 1899, 1, p. 133. "Wolff: Dissertation, Giessen, 1902, p. 9. * His: Archiv fiir Anatomie, 1903, p. 345. “ Boldireff: Joe. cit., p. 1. * Boldireff: loc. cit., p. 96. * Cannon and Lieb: American Journal of Physiology, 1911, xxix, p. 267. * Duceeschi: Archivio per le Scienze Mediche, 1897, xxi, p. 154. * Cannon: American Journal of Physiology, 1903, vili, p. xxi; 1905, xiv, p. 344. : * Cannon and Murphy: Journal of the American Medical Associa- tion, 1907, xlix, p. 840. ” Boldireff: loc. cit., pp. 108-111. “Cannon: American Journal of Physiology, 1911, xxix, p. 250. “FHaudek and Stigler: Archiv fiir die gesammte Physiologie, 1910, CXxxili, p. 159, THE CONTINUOUS ORIGIN OF CERTAIN UNIT CHARACTERS AS OBSERVED BY A PALEONTOLOGIST * PROF. HENRY FAIRFIELD OSBORN Columbia University. NE method of ascertaining the height of a mountain is with a single instrument, the barometer; another method is by triangulation with several instruments. Thus we may differ from Johannsen in his remark that morphology as a science of great collections in museums is of no value in genetics. The brilliant progress in heredity of the last nine years, beginning in 1903 with the rediscovery of Mendel’s law, should not blind us to the four broad inductions from Paleontology,: that transformation is a matter of thousands or hundreds of thousands of years, that to the living observer all living things may be delusively stationary, that invisible tides . of genetic change may be setting in one direction or another and yet observable only over very long periods of time, that dis- continuous mutations or saltations may be mere ripples on the surface of these tides. Whatever the truth as to these reflections, by a strange paradox it is certain that some stationary characters, some apparently dead things in the eyes of the zoologist and botanist, become movable and alive in the eyes of the paleontologist. Thus a paleontologist comes before the Harvey Society of Physiologists and Physicians with the conviction that his vision is of a different angle from that of the experimentalist, and that by the triangulation of experiment, of anatomy and of paleon- tology the truth may at least be more nearly approached. * Delivered January 20, 1912. *Osborn, Henry F., Darwin and Paleontology. One of the addresses in Fifty Years of Darwinism. 8vo. Henry Holt & Co., New York, May 1, 1909. 153 154 HARVEY SOCIETY The origin and history of ‘‘characters’’ is our quest, and now that attention is concentrated all along the line of observation in plants and animals, living and fossil, on the genesis and behavior of single characters, we have laid the train of sub- stantial progress. A vast gain is that which relegates the problem of species to a side issue, or rather to an incidental result of the accumulation and modification of a greater or less number of units. Among mammals a ‘‘character’’ may be racial shape of head or length of limb, it may be a cusplet on a grinding tooth, color of hair, or a sportive white lock of hair, it may be the brown or blue color of the eye, it may be the speed of a horse, or the obstinacy of a mule, in short, any structure or function, simple or extremely complex, which is stable and distinct in heredity. A ‘‘new character’’ is something which is unknown before, it may be a new unit, like the horns of cattle, it may be a new form or proportion of such a unit. ‘‘I understand by the term unit character,’’ observes Morgan, ‘‘any particular structure or function that may appear in heredity independent of other characters. Such unit characters may in themselves be extremely complex and include the possibility of further splitting up.’? The point where Mendelism bears on the problem is, therefore, in its bearing on the continuous or dis- continuous origin of the thousands of characters which display this more or less complete discontinuity in heredity. Is there more evidence of discontinuity and of lawlessness, or of continuity and of law, in the origin of such new charac- ters? Perhaps no more appropriate question could be chosen as the subject of a lecture in memory of William Harvey, the author of the doctrine of epigenesis, for the essence of this doctrine is that of ‘‘successive differentiation of a relatively homogeneous rudiment into the parts and structures which are characteristic of the adult.’? Paleontology is at one with embryology in the belief that differentiation is in the main gradual and continuous. Yet, to our question, the answer prevailing among ex- perimentalists and Mendelians at the present time is that ORIGIN OF UNIT CHARACTERS 155 there is little evidence either for continuity or for law; this despite the fact that a large part of the evidence for discon- tinuity in the origin of characters is most unsound. In fact, our first purpose in this Harvey Lecture is to show how surprisingly unsound this evidence is when we consider that discontinuity has become practically a dogma among a very large number of zoologists and botanists. It will appear that the evidence for discontinuity in the heredity of characters is as convincing as that for discon- tinuity in the origin of characters is most unsound. Our second purpose in this Harvey Lecture is to show that the evidence for continuity in the genesis of certain characters in man and other mammals is very strong indeed, further, that some of these characters, while apparently con- tinuous in origin, certainly become discontinuous in heredity ; from which it follows that discontinuity in heredity con- stitutes no proof of discontinuity in origin. How then do these manifold characters of which the body is made up arise, continuously or discontinuously? T;! * Vertebrate cicero cscs Ce aero 17 27° (asymmetry) TW Déethie eateries: oo eee eae 8 10t 67 DLT: CCH eres hsp a) os MAR Soroetee s sl coterie eee 110 210 37 67 * Numerical variations of cervical, dorsal and lumbar vertebre. 