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Digitized by the Internet Archive 
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http://www.archive.org/details/narveylectures 16harv 


THE HARVEY SOCIETY 


THE 
HARVEY LECTURES 


Delivered under the auspices of 
THE HARVEY SOCIETY 
OF NEW YORK 


Previously Published 


TELS TS Pa Ens eerie 1905-1906 
SECOND SERIES..... 1906-1907 
DHE DSS ERE Se aoe 1907-1908 
LOURDH SERIE See ae 1908-1900 
L EC SHC LE SE eee I909-I9IO 
| YOM EL VARUUDYS ee thos: IQIO-1QIT 


SEVENTH SERIES... 1911-1912 
Pel GHEE SEARLES ere IQI2-1913 
INGEN TBED SS RUS eee oe 1913-1914 
TENTH SERIES jo 1914-1915 
| ELEVENTH SERIES. . 1915-1916 
TWELFTH SERIES... 1916-1917 
THIRTEENTHSERIES 1917-1918 
FOURTEENTH SERIES1918-1919 
FIFTEENTH SERIES. 1919-1920 

SIXTEENTH SERIES. 1920-1921 


‘The Harvey Society deserves the thanks 
of the profession at large for having organized 
' sucha series and for having made it possible 
| for all medical readers to share the profits of 
the undertaking,”’ 

—Medtcal Record, New York, 


J. B. LIPPINCOTT COMPANY 
| Publishers Philadelphia 


W 
THE HARVEY LECTURES 


DELIVERED UNDER THE AUSPICES OF 


THE HARVEY SOCIETY 
OF NEW YORK 


UNDER THE PATRONAGE OF THE NEW YORK ACADEMY OF MEDICINE 


1920-1921 


BY 
Dr. JACQUES LOEB Dr. ALFRED F. HESS 
Pror. JULES BORDET Stir ARTHUR NEWSHOLME, M.D. 
Dr. NELLIS B. FOSTER Dr. A. N. RICHARDS 
Dr. CARL J. WIGGERS Dr. S. B. WOLBACH 


Dr. F. GOWLAND HOPKINS 


SERIES XVI 


PHILADELPHIA AND LONDON 


Jano LIPPINCOTT: COMPANY 


Sev. 16 


PREFACE 


Tue Lectures of the Harvey Society have become so well 
recognized and occupy such a prominent place in medical 
literature that prefatory remarks are superfluous. The inten- 
tion of the founders of the Society was to have each year a series 
of contributions each one of which was to bring to date the 
particular subject under discussion. The various lecturers have 
appreciated this object, and thus helped to make continuous a 
definite policy. 

The secretary takes pleasure in acknowledging the kindness 
of the editors of various journals for permission to reprint the 
following lectures: Science, for the lecture of Dr. Loeb; Journal 
of the American Medical Association for the lectures of Dr. Hess 
and Dr. Foster; Archives of Internal Medicine for the lecture 
of Dr. Wiggers; the American Journal of Medical Science for 
the lecture of Dr. Richards; and the Quarterly Publication of the 
American Statistical Association for the lecture of Sir 
Arthur Newsholme. 


Homer F. Swirt, Secretary. 


THE HARVEY SOCIETY 


A SOCIETY FOR THE DIFFUSION OF KNOWLEDGE OF THE 
MEDICAL SCIENCES 


CONSTITUTION 
I. 
This Society shall be named the Harvey Society. 
Th. 


The object of this Society shall be the diffusion of scientific 
knowledge in selected chapters in anatomy, physiology, pathology, 
bacteriology, pharmacology, and physiological and pathological 
chemistry, through the medium of public lectures by men who are 
workers in the subjects presented. 


TET. 


The members of the Society shall constitute three classes: 
Active, Associate, and Honorary members. Active members 
shall be laboratory workers in the medical or biological sciences, 
residing in the City of New York, who have personally con- 
tributed to the advancement of these sciences. Associate members 
shall be meritorious physicians who are in sympathy with the 
objects of the Society, residing in the City of New York. 
Members who leave New York to reside elsewhere may retain 
their membership. Honorary members shall be those who have 
delivered lectures before the Society and who are neither active 
nor associate members. Associate and honorary members shall 
not be eligible to office, nor shall they be entitled to a vote. 

Members shall be elected by ballot. They shall be nominated 
to the Executive Committee and the names of the nominees 
shall accompany the notice of the meeting at which the vote 
for their election will be taken. 

Ai 


CONSTITUTION 


DW: 


The management of the Society shall be vested in an execu- 
tive committee, to consist of a President, a Vice-President, a 
Seeretary, a Treasurer, and three other members, these officers 
to be elected by ballot at each annual meeting of the Society to 
serve one year. 


V: 


The Annual meeting of the Society shall be held soon after 
the concluding lecture of the course given during the year, at a 
time and place to be determined by the Executive Committee. 
Special meetings may be held at such times and places as the 
Executive Committee may determine. At all the meetings ten 
members shall constitute a quorum. 