4 eee molars, cf. Octocyon, Myrmecobius, Cetacea. Six cases insufficiently escribed. ORIGIN OF UNIT CHARACTERS 163 The fact that the vast majority of germinal anomalies examined in the above review of Darwin and of Bateson have no significance in evolution in a state of nature, throws all germinal anomalies under suspicion as natural processes, important as they may be in artificial breeding and hybridiz- ing. Yet some of these anomalies in mammals are less pro- foundly discontinuous than those which De Vries has cited in plants under the designation of ‘‘mutations.’’ The most important of these De Vries’ mutations may now be considered. 3. Evidence for De Vries’ Mutation Theory In 1901 the biological world was aroused, as it had not been since 1859, by the publication of De Vries’ hypothesis."* Here was a new and apparently sure foundation for discon- tinuity in the supposed sudden appearance of elementary species or ‘‘mutants’’ arising with the acquisition of entirely new characters, new forms of plants or animals quite free from their ancestors and not linked to them by intermediates. The influence and vitality of this great work is shown in a citation from Darbishire (1911, op. cit., p. 5): The view that species have originated by mutation is based on Prof. de Vries’ observations on the Evening Primrose (@nothera Lamarck- tana) (Fig. 1). Working with this form, he was able to witness, for the first time, the actual process of the origin of new species. Critical analysis during the past two years by Davis and by Gates’? of the very species @nothera Lamarckiana on which De Vries chiefly based his monumental work, tends to show that O. Lamarckiana is possibly a hybrid of O. biennis and O. grandiflora and not a natural species. Thus the “‘elementary species’’ which are springing from it in various "De Vries, Hugo: Die Mutationstheorie, Leipzig, 1901, p. 24. * Davis, Bradley Moore: Genetical Studies on Cinothera. II. Some Hybrids of Gnothera biennis and O. grandiflora that resemble O. Lamarckiana, Amer. Naturalist, vol. xlv, April, 1911, pp. 193-233. Gates, R. R.: The Mutation Theory. The American Naturalist, vol. xlv, No. 538, April, 1911, pp. 254-256. Mutation in Ginothera, Amer. Naturalist, vol. xlv, No. 538, October, 1911, pp. 577-606. 164 HARVEY SOCIETY gardens may prove to be comparable to the familiar results of hybridization in mammals and birds. Davis, on the basis of his prolonged experimental researches, says (p. 193) : Indeed, the theory of De Vries may fairly be said to rest chiefly upon the behavior of this interesting plant, the account of which forms so large a part of his work “Die Mutationstheorie” (2 vols., Leipzig, (1901) ces Gates makes the following statement (pp. 255-296) : In a reperusal of the work one is struck by the optimism of its author and the brilliancy and breadth of his exposition of the views set forth. ... The analysis of the data amassed by Darwin, in which it is shown that Darwin’s single variations are the same as De Vries’ mutations, seems to the reviewer particularly effective. .. . Probably the time will soon come when nearly all biologists will be ready to admit that mutation, or the sudden appearance of new forms, has been an important factor at least, in species formation of plants and animals. Admitting this, it remains to be discovered what rela- tion these sudden appearances bear to the general trends of evolution which are apparent in so many phylogenies [italics our own]... For, granting the facts of mutation, we have only accounted for micro- evolution, and it is still to be shown that the larger tendencies can be sufficiently accounted for by the same means, without the intervention of other factors.... The skepticism of both these botanists is striking. Their opinions as to the existence of larger evolutionary trends are exactly in accord with those of paleontologists. 4. Evidence for Discontinuity from Mendehan Heredity and Experimental Selection The newest bulwark of the discontinuity hypothesis is that erected since 1903 by the revival of the great discovery of Mendel (1865) and by the negative results of experiments on fluctuating or quantitative variation. From the prevalence of discontinuity in heredity, the separateness of ‘‘unit characters’’ as they appear in the body and the equally sharp separableness of their complex of ‘‘fac- tors,’’ ‘‘determiners’’ or ‘‘genes’’ in the germ has arisen the purely theoretical assumption of the discontinuity of origin of ORIGIN OF UNIT CHARACTERS 165 all characters in the germ. We shall attempt to show that this assumption is a non-sequitur. First, however, the truly marvellous and epoch-making Mendelian discoveries require our special examination in their bearing on the problem of continuity and discontinuity. We have reviewed 2* the contributions of Allen, Bateson, Castle, Cannon, Cuénot, Darbishire, Davenport, Durham, Farrabee, v. Guita, Haacke, Hagedoorn, Harmon, Hurst, Laughlin, Mor- gan, Pearson, Plate, Punnett, and Rosenoff. This review covers unit characters only as observed in mammals, to which none the less the principles discovered by Mendel in the common garden pea (Pisum sativum) apply with striking uniformity. The prevailing field of the researches of these talented investigators in mammals has been in color characters, chemical in essence, in various species of rodents, chiefly mice and guinea pigs, also in Ungulates, such as horses and cattle, the latter studied less by experiment than from stud books. Hair form in rodents and in man and skin pigment have also been exactly investigated. The most striking general result is the principle of antithesis of characters which mutually exclude each other, as typified by the antithesis of Mendel’s ‘‘tallness’”’ and ‘‘shortness’’ in peas. The second great result is that when these antithetic characters meet in the germ cells, one dominates over the other ; this dominance is a sort of perpetual prepotency. ‘‘Prepo- tency,’’ observes Darbishire, ‘‘is an attribute of individuals and capricious in its appearance... . Whatever be the nature of this power .. . it is clear that it has nothing to do with dominance .. . dominance is an invariable attribute of particu- lar characteristies.’’?* Plate (1910), on the contrary, observes, “But a variety of facts seem to indicate that a reversal of dominance may occur under certain circumstances and a domi- EE Lice AER AS a * With the aid of Miss Mary M. Sturgess, now attached to the Carnegie Institution Station for Experimental Evolutions at Cold Spring Harbor, L. I. * Darbishire: op. cit., p. 96. 166 HARVEY SOCIETY nant character may become recessive, and vice versa.’’*> Such reversal of dominance would appear to be the case in a com- parison of the mule (cross between ass ¢' and horse 2 ) and the hinny (cross between the horse 6’ and the ass @ ). When antithetic characters or functions meet in heredity, there is either ‘‘prepotency,’’ or ‘‘dominance,’’ or ‘‘recession”’ (i.e., latency), or ‘‘inhibition,’’ a something which indirectly prevents the appearance of characters, or ‘‘imperfect domi- nanee,’’ of ‘‘blending.’’ In brief, there are degrees of separa- bleness and antithesis. Dominance, Conservative or Progressive—tlt will be seen at once that progressive evolution through discontinuity would depend on the dominance of racially new characters and types. The experimental evidence is conflicting, it does not show that new characters are necessarily dominant. There are many instances of dominance of wild species (older type) over domesticated species (newer type); thus De Vries suggested (1902) that the dominant characters are those which are racially older. One case among the mammals is that the wild gray color in mice dominates over grades below it, black, brown, and white (Plate, 1910). Examples of dominance in single characters are that more intense dominate over less intense colors (Plate, 1910, Daven- port, 1907); in the eyes, brown over gray, gray over blue; in the skin, brunettes over blondes (Davenport, 1909), piebalds over pure albinos (Plate, 1910); in the hair, wavy or spiral forms dominate over straight (Davenport, 1908). These facts of experiment are directly opposed to the natural fading out of color in desert races like the quagga, which lost all the stripes of its intensely colored relative the zebra. The idea that the positive or present character dominates over the negative, latent or absent character has become a prevailing one. It seems highly probable, observes Davenport (1910), that the fu- ture will show that many more advanced or progressive conditions are really due to one or more unit-characters not present in the less ad- ye * Plate. ORIGIN OF UNIT CHARACTERS 167 vanced condition. In that case it will appear that there is a perfect accord in the two statements that the progressive and the “present” factor are dominant (pp. 89-90) .. . the specific characteristies are mostly those that appear late in ontogeny (p. 86) ... the potency of a character may be defined as the capacity of its germinal deter- miner to complete its entire ontogeny. If we think of every character as being represented in the germ by a determiner, then we must recog- nize the fact that this determiner may sometimes develop fully, some- times imperfectly and sometimes not at all [italics our own]... . When such a failure occurs in such a normal strain a sport results. . . . Potency is variable. Even in a pure strain a determiner does not always develop fully and this is an important cause of individual variability (Davenport, 1910, p. 92). Plate similarly favors the hypothesis of dominance of newer or progressive characters. He observes (1910): The [Mendelian] laws of inheritance favor progressive evolution in two ways, for... higher, more complicated characters are generally dominant to the lower, and .. . qualitative characters usually follow the Mendelian principle in the ease of closely related forms (races, varieties), while in the crossing of species they follow intermediate [or blended] inheritance as a rule. In the latter case there is the pos- sibility that the crossing may have a swamping effect, but this can play no large réle on account of the infrequency of hybrids between species (Plate, 1910, p. 606). Plate is of the opinion that phyletie evolution is discon- tinuous as regards the transformations of the determinants [determiners], but in most cases is continuous in their visible outward workings. He thus maintains that while germinal transformations are discontinuous there may be no real antithesis between continuous and discontinuous somatic variation. Mendelians appear to agree, first, that there are grades of continuity and discontinuity, that there are antithetic characters which are sharply discontinuous, others which are partly con- tinuous, blended or intermediate. Second, some new characters are dominant, others are recessive. Third, it would appear that complete discontinuity or entire dominance or recession are qualities in heredity which may gradually evolve. Many characters show imperfect dominance (Castle, 1905) ; gametic purity is not absolute (Castle, 1906) ; selection is of importance 168 HARVEY SOCIETY in the improvement of races (Castle, 1907). There are a num- ber of truly blending characters, such as lop-earedness in rabbits (Castle, 1909); cross blends of long and short hairs . (Castle, 1906), cross blends between short- and lopeared rabbits which are permanent (Castle, 1909), blends in weight inherit- ance and in skeletal proportion (Castle, 1909). Recent work has led to the opinion (Hatai, 1911)** that blended inheritance may be considered to be a limited ease of alternative inheritance where dominance is imperfect; Mendel’s law of alternative inheritance may be considered as the standard in all the cases referred to it (Hatai, 1911, p. 106). Certain characters which were considered formerly to blend are now regarded as showing a certain kind of segregation or unit inheritance. Thus Davenport (1909) observes: Skin pigment does not show thorough blending inheritance, but segregation (sometimes imperfect), a more pigmented being imper- fectly dominant over a less.” ... The reason, the same author observes (1909), for the blending of hair and skin color in man is the non-development of distinct color unit-determiners owing to the fact that in man for a long period there has been no selection for intensity of color, whereas in the lower mammals definite color determiners have long been maintained by selection. Thus the prevalent recent opinion or hypothesis among Mendelian observers is that there is a