VI. 
Changes in the Constitution may be made at any meeting of 


the Society by a majority vote of those present after previous 
notification of the members in writing. 


OFFICERS OF THE HARVEY SOCIETY 


OFFICERS COUNCIL 
1921-1922 1921-1922 
Rurus Coz, President GRAHAM LUSK 
S. R. Benepict, Vice-President Hans ZINSSER 
A. M. PapPpENHEIMER, Treas. H. C. JacKson 
Homer F. Swirt, Secretary W. T. Lonacore 


The Officers Ex-Officio. 


ACTIVE MEMBERS 


Dr. JoHN S. ADRIANCE Dr. F. C. BULLOCK 
Dr. F. M. ALLEN Dr. R. Burton-Opitz 
Dr. H. A. Amoss Dr. G. O. Broun 

Dr. Huan AUCHINCLOSS Dr. WADE H. Brown 
Dr. J. Haroup AUSTIN Dr. ALEXIS CARREL 
Dr. JOHN. AUER Dr. Russett L. Cecm 
Dr. O. T. AVERY Dr. Joon W. CHURCHMAN 
Dr. George BAEHR Dr. A. F. Coca 

Dr. C. V. BAILEY Dr. A. E. Coun 

Dr. F. W. BANcROFT Dr. Rurus Coie 

Dr. W. H. Barser Dr. Ropert CooKE 
Dr. D. P. Barr Dr. C. B. CouLTER 
Dr. Emin BAUMAN Dr. GLENN E. CULLEN 
Dr. Louis BAUMANN Dr. H. D. DakIN 

Dr. 8. R. BENeEpIcT Dr. P. H. pE Kruir 
Dr. HERMANN M. Biaes Dr. A. R. DocHez 

Dr. Caru A. BINGER Dr. E. F. Dusors 
Dr. Francis G. BLAKE Dr. C. B. DUNLAP 

Dr. CHARLES F’. BoLDUAN Dr. P. L. pu Nouy 
Dr. Rautpeu H. Boors Dr. A. H. EBELING 
Dr. Hartow Brooks Dr. WALTER H. Eppy 