real discontinuity between the germinal or blastic characters and what the paleontologist or morphologist generally observes, is only an apparent con- tinuity between somatic characters. Since, however, the behavior of visible or somatic characters forms our only means of knowing whether the determiners are continuous or discontinuous, it is obvious that this opinion or rather this ingenious hypothesis requires further examina- tion and experiment. * Hatai, Shinkishi: The Mendelian Ratio and Blended Inheritance, Amer. Naturalist, vol. xlv, No. 530, February, 1911, pp. 99-106. Piomentation of the skin seems to depend in man on a series of color intensity units, possibly one or a few large units, more probably a number of small units so close together as to be almost continuous (Davenport, 1910). ORIGIN OF UNIT CHARACTERS 169 5. Johannsen’s Pure Line Theory}® The hypothetical contrast between a real discontinuity of the blastic determiners and a delusive continuity of visible or somatic form is pushed to its extreme in the ‘‘pure-line’’ con- ception which marks the latest development in heredity, an advance upon Weismann’s germ-plasm theory and Mendel’s unit-character law. Through experiments on successive genera- tions of self-fertilizing plants (the garden bean), Johannsen has reached a standpoint which may be briefly stated as follows: A “pure line” is composed of the descendants of one pure strain or homozygotie organism exclusively propagated by self fertilization; such pure lines demonstrate the stability of hereditary constitution in successive generations where undisturbed by cross breeding or ming- ling with other strains, showing that the only real changes in organ- isms are those due to the sudden appearance of new determiners in the germ. To replace the word determiner the term gene is proposed. The genotype represents the sum total of all the genes in the fertilized germ cell, gamete or zygote; we do not know a venotype, but we are able in experiment to demonstrate “genotypical differences.” The biotype is a group of similar genotypes or pure strain individuals. Gene, genotype, and biotype are not seen; they are the smaller and larger units of heredity. The phenotype is what we see; it is the developing organism. Morphology supported by the huge collections of the museums has operated with “phenotypes” in phylogenetic speculation. It is thus a science of phenotypes and is not of value in genetics because pheno- type description is inadequate as the starting point for genetic in- quiries. The adaptation of phenotypes through the direct influence of environment [Buffon’s factor] or of use and disuse [Lamarck’s fac- tor] is not of genetic importance. Ontogenesis is a function of the genotype, but the genotype is not a function of ontogenesis. The idea of evolution by continuous transitions from one type to another has imposed itself upon zoologists and botanists, who are examining chiefly shifting phenotypes in very fine gradations. There is such a econtinu- ity in phenotypes but not in the genotypes from which they spring. All degrees of continuity between phenotypes may be found, but real genetic transitions must be distinguished from the transitions which we find in museums. * Johannsen, W.: The Genotype Conception of Heredity, Amer. Naturalist, vol. xlv, No. 531, March, 1911, pp. 129-159. 170 HARVEY SOCIETY Genotypes, it is true, can only be examined by the qualities and re- actions of the phenotypes. Such examination shows that within pure lines—if no new muta- tions or other disturbances have been at work—there are no geno- typical differences in the characters under examination. The only real discontinuity is that between different genotypes. The mutations ob- served in nature have shown themselves as considerable discontinuous saltations. There is no evidence for the view that mutations are prac- tically identical with continuous evolution. In pure lines no influence of special ancestry ean be traced; all series of progeny keep the geno- type unchanged through long generations. Discontinuity between genotypes and constant differences between the genes show a beautiful harmony between Mendelism and pure line work. Selection will have no hereditary influence in changing genotypes. Even the selection of fluctuations in pure lines is ineffective to produce a new genotype. Heredity may thus be defined as the presence of identical genes in ancestors and descendants, or heredity stands for those properties of the germ cells that find expression in the developing and developed phenotype. Jennings observes: What distinguishes the different genotypes, then, is a different method of responding to the environment. And this is a type of what heredity is; an organism’s heredity is its method of respond- ing to the evironmental conditions [p. 84]... . It appeared clear, and still appears clear, that a very large share of the apparent progressive action of Selection has really consisted in the sorting over of pre- existing types, so that it has by no means the theoretical significance that had been given to it [p. 88]... . I had hoped to accomplish this myself, but after strenuous, long-continued and hopeful efforts, I have not yet succeeded in seeing Selection effective in producing a new genotype. This failure to discover Selection resulting in progress came to me as a painful surprise, for like Pearson I find it impossible to construct for myself a “philosophical scheme of evolu- tion,” without the results of Selection, and I would like to see what I believe must oceur [pp. 88-89]. . . . It would seem that the diverse genotypes must have arisen from one, in some way, and when we find out how this happens, then such Selection between genotypes will be all the Selection that we require for our evolutionary progress [p. 89]. Johannsen’s general conception of the origin of progressive or retrogressive new characters is that ‘‘it is sufficient to state that. the essential point in evolution is the alteration, loss or ORIGIN OF UNIT CHARACTERS 171 gain of the genes or constituents of the genotypes .. . all evidences as to ‘mutations’ point to the discontinuity of the changes in question.”’ 6. Negative Results of Experiments on Quantitative Variation We agree with Johannsen that an appearance of continuity might arise through the selection of degrees of hereditary fluctuation in structure or function, for example, of tallness or shortness of stature, of intensity or faintness of color. This brings up the problem of fluctuation in the germinal de- terminers. Some Mendelians discard fluctuations altogether as non-hereditary; thus Punnett (1911, p. 138)?® observes: ‘‘At the present time we have no valid reason for supposing that they [fluctuations] are ever inherited.”’ The problem, however, is not as to quantitative ontogenic variations caused by favorable or unfavorable environment or by changes or habit, but as to heritable fluctuations springing from the germ plasm. Experiments have been directed to the point whether variations in size, in proportion, etc., of heredi- tary unit characters are transmitted and accumulated by selection. Davenport also has reached negative results; he observes (1910) : In the last few decades the view has been widespread that char- acters can be built up from perhaps nothing at all by selecting in each generation the merely quantitative variation that goes farthest in the desired direction. The conclusion upon which De Vries laid the greatest stress, that quantitative and qualitative characters differ fundamentally in their heritability, is supported by our experiments (p. 96). I have made two tests of this view using the plumage color of poultry (p. 94). ... After three years of selection of the reddest offspring no appreciable increase of the red was observed except in one case, which looks like a sport (p. 96). These fluctuating quanti- tative conditions depend on variations in the point at which the ontogeny of the character is stopped; and the stopping point is in turn often if not usually determined by external conditions which favor or restrict the ontogeny. Thus the selection of redness of comb, of polydactylism, of syndactylism, have not proven the inheritance of quantitative variations. Apparently, within limits, these quantitative * Punnett, R. C.: Mendelism, Macmillan Co., 1911 (3d edition). 172 HARVEY SOCIETY variations have so exclusively an ontogenie signification that they are not reproduced so long, at least, as environmental conditions are not allowed to vary widely. Similarly Love 7° from experiments on the yielding power of plants remarks: Unless further studies produce different results we can say from the facts at hand that there is no evidence to show that a basis exists for cumulative selection. Similar conclusions have been reached by Pearl (1909) ”* in the breeding of fowls for laying purposes. All the above results are negative. Even the positive or affirmative results obtained by Cuénot and later by Castle, wherein quantitative characters may be shifted in one direction or the other by selection, are now given a new interpretation by certain Mendelians. On the other side Cuénot showed by continued selection of lighter colored mice that the coat became paler; and Castle has shown that in rats the coat through selection may be made darker. Castle remarks (1911) :* I prefer to think with Darwin that selection . . . can heap up quantitative variations until they reach a sum total otherwise un- attainable, and that it thus becomes creative. He cites cumulative results in the development of a fourth toe in the hind foot of guinea-pigs and in the modification of the dorsal striping of hooded rats. Morgan’s remarks (1912) on these positive experiments are as follows: Castle has been very guarded in regard to the interpretation of the results of selection in this case. It is probable that extreme selection * Love, Harry H.: Are Fluctuations Inherited? Contr. VI, Lab. Experim. Plant-Breeding, Cornell Univ., Amer. Naturalist, vol. xliv, No. 523, July, 1910, pp. 412-423. “Pearl, Raymond: Is there a Cumulative Effect of Selection Abstammungs und Verebungslehre, 2, 1909, H. 4. ™ Castle, W. E.: The Nature of Unit Characters, The Harvey Lec- tures, delivered under the Auspices of the Harvey Society of New York, 8vo, J. B. Lippincott Co., pp. 90-101. ORIGIN OF UNIT CHARACTERS 173 is necessary to maintain the higher stage reached. It does not breed true and slips back easily. If this is correct it suggests: first, that nothing permanent has been effected in the germ-cells; and second, that the result is due to the discovery of more extreme cases of fluctuating variations than ordinarily occur. The general import of these experiments and opinions 7s that fluctuations in the determiners, or genes, can be utilized to establish a new quantitative mean. It is obvious that what have been measured by biometricians as hereditary ‘“fluctuations’’ might be regarded as ‘‘saltations’’ of all de- grees, but such saltations do not represent new determiners in the Mendelian or Johannsen sense; they are mere fluctuations in existing determiners. Pure Mendelians would allege that tallness in man or other mammals can only be accumulated ‘through the saltatory origin of ‘‘tall’’ determiners which are not connected continuously through intermediate forms with the antithetic ‘‘short’’ determiners. As to stature Brownlee observes (1911, p. 255) : 78 I think that I have shown that there is nothing necessarily antago- nistic between the evidence advanced by the biometricians and the Mendelian theory. ... (1) If the inheritance of stature depends upon a Mendelian mechanism, then the distribution of the population as regards height will be that which is actually found, namely, a distri- bution closely represented by the normal curve. 6. Summary as to Discontinuity and Mendelism Genetics is the most positive, permanent and triumphant branch of modern biology. Its contributions to heredity are epoch-making. But heredity is the conservative aspect of biology, and experimental genetics thus far chiefly reveals the laws of conservation rather than of natural progression. Genetics has not yet brought us one single step nearer the solution of the problem of the progressive origin of new char- * Brownlee, J.: The Inheritance of Complex Growth Forms, such as Stature, on Mendel’s Theory, Proce. Roy. Soc. Edinburgh, vol. xxxi, Pt. II, 1911, pp. 251-256. 