Dr, Leo BUERGER Dr. D. J. Epwarps 


ACTIVE MEMBERS—Continued 


. Cary Eaaueston 

. W. J. ELSER 

. A. ELwyn 

. HAVEN EMERSON 

. EpHrar M. Ewine 
. JAMES EWING 

.L. W. FAMULENER 


. Luoyp D. Frutron 
.J.S. FeRGuson 
. Cyrus W. Freip 


. Morris 8S. FIne 


. SIMON F'LEXNER 
. Neuuis B. Foster 
. ALEXANDER F'RASER 


. FRANCIS R. FRASER 
. FREDERICK L. GATES 


. W. J. Geis 


. ALEXANDER O. GETTLER 


. H. R. GEYELIN 

. 8S. GoLDSCHMIDT 

. FREDERIC GOODRIDGE 
. T. W. Hastines 

. Ropert A. HatcHer 
. M. HEMELBERGER 

. A. F. Hess 

. J. G. Hopkins 

. Paut BE. Howe 


. JOHN HOWLAND 

.G. S. HunTINGTON 

. R. G. Hussey 

. Houmes C. Jackson 
. W. A. Jacoss 

. JAMES W. JOBLING 

. Don R. JoserpH 

. D. M. Kapuan 


10 


. JOHN A. Kilian 
. I. S. Kuerner 


. CHARLES KRUMWIEDE 


.R. V. LAMAR 


. Ropert A. LAMBERT 

. Nizs P. Larsen 

. BS. tne 

. E.S. L’ Esperance 

. P. A. LEVENE 

. Isaac LEVIN 

. Ropert L. Levy 

. E. LiBMAN 

. C. C. Lizs 

. WARFIELD T’. LONGCOPE 
. GRAHAM LusK 

. GeRTRUDE F. McCann 
. W.S. McCann 

. F. H. McCruppen 


. W. G. MacCattum 


. GeorceE MacKenzie 
. F. C. McLean 

. P. D. McMastEerR 

. W. J. McNgEau 

. A. R. MANDEL 

. JOHN A. MANDEL 

. F.S. MANDLEBAUM 

. Hupert MANN 

. W. H. MaAnwariIna 


. Davin MARINE 


. ADOLF MEYER 


. G. M. Meyer 

. C. P. MILuer 

. Epaar G. Miuer, JR. 
. L. S. Minne 

. C. V. Morrinu 


ACTIVE MEMBERS—Continued 


. H. O. MosENTHAL 
. J. R. Muruin 

. J. B. MurPHY 

. Victor C. Myrrs 


. W. C. NoBLe 
. Hipeyvo NogucHi 
. CHARLES Norris 


. Horst OERTEL 


. Peter K,. OuItTsKY 


. EUGENE L. OPIE 


. B. S. OPPENHEIMER 
. REUBEN OTTENBERG 
. WALTER W. PALMER 
. A. M. PAPPENHEIMER 
. Wo. H. Park 

. JULIA PARKER 

. F. W. PEABODY 

. LOUISE PEARCE 

. KE. J. PELLINI 

.d. P. PETERS 

we. H>-PiKE 

. Harry PLotz 

. Leo M. PowELu 

. P. V. PREWETT 

. FREDERICK PRIME 

. T. M. PRuDDEN 

. A. N. RicHarps 

. A. I. RINGER 


. G. C. Roprnson 

. G. L. ROHDENBURG 

. A. R. Rose 

. Peyton Rous 

. M. A. RorHscHILp 

. H. Von W. ScHULTE 
. Orro H. ScHULTZE 

. KH. L. Scorr 


11 


H. D. SEnror 
C. P. SHERWIN 


. M J. SirtENFIELD 

. W. C. STAdIEe 

. FRANKLIN A. STEVENS 
. EB. G. STILLMAN 

. EDGAR STILLMAN 

. ARTHUR P. Stout 

. I. STRAUSS 

. OLIVER S. STRONG 

. Homer F.. Swirt 

. DouGLAS SYMMERS 

. OscaR TEAGUE 

iB. Le DERRY 

. Wn. C. THRO 

. FREDERICK TILNEY 
dd. C. TORREY. 

. JAMES D. TRASK, JR. 
. KE. UHLENHUTH 

. D. D. Van SLYKE 

. Karu M. VoceEL 

. W. C. Von GLAHN 

. AuausTtus WADSWORTH 
. A.J. WAKEMAN 

. G. B. WALLACE 

. Wo. H. WELKER 

. J. S. WHEELWRIGHT 
. Cart J. WIGGERS 

. ANNA WILLIAMS 

. H. B. WiuiaMs 

. Ropert J. WILSON 

. Wo. H. WoeLtom 

. Martua WOLLSTEIN 
. JONATHAN WRIGHT 

. Hans ZINSSER 


Dr 
Dr 


ASSOCIATE MEMBERS 


. T. J. ABBoT 
. F. H ALBEE 


Dr. H. L. ALEXANDER 


Dr 


Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 


. R. T. ATKINS 
HaARoLD BAILEY 
Davin N. Barrows 
F. H. BartTLerr 
Water A. BasTEDO 
EpWIN BEER 
CoNRAD BERENS 

. JOSEPH A. BLAKE 
. 8. R. BLAttTeis 

. GEORGE BLUMER 

. ERNEST Boas 

. A. BoOoKMAN 

. Davip Bovairp, JR. 
. S. BRADBURY 

. STANLEY BrRapy 

. J. W. BRANNAN 

. J. BRETTAUER 

. GzorcEe E. BREWER 
. NatHan E. Briuu 
. SAMUEL A. Brown 
. JESSE G. M. BULLOWA 
. Cart BurpDIcK 


. SYDNEY R. BuRNAP 
. GLENTWoRTH R. BuTLER 


. W. E. CALDWELL 
. We. F. CAMPBELL 
. R. J. CARLISLE 


. HERBERT S. CARTER 


. L. CASAMAJOR 

. ARTHUR F.. CHACE 

. H. T. CHICKERING 

. F. Morris Cuass 

. MATHER CLEVELAND 

. CoRNELIUS G. COAKLEY 


12 


Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 


Dr 


Dr. 


Dr 


Martin CoHEN 

L. G. CoLe 

WARREN COLEMAN 
WiuiaM B. CoLey 
Cuas. F. CoLiins 
Lewis A. CONNER 

G. W. CRARY 
EDWARD CUSSLER 
Cuas. L. Dana 
THomMaAs DARLINGTON 
WILLIAM DARRACH 
D. Bryson DELAVEN 
Ep. B. DENcH 
BuakeE F’. DoNALDSON 
W. K. DRAPER 
ALEXANDER DUANE 
THEODORE DUNHAM 
Max Ernuorn 

C. A. ELsBEere 

A. A. EpstTern 
SEWARD ERDMAN 
Evan M. Evans 

S. M. Evans 

Liuuian K. P. Farrar 
MAURICE FISHBERG 
Ep. D. FIsHER 
Ro.Fe FLoyp 

JoHN A. ForDYCE 

R. G. FREEMAN 
Wo.rr FREUNDENTHAL 
E. D. FrrmpMaNn 
Lewis F. FRIssELL 

. H. Dawson FurRnNIss 
CHARLES GOODMAN 

. S. S. GoLDWATER 


Dr. MaLcoumM GOODRIDGE 


Dr. 