174 HARVEY SOCIETY acters in mammals. The very independence, multiplicity and discontinuity of the units leave us farther afield. In place of what used to be regarded as the instability of the organisms, as a whole, we now have to conceive of the instability of thou- sands, nay hundreds of thousands of units. As shown in our analysis of the saltations cited by Darwin and Bateson, Mendelism has revealed the fact that the majority of saltations simply refiect failures in the germinal mechanism. The inference is natural that the remaining minority also represent anomalies, or lawless conditions. Over a half century of anatomical research among mammals in a state of nature has failed to demonstrate the sudden origin of a single new progressive character which has become fixed in the race. Nor have Mendelism and experimentalism released us from the hard confines of examination of the germ through the soma; behavior of unit characters in the soma is the sole means of knowing the behavior of the ‘‘determiners’’ in the germ. If the unit characters in the soma behave discontinuously we are forced to the conclusion that their determiners behave dis- continuously ; if, on the contrary, these unit characters behave continuously, are we not forced to the conclusion that there is a continuity in the behavior of the corresponding determiners? Let us therefore proceed to consider the value of some of the evidence for continuous behavior in the germinal origin of certain new somatic characters, again repeating our opinion that certain other characters are essentially antithetic, without intermediates, and consequently discontinuous both in heredity and in origin. JI. EVIDENCES FOR CONTINUITY Abandoning the historical background, we come to our own subject, the origin and establishment in continuity of certain characters which when established exhibit many of the dis- tinctive features of unit characters, namely, segrega- tion, stability, pure heredity, and possibly, although this has not yet been demonstrated, dominance and recession in suc- cesswe generations. ORIGIN OF UNIT CHARACTERS 175 1. Rectigradations and Allometrons. In fifteen previous papers by the writer beginning in 1889** the observation is repeatedly made that all absolutely new characters which we have traced to their very beginnings in fossil mammals arise gradually and continuously. One by one these characters, which are independently changing in many parts of the organism, at the same time accumulate until they build up a degree of change which paleontologists designate as a ‘‘mutation’’ in the sense of Waagen, who proposed this inter-specific term in 1869; finally these new characters attain a sufficiently important phase to designate the stage as a species.”° These new characters were first (1891) termed ‘‘definite variations’’; subsequently (1907)?* the term “‘rectigradations”’ was applied to them. Rectigradation is merely a designation for the earliest dis- cernible stages of certain absolutely new characters; it involves no opinion nor hypothesis as to genesis; it is a simple matter of observation. Referring to the figure (p. 200) of the upper grinding teeth of the horse, the majority of the fourteen char- acters have been observed to arise as rectigradations. Quite different is the allometron. This is a new designation for the continuous change of proportion in an existing char- acter which may be expressed in differences of measurement. Since 1902 and especially during the past year the behavior * Osborn, H. F.: The Paleontological Evidence for the Transmis- sion of Acquired Characters, Amer. Naturalist, vol. xxiii, No. 271, July, 1899, pp. 561-566. * This sentence may be contrasted with that of Punnett (op. cit., p. 15): “Speaking generally, species do not grade gradually from one to the other, but the differences between them are sharp and specific. Whence comes this prevalence of discontinuity if the process by which they have arisen is one of accumulation of minute and almost imper- ceptible differences? Why are not intermediates of all sorts more abundantly produced in nature than is actually known to be the case?” * Osborn, H. F.: Evolution of Mammalian Molar Teeth to and from the Triangular Type, 8vo, Macmillan Company, September, 1907. 176 HARVEY SOCIETY of allometrons has been very carefully investigated by myself and by my colleague, Dr. W. K. Gregory. RECTIGRADATION —a qualitative change, the genesis of a new character in an adap- tive direction. ALLOMETRON =a quantitative change, the genesis of new proportions in an ex- isting character. The distinction between a rectigradation and an allometron is readily grasped: when the shadowy rudiment of a cusp or of a horn first appears it is a rectigradation; when it takes on a rounded, oval or flattened form this change is an allometron. In mammals rectigradations are comparatively few and in- frequent, while allometrons comprise the vast number of changes in the hard parts. In the origin of cusp and horn rudiments rectigradations are parallel or convergent (see Fig. 3), in the changing proportions of a skull allometrons are divergent (Figs.-1, 3). Granting, without at present considering the evidence,” that these rectigradations and allometrons arise continuously through entirely unknown laws, also that they are blastic or germinal characters, the question arises, Do they become sepa- rable as unit or alternating characters in heredity? In general, paleontology furnishes quite as strong proof as Mendelism or experimental zoology as to the individuality, separableness, and integrity of single characters in evolution. But, whether both rectigradations and allometrons are separable in heredity can only be demonstrated through experiments on eross breeding or hybridizing. The special object of this Harvey Lecture is to show that certain at least of the rectigradations and allometrons observed in mammals are separable in heredity, that they split up into larger and smaller groups or units, some into partially blend- 7 This evidence is for the first time fully presented