RopeEriIcK V. GRACE 


ASSOCIATE MEMBERS—Continued 


Dr. N. W. GREEN 

Dr. J. C. GREENWAY 

Dr. Menas S. GREGORY 
Dr. Rosert H. HAusey 
Dr. JoHN M. Hanrorp 
Dr. T. S. Hart 

Dr. J. H. Harrar 

Dr. Jonn A. HARTWELL 
Dr. H. A. Havusoup 

Dr. Roya S. Haynes 
Dr. Henry HeIMAn 

Dr. W. W. HERRICK 

Dr. C. Gorpon Hryp 

Dr. WALTER HIGHMAN 
Dr. J. Mortey Hitzror 

. FREDERICK C. HoLDEN 
. A. W. Houuis 

. H. A. Houecuton 

. Husert S. Howe 

. FRANCIS HuBER 

. KE. Livineston Hunt 
. Woops HutTcHINSON 
. Harotp T. Hyman 

. H. M. ImpopEn 

. SERGIUS INGERMANN 
. LEOPOLD JACHES 

. Gzo. W. JACOBY 

. RALPH JACOBY 

. WALTER B. JAMES 

. 8. E. JELIFFE 

. FREDERICK KAMMERER 
. L. Kast 

. JACOB KAUFMANN 

. F. L. Keays 

Dr. Foster KENNEDY 
Dr. C. G. KERLEY 

Dr. Luo KEssen 


13 


Dr 
Dr 


Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 


. KE. L. KEyEs, JR. 
. R. A. KINSELLA 
GerorceE H. Kirsy 
ARNOLD KNAPP 
ALBERT R. LAMB 

E. Linnarus La Fetra 
ADRIAN V.S. LAMBERT 
ALEXANDER LAMBERT 
S. W. LAMBERT 
BoLEsLaw LAPOWSKI 
Berton LATTIN 

B. J. LEE 

JEROME S. LEOPOLD 
. L. T. LEWatp 


. RICHARD LEWISOHN 


. Evi Lone 


. Wo. C. Lusk 
. D. Hunter McALpPIn 


. KENNETH McALPIN 


. JoHN McCoy 


. CHarRLtes A. McKRENDREE 


. L. B. MACKENZIE 
. JOHN T. MacCurpy 


. Morris MANGES 


. GeorcE MANNHEIMER 


. WALTON MARTIN 


. Howarp H. Mason 


. FRANK S. Meara 


. Victor MELTZER 


. ALFRED MEYER 
. Witty MEYER 
. MicHAEL MICHAILOVSKY 


. G. N. Miner 


. JAMES ALEXANDER MILLER 
. A. V. MoscHow1Tz 

. Ext MoscHowI1tz 

. ARCHIBALD Murray 


ASSOCIATE MEMBERS—Continued 


. JOHN P. MuNN 

. JAMES F’. NaGueE 
. P. W. NATHAN 

. A. E. NEERGAARD 
. Harotp NEUHOF 


. WALTER Li. NILES 
. VAN Horne Norrie 


.N. R. Norton 
. W. P. NortTHrup 
. ALFRED T. Oscoop 


. H. Mc. M. PantTER 


. ELEANOR PARRY 

. W. B. Parsons 

. STEWART PATON 

. Henry S. PATTERSON 
. RicHarp M. PEARCE 
. CHas. Hi: Prox 


. JAMES PEDERSON 


. FREDERICK PETERSON 


. SIGISMUND POLLITZER 


. EUGENE H. Poon 
. Epwarp L. Pratt 
. Wo. J. PULLEY 

. Ep. QUINTARD 


. Francis M. RACKAMANN 


. Minton RAIsBECK 
. R. G. REESE 
. FREDERICK W. RICE 


. JOHN H. RIcHARDS 


. Henry B. RicHARDSON 
. A. F. Riees 

. Henry A. RILEY 

. ANDREW R. ROBINSON 

. J. C. ROPER 

. BERNARD SACHS 

. T. W. SALMON 


14 


Dr. 
Dr. 
Dr. 