in the writer’s monograph on the “ Titanotheres,” in preparation for the U. 8S. Geological Survey. ORIGIN OF UNIT CHARACTERS 177 ing units, others into absolutely distinct or non-blending units; finally that at least in the first cross they exhibit dominance. The very important remaining question whether, like the quality of ‘‘tallness’’ or ‘‘shortness’’ in Mendel’s classic experi- ments on the pea, these allometrons continue to split into - dominants and recessives in later crosses, has not been investi- gated, but is probably capable of investigation in mammals which do not become sterile in the first hybrid generation. Fig. 1. Continuous ORIGIN or ALLOMETRIC ‘‘ UNIT CHARACTERS’ IN THE ; CRANIUM (A) AND SKULL (B) oF MAN AND TITANOTHERES. A, Man Brachycephaly Mesaticephaly Dolichocephaly B, Titanotheres Brachycephaly Mesaticephaly Dolichocephaly (Paleosyops) (Manteoceras) (Dolichorhinus) Five examples of the continuous evolution of rectigrada- tions and allometrons may be cited, namely: . Skull and horns of titanotheres (Figs. 1, 3, 4). The horns of eattle (Fig. 2). . The cranium of man (Fig. 1). . The skull of horses (Figs. 4, 5, 6, 7). 5. Teeth (Fig. 8). 178 HARVEY SOCIETY One of the most salient examples of the genesis of unit characters through continuity is that of the evolution of horns, v.€., of the osseous prominences on the skull. Horns are now known definitely to be ‘‘unit characters,’’ first through their sudden and complete disappearance in the niata and polled breeds of cattle; second, because they conform to the laws of sex-limited inheritance. The pertinent question is, Do horns originate continuously or discontinuously ? 2. Horns of Titanotheres The titanotheres are an extinct family of quadrupeds dis- tantly related to the horses, tapirs and rhinoceroses, to the evolution of which the author has devoted twelve years of investigation, assisted by Dr. W. K. Gregory. As set forth in an earlier contribution ** the genesis of horns as rectigrada- tions has been observed in four or five distinct phyla of titan- otheres. These phyla descend independently from a single ancestor of remote geologic age. Both in respect to new cusps on the teeth and new horn rudiments on the skull there is observed what in our ignorance may be ealled an ancestral predisposition to the genesis of similar rectigradations. This predisposition betrays the existence of law in the origin of certain new characters; it recalls a sagacious remark of Darwin: ... The principle formerly alluded to under the term of analogical variation has probably in these cases often come into play; that is, the members of the same class, although only distantly allied, have in- herited so much in common in their constitution, that they are apt to vary under similar exciting causes in a similar manner; and this would obviously aid in the aecquirement through natural selection of parts or organs, strikingly like each other, independently of their direct inheritance from a common progenitor.” Briefly, the history of the origin of the titanothere horns *The Four Inseparable Factors of Evolution. Theory of Their Distinct and Combined Action in the Transformation of the Titanotheres, an Extinet Family of Hoofed Animals in the Order Perissodactyla, Science, N. S., vol. xxvii, No. 682, January 24, 1908, pp. 148-150. ” Origin of Species, vol. ii, p. 221. ORIGIN OF UNIT CHARACTERS 179 is as follows: (a) from excessively rudimentary beginnings, 7.e., rectigradations, which can hardly be detected on the surface of the skull; (b) there is some predetermining law or similarity of potential which governs their first existence, because (c) the rudiments arise independently on the same part of the skull in different phyla at different periods of geologic time; (d) the horn rudiments evolve continuously, and they grad- ually change in form (2. e., allometrons); (e) they finally be- come the dominating characters of the skull, showing marked variations of form in the two sexes; (/) they first appear in late or adult stages of ontogeny, but are pushed forward gradually into earlier and earlier ontogenic stages until they appear to arise prenatally. In the titanotheres (Fig. 3) the bony swelling is seen at the junction of the nasals and frontals (black shading), in dolichocephalic skulls it appears chiefly on the nasals, in brachycephalic skulls chiefiy on the frontals. Its original low, rounded shape is like that seen in the ontogeny of the horns in cattle (Fig. 2). 3. Horns of Cattle The phylogenesis of the horns in titanotheres (Fig. 3) is exactly similar to the ontogenesis of the horns in Bovide (Fig. 2), in which the dermal rudiments first appear soon after the complete formation of the bones of the skull in the unborn young, and the osseous rudiments appear as rounded pro- tuberances in the 8th month. In the ontogenesis of horns in cattle three distinct elements are involved: (a) a psychic predisposition to use the horn, (0) a dermal thickening over the bony horn region which in ontogeny precedes the bony swelling, (c) appearance of the bony swelling itself. The ontogenesis is observed to be accompanied by a marked allometric change in the skull which shifts the horn back- ward from the side of the cranium to the side of the occiput by the obliteration of the parietal bones (Fig. 2). HARVEY SOCIETY 180 ‘sarey pe1oj}80S OF YIM Po1OAOCO ‘duTjoms [eUIepida ‘yyUOoU 44g 4 ‘edVIs [BIO “LZ “45N} IBY pejyutod gyi por9ao0o ‘Zuyjoms jeutsepide ‘qjzu0u 447-9 4 ‘9dBI8 [BOT “9 ‘poquiod Zuyjems [euliepide pus ‘suyjoms Auoq ‘qjuOUI 446 ‘AdBIs [BID “G *qnd1000 03 uIOY SsNoosso JO Surzjrqs snonutjaoo ‘sxooM Z| ‘JBOD “P *qnd1000 0} U1OY SNOessO JO ZUIZJTYS SNONUIZUOO ‘sy}UOU Z ‘*}[VD *4nd1000 03 UOY SNOassO JO FuIWJIGs snonurjUod ‘syJUOU QT ‘suTjIwSOA "Z “YGvoysS AuI0Y pase u10y snoasso pazoduioo ‘siv0Ed 6 ‘4INPY “T ‘AIOPSIP, [BAINYBNY JO UINEsN]T UBOIIOUTY 94} JO SUOTZOOTIOO 94} UI qqnyD “A ‘Ss “JW 4q suoneiedoid 10jJy ‘2-[ ‘SUDVLG NUAGYG NI QILLVO NI HLVGHG NUO}] GNV NUOP{ AHL AO SISANADOINO AHL NI ALIQNILNOD °% ‘DIT ORIGIN OF UNIT CHARACTERS 181 4. Cranium of Man A third instance of continuous development is that of the form of the cranium