Dr 


BERNARD SAMUELS 
B. J. SANGER 
Tuos. B. SATTERWHAITE 


. REGINALD H. SAYRE 
Dr. 
. H. J. Sco wartz 

. Howarp F. SHarruck 
. E. P. SHELBY 

. WiiuiAM H. SHELDON 

. H. M. SInver 

. ALAN DE F. SmitH 

. HaRMoN SMITH 

. M. DeForest Smite 

. THayer A. SMITH 

. R. G. SNYDER 

. F. P. SouLEY 

. KF. KE. SonDERN 

. J. BENTLEY SQUIER, JR. 
. F. B. St. JoHN 

. Wo. P. St. LAWRENCE 
. WM. STEINACH 

. ANTONIO STELLA 

. ABRAM R. STERN 

. GeorGE D. STEWART 

. A. R. STEVENS 

. LEO. STIEGLITZ 

. RALPH G. STILLMAN 

. Puitie STIMSON 

. WiuuiAM §S. STONE 

. A. McI. Strone 

. Mitts STURTEVANT 

. A. S. TAYLOR 

. JOHN 8S. THACHER 

. A. M. THomas 

. WiuuiAM B. TRIMBLE 

. CoRNELIUS J. TYSON 


Oscar M. ScHioss 


ASSOCIATE MEMBERS—Continued 


Dr. F. T. Van BEvREN, JR. 
Dr. Pumire VAN INGEN 

Dr. ALBERT VANDER VEER 
Dr. H. A. VERMILYE 

Dr. J. D. VOORHEES 

Dr. S. WACHSMANN 

Dr. R. P. WADHAMS 

Dr. JoHN B. WALKER 

Dr. Grorce G. Warp 


Dr. JAMES SEARS WATERMAN 


Dr. R. W. WEBSTER 
Dr. JoHN E. WEEKS 


PROF 
PrRor 
PrRor 


Dr. Wess W. WEEKS 
Dr. HERBERT WIENER 
Dr. RicHARD WIENER 
Dr. A. O. WHIPPLE 

Dr. H. B. WiLcox 

Dr. Linsty R. WiLuiAMs 
Dr. Marcaret B. Winson 
Dr. JosepH E. WINTERS 
Dr. J. OGDEN WoopRUFF 
Dr. J. H. Wyckorr 

Dr. CHARLES H. Youne 
Dr. JOHN Van Doran YouNG 


HONORARY MEMBERS 


. J. G. ADAMI 
. C. A. ALSRERG 
. J. F. ANDERSON 


Pror. E. R. BALDWIN 
Mr. Jos. Barcrort, F. R. 8. 


PROF 


. LEWELLYS F’. BARKER 


Pror. F. G. BENEDICT 
Pror. R. R. BENSLEY 
Dr. J. BorDET 


PRoF. 
PRoF. 
PRoF. 


PRor 


PRoF. 


PrRor 


PRor. 
PRor. 
PrRor. 
PROF. 
PROF. 
PRor. 
PRor. 
PRoF. 


A. CALMETTE 

W. B. CANNON 

A. J. CARLSON 

. W. E. Caste 
Cuas. V. CHAPIN 

. R. H. CuoitTENDEN 
H. A. CuristIaAn 
E. G. ConKLIN 

W. T. CouNCILMAN 
G. W. Crite 
Harvey CusHING 
ARTHUR CUSHNY 
H. H. Date 
Henry H. DoNALDSON 


Pror. GEORGES DREYER 
Pror. Davin L. EpsALu 
Pror. JOSEPH ERLANGER 
Pror. Orro FoLin 
Pror. F. P. Gay 
Pror. J. 8S. HALDANE 
Pror. W .S. HALsTEApD 
Pror. Ross G. Harrison 
Pror. SveN G. HeEpDIN 
Pror. Lupwig HEKTOEN 
Pror. L. H. HENDERSON 
Pror. YANDELL HENDERSON 
Pror. W. H. Howe. 
Pror. Cart G. HuBER 
Pror. JOSEPH J ASTROW 
Pror. H. S. JENNINGS 
Pror. E. O. JoRDAN 
Pror. E. P. Josuin 
Dr. E. C. KENDALL 
Dr. ALLEN K. KRAUSE 
Pror. J. B. LEATHES 
Pror. A. Magnus Levy 
Pror. Pauut A. Lewis 

15 


ASSOCIATE MEMBERS—Continued 


Pror. THomas LEwIs 

Dr. C. C. Little 

Pror. JACQUES LOEB 

Pror. A. S. LOEWENHART 
Pror. A. B. MacCaLtutum 
Pror. J. J. R. MacLeop 
Pror. E. V. McCottuM 
Pror. F. B. MALLory 
Pror. W. McKim Marriott 
Pror. L. B. MENDEL 

Pror. T. H. Morgan 

Sm ArtHuR NewsHouME, M.D. 
Pror. Frep G. Novy 

Pror. G. H. F. Nutrauu 
Pror. Henry FAIRFIELD OSBORN 
Pror. T. B. OSBORNE 

Dr. W. J. V. OSTERHOUT 
Pror. G. H. PARKER 

Dr. RAYMOND PEARL 
Pror. CLEMENS PIRQUET 
Pror. W. T. PoRTER 

Pror. T. W. RIicHARDS 
Pror. M. J. Ros—ENau 

Cou. E. F. RussELL 

Pror. FLORENCE R. SaBIN 
Sir E. A. ScHAEFER 

Pror. THEOBALD SMITH 
Pror. Henry C. SHERMAN 
Pror. E. H. STARLING 
Pror. G. N. STEWART 