in man (Fig. 1), an allometric evolution, or change of proportion, which is of especial significance be- cause, according to the unanimous testimony of anthropolo- gists,°° head form is the result of very gradual change either in the elongate (dolichocephalic) or broadened (brachyce- phalic) direction. The matter is directly pertinent to the present discussion because human ‘‘long heads’’ and ‘‘broad heads’’ are con- tinuously crossing and we know what the direction and ultimate effects of such crosses are. The evidence has important theoretical bearing also on the influence of selection, environ- ment, and inheritance or the effects of use and disuse. Determination of the proportions of the cranium or the cephalic index is one of the standard tests of race; it is an expression of the greatest breadth of the head above the ears and the percentage of its greatest length from the forehead (glabella) to back, the latter measurement being taken as 100. Three types adopted by anthropologists are: Extreme Range Brachycephalic, 80.1 and above ..........-sseee-- 100-80 NPE IEC FOE OO! We a bisralefe in cla icc a cgca's wiere tie sscatp 80-75 Dolichocephalic, 75 and below ........--++esseeeee 75-62 Among the present races of Europe the widest limits of variation between brachycephaly and dolichocephaly are in the averages between 73 and 87; individual extremes of 62 and 100 have, however, been observed. These extremes in Huropean head form do not coincide either with geographic or political boundaries, but are attributed to the entrance into Europe of brachycephalie and dolichocephalie types which evolved in Asia. Similarly among the aborigines of America the indices range from a low dolichocephaly as among the Delaware, Pima Indians, ete., to a decided brachycephaly as among the Ripley, Wm. Z.: The Races of Europe, a Sociological Study, 8vo, D. Appleton & Co., 1899, 624 pp. 182 HARVEY SOCIETY Athabasean tribes in Panama, Peru, and other localities. A significant fact in Europe is that dolichocephaly and brachy- cephaly are extremely stable characteristics in heredity. The significant fact again is that through a very long period of time the various races of Indians, who are believed to have had originally a similar origin, have acquired under conditions of geographic isolation considerable diversity in the propor- tions of the head. Similarly A. Keith *t from the present distribution of the Negro tribes in equatorial Africa has reached the following conclusions : There has been free intermigration; in the course of their evolu- tion, the tendency of one tribe has been towards the accentuation of one set of characters, of another towards another set. Thus the Dinka acquire high stature and narrow heads; the typical Nigerians low stature and narrow heads; the Basoko wide, short heads and low stature; the Buruns wide heads and high stature. Interbreeding may have played its part; but if it had played a great part we should have found greater physical uniformity than there is. The influence of Arab blood on these tribes has probably been exaggerated. It appears that environment has not any direct influence on head form, but that geographical isolation affords the sev- eral varieties of man as well as other mammals a chance to develop their peculiar head characters. Thus Elliot Smith states (letter, August 12, 1911): In my opinion the conditions of dolichocephaly and brachycephaly must have developed very slowly through exceedingly long periods of time and in widely separated areas amidst widely different environ- ments. Brachycephaly is especially distinctive of the Central Asian high plateau populations, dolichocephaly of the littoral and plain- dwelling peoples; but these “unit characters” are now so fixed that environment is powerless to modify them in a thousand years or so. ... 1 do not believe for a moment in Boas [that is, in Boas’s observa- tions (1911) on the rapid influence of environment in modifying head form]. "Keith, A.: Journ. Royal Anthropological Institute, 1911. See Nature, vol. 88, No. 2195, November 23, 1911, p. 119. ORIGIN OF UNIT CHARACTERS 183 Elliot Smith takes very strong ground as to the lack of evidence that environment directly produces any modification of head form; he implies that such modification, if natural, would only show itself after thousands of years of residence; environment no doubt has indirect influence. Hrdlicka, on the other hand, believes he has obtained definite results in the influence of environment [or habit, H. F. O.] on the vault and face form of the Eskimo;** it remains to be shown how far these changes are ontogenic. The recent conclusions of Boas (1911)** that dolichocephaly and brachycephaly are congeni- tally altered by environment in the first generation are modified by his statement that this action in bringing diverse head forms together would not go so far as to establish a uniform general type. No anthropologist has offered any satisfactory explanation as to the adaptive significance of dolichocephaly or brachy- cephaly. It is well known that these differences of head form are not associated with intellectual ability or mental aptitude. Boas writes (April 8, 1911): So far the matter is very perplexing to me. I feel, however, very strongly with you that changes in type are very liable to be progres- sive in definite directions. . . . To my mind it seems no more difficult to assume that this predetermined direction should continue from generation to generation than to make the much more difficult assump- tion that notwithstanding all internal changes the egg-cell of one generation should be absolutely identical with that of the preceding generation. Apart from the disputed problems of the direct influence of environment and of human selection there is absolute unanimity of evidence and of opinion on the one point essential to the present discussion, namely, as to the continuity of * Hrdlicka, Ales: Contribution to the Anthropology of Central and Smith Sound Eskimo, Anthr. Paper Am. M. N. H., v, Pt. IL, 1910, p. 214. *® Boas, Franz: The Mind of Primitive Man, 8vo, Maemillan Com- pany, New York, 1911, 924 pp. 184 Qe P HARVEY SOCIETY oS