Pror. C. W. STmEes 

Dr. C. R. StocKarpD 
Pror. RicHArD P. STRONG 
Pror. A. E. TAYLor 
Pror. W. S. THAYER 
Pror. F. P. UNDERHILL 
Pror. Victor C. VAUGHAN 
Dr. CARL VOEGTLIN 
Pror. KARL vON NoOORDEN 
Pror. A. D. WALLER 
Pror. A. S. WARTHIN 
Pror. J. CLARENCE WEBSTER 
Pror. Wm. H. WELCH 
Pror. H. GipzEoN WELLS 
Dr. Gro. H. WHIPPLE 
Cou. EUGENE R. WHITEMORE 
Pror. E. B. Winson 
Pror. J. GoRDON WILSON 
Pror. 8. B. WoLBacH 
Pror. R. T. Woopyatt 
Sir ALMROTH WRIGHT 
Masor R. M. YERKES 
Pror. WM. Fata 

Pror. OTto KESTNER 
Pror. Franz Knoop 
Pror. ALBRECHT KossEL 
Pror. Hans Horst Mreyer 
Pror. FRIEDRICH MULLER 
Pror. Max RuBNER 

Pror. Max VERWORN 


DECEASED MEMBERS 


Dr. Isaac ADLER 

Dr. SAMUEL ALEXANDER 
Dr. W. B. ANDERTON 

. PEARCE BAILEY 

Dr. Botton Banes 


Dr. J. B. BoRDEN 

Pror. T. G. Bropre 

Dr. F. TipDEN Brown 

Dr. S. M. BricKNER 

Dr. JOSEPH D. BRYANT 
16 


Dr. 


DECEASED MEMBERS—Continued 


CarL Beck 


Pror. Hans CHIari 


Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
. Emit GRUENING 

. FRANK HARTLEY 

. CHRISTIAN A. HERTER 

. Puiuie Hanson Hiss 

. Aucustus Hocu 

. EUGENE HopENPYL 

. JoHN H. HuppLeston 

. ABRAHAM JACOBI 

. Epwarp G. JANEWAY 

. THEODORE C. JANEWAY 
. H. H. JANEway 

. E. L. Keyes 

Dr. 
Dr. 
Dr. 
Dr. 
Dr. 
Dr. 


JOHN G. CuRTIS 
Epwin B. Cracin 
Fioyp M. CranpaLu 
E. K. DuNHAM 
AvsTIN Fuint 
JOSEPH FRAENKEL 
C. Z. GARSIDE 


Francis P. Kinnicutt 
HERMANN Knapp 
GusTAvE LANGMAN 
Eepert Le Frevre 
Cuas. H. Lewis 
SIGMUND LusTGARTEN 


Dr. W. B. Marpie 

Dr. Cuas. McBurney 
Dr. George McNauauton 
Dr. S. J. Mevrzer 

Dr. CHarugs 8S. Minor 
Dr. S. Wetr MircHe.n 
Dr. Goprrey R. Pisex 
Dr. G. R. Pogur 

Dr. Wiuu1AM M. Pox 
Dr. NATHANIEL B. Porrer 
Pror. J. J. PutMAan 

Dr. C. C. Ransom 

Dr. E. F. Sampson 

Pror. Apotex ScHMipT 
Pror. W. T. Sepawick 
Dr. Wo. K. Simpson 
Dr. A. ALEXANDER SMITH 
Dr. Ricuarp Stew 

Dr. H. A. Stewart 

Dr. L. A. Stimson 

Dr. W. Hanna THompson 
Dr. WISNER R. TOWNSEND 
Dr. R. VAN SANTVOORD 
Dr. H. F. WaLKER 

Dr. Ricuarp WEIL 

Dr. H. F. L. Zeer 


17 


CONTENTS 


Pace 
iheserotems) and Colloidal Chemistry... 2.65.66 deh es ase cece ors cote 23 
Jacques Lors—Rockefeller Institute for Medical Research. 
iinemeneonies,oL Blood: Coagulation a. ccciccs 5. cs einle ccc so ciao wickets oe e's 36 
Jutes Borpet—Director of the Pasteur Institute of Brussels. 
UPRLSEREES & bc6'00: CeO RR RRS POL GREE ORCS CE CC ea ee Te ae ee 52 


Neus B. Foster—Assistant Professor of Medicine, Cornell 
University Medical College. 


The Present Status of Cardio-Dynamic Studies on Normal and Patho- 66 
logical Hearts. 
Cari J. Wiacers—Professor of Physiology, Western Reserve 
University. 


Newer Aspects of Some Nutritional Disorders...................... 100 
AutFrreD F. Hess—Professor of Clinical Pediatrics, New York 
University and Bellevue Hospital Medical College. 


National Changes in Health and Longivity................65.00000: 124 
Str ArTHUR NEwsHOLME—Resident Lecturer in Charge of Public 
Health Administration, School of Hygiene and Public 
Health, Johns Hopkins University. 


MMS M TERED sy o0 Foto ce t's os Uo, Gesis. Hes ve ins B ojei ws a OE SENS He colet te 163 
A. N. RicHarps—Professor of Pharmacology, University of 
Pennsylvania. 

IEMEECE MUR EMICICO ELSIE s\0) acto w/a. 6 6 sic sia s)2 leveidiawie 4 dele ew erele aoe ele ae velae 188 


S. B. Wo.pacH—Associate Professor of Pathology and Bacteri- 
ology, Harvard University. 


Sane HAINICS OL IVELIBGIE:s | 5, oie bs od cc voles ele cle’ 0 Sela ab se alee tne 210 
F. Gowtanp Horxins—Professor of Biochemistry, University 
of Cambridge. 


ILLUSTRATIONS 


PAGE 


The ordinates represent the c.c. of O. 1. N. acid in 100 c.c. of 1 per cent 
solution of isoelectric gelatin required to bring the solution to the p. 
Pernod ted tla Tne ADACIESE, «3.7 Gena chiale-c laa bo) SAA Su otaelos gore nsie 30 


Influence of different acids upon the swelling of gelatin when plotted 
OVCED MEH AS ATUADSCISSEBL nln craves ails sie accinw e cuctomre enact bste oieulee 33 


Schematic representations of principles employed to record pressure 
curves optically from auricles, ventricles and aorta.............. 69 


Superimposed curves of pressure changes in ventricle, aorta and auricle 70 
Series of pictorials illustrating the consecutive phases of the cardiac cycle 


established from pressure and volume curves................... 72 
Diagram showing arrangement of muscle activating a work adder..... 77 
Diagrammatic representation of ventricular volumes and pressure changes 

ro) WHECTA, AGCEEAETEAS( (2) Ak ROE SAR Sees NR ile ka ogre ery Caer Pena cro nee eae 80 
Diagrammatic representation of pressure changes in right and left 

apRL MAAR yt yc yn the. Sees fiatiays, Ale eave ysis aay ee cis wtotoais, © oes 81 
Superimposed tracings of right and left intraventricular pressure curves, 

ECCI RMEFIMENGS OF AULNOM: << 2 s\c/4 34-4 arevasciae og sles ae cs leiele odd de 87 
Series of diagrammatic volume curves showing mechanical decrease in 

diastolic volume when the heart accelerates................... 94 
Diagram illustrating principle of measuring volume—elasticity coefficient 

SUmPmEPECRE CRC OTAUEICIGR a rode ce # ycrer oa eee ete oy heir NCE tev ale) eed ener 96 
Result of microscopic study of the bones of 386 consecutive necropsies 

RPAMMBIRSEEEL SNIPS rh iui rhe aaa Sains: Stic ocbked acs, sia ecayeete ta 113 
An aspect of the calcium metabolism in rickets..................-005 118 
Life Table experience, England and Wales, for four periods............ 135 
Life Table experience of the United States (1909-11) ..............: 141 
Death rate per million males at each age period in 1881-90 and 1901-10 145 
Illustrating transference of causes of death..............20 0.000000 147 
Death rate per million males at each age period over 25 in 1881-90 and 

EINER errr eo yt) cy chats Lit he cuays yA uel aiava eid Mh Naa BT, oe 148 
Death rate per million males at different age periods in 1881-90 and 

Lo Lely 5 eal RRs ABO RU Ae Poa Ree Ae ote dee La fe Mer niin 149 
Death rate per million males at different age periods in 1881-90 and 

EMMONS IS) Mey one Na Sys NY airs kh leper aan fei Mee Wate castes we agaiaiagtes a 153 


Showing the number of survivors at each successive year of life out of 
1,000 infants born in England and Wales and in selected healthy 


RETR TEEN Sroka. Phare a el Gra ecg ds eed ual eas a tuatelel a Gam aaatats 161 
Smear preparation, gut of louse infected with Rickettsia prowazeki.... 209 
Early typhus lesion in a human artery of the skin.................... 209 
Rickettsia prowazeki in endothelial cells of a capillary of the skin..... 209 


Cell distended with Rickettsia from the stomach epithelium of an experi- 
MEPL UsIN LO CLC MOUSE), «55 4105 o:sare nia) svete pein Sins vo aw ar omanel le, Dncudlnta 8 209 


A 


THE PROTEINS AND COLLOIDAL 
CHEMISTRY* 


DR. JACQUES LOEB 
Rockefeller Institute for Medical Research 


I 


HE proteins, like certain other constituents of protoplasm, 
are colloidal in character, 7. e., they are not able to diffuse 
through animal membranes which are permeable to erystalloids. 
For this reason a number of authors have tried to explain the 
behavior of proteins from the viewpoint of the newer concepts 
of colloid chemistry. Foremost among these concepts is the idea 
that the reactions between colloids and other bodies are not 
determined by the purely chemical forces of primary or second- 
ary valency but follow the rules of ‘‘adsorption.’’ Although a 
number of authors, during the last twenty years, e.g., Bugarszky 
and Liebermann, Hardy, Pauli, Robertson, Sorenson, and others, 
have advocated a chemical conception of the reactions of pro- 
teins, their experiments failed to convince the other side since 
these experiments could just as well be explained on the basis 
of the adsorption theory. There were two reasons for this failure: 
First, the experiments did not show that ions combined with 
proteins in the typical ratio in which the same ions combine with 
erystalloids. This proof only became possible when it was recog- 
nized that the hydrogen ion concentration of the protein solu- 
tion determines the amount of ion entering into combination with 
a protein, and that therefore the ratios in which different ions 
combine with proteins must be compared for the same hydrogen 
ion concentrations. Since the former workers were in the habit 
of comparing the effects of the same quantities of acid or alkali 
*Delivered October 16, 1920. 
The writer’s experiments, on which this address is based, have appeared 
in the J. Gen. Physiol., 1918-19, I., 39, 237, 363, 483, 559; 1919-20, II.; 87; 
1920-21, III., 85. 


23 


24 HARVEY SOCIETY 


added instead of comparing the behavior of proteins at the same 
hydrogen ion concentration they were not able to furnish the 
final proof for the purely chemical character of the combination 
between ions and proteins, and nothing prevented chemists from 
assuming that proteins formed only adsorption compounds with 
acids, bases, and neutral salts. 

The second reason for the failure to prove the purely chemical 
character of the protein compounds lay in the so-called Hof- 
meister series of ion effects. Hofmeister was the first to invest- 
igate the effects of different salts on the physical properties of 
proteins, and he and his followers observed that the relative 
effects of anions on the precipitation, the swelling, and other 
properties of proteins were very definite and that the anions could 
be arranged in definite series according to their relative efficiency, 
the order being independent of the nature of the cation. Similar 
series were also found for the cations, though these series seemed 
to be less definite. These Hofmeister series were a puzzle inas- 
much as it was impossible to discover in them any relation to 
the typical combining ratios of the ions, and this lack of chem- 
ical character in the Hofmeister series induced chemists to ex- 
plain these series on the assumption of a selective adsorption of 
these ions by the colloids. 

To illustrate this we will quote the order which, according 
to Pauli, represents the relative efficiency of different acids on 
the viscosity of blood albumin, 


HCl = monochloracetic > oxalic > dichloracetic < citric < acetic = 
sulfuric > trichloracetic acid, 


where HCl increased the viscosity most and trichloracetie or 
sulfuric least. In this series the strong monobasic acid HCl is 
followed by the weak monochloracetic¢ acid, this is followed by 
the dibasic oxalic acid ; later follows the weak tribasiec citric acid, 
then the very weak monobasic acetic acid, then the strong dibasic 
sulfuric acid, and finally again a monobasic acid, trichloracetiec. 
Pauli is a believer in the chemical theory of the behavior of 
proteins but it is impossible to harmonize his series of anions 
with any purely chemical theory of the behavior of proteins. 
The ion series of Hofmeister are no more favorable for a 


PROTEINS AND COLLOIDAL CHEMISTRY 25 


chemical conception. Thus, according to Hofmeister, gelatin 
swells more in chlorides, bromides and nitrates than in water, 
while in acetates, tartrates, citrates or sugar it swells less than 
in water. R. Lillie arranges ions according to their depressing 
effect on the osmotic pressure of gelatin solution in the follow- 
ing way, 

Cl > SO, > NO; > Br > I > ONS. 

These series again betray no relation to the stoichiometrical 
properties of the ions. As long as these Hofmeister series were 
believed to have a real existence it seemed futile to decide for or 
against a purely chemical theory of the behavior of colloids since 
even with a bias in favor of a chemical theory the Hofmeister 
series remained a puzzle. 

The writer believes to have removed these difficulties by using 
protein solutions of the same hydrogen ion concentration as the 
standard of comparison. In this way he was able to show that 
acids, alkalies, and neutral salts combine with proteins by the 
same chemical forces of primary valency by which they combine 
with ecrystalloids, and that, moreover, the influence of the different 
ions upon the physical properties of proteins can be predicted 
from the general combining ratios of these ions. The so-called 
Hofmeister series have no real existence, being the result of the 
fact that the older workers failed to measure the most important 
variable in the case, namely the hydrogen ion concentration of 
their protein solutions, a failure for which they can not be blamed 
since the methods were not sufficiently developed. 


II 


Pauli and a number of other workers assume that both ions 
of a neutral salt are adsorbed simultaneously by non-ionized 
protein molecules. If we consider the hydrogen ion concentra- 
tion of the proteins we can show that only the cation or only the 
anion or that neither ion can combine at one time with a protein; 
and that it depends solely on the hydrogen ion concentration of 
the solution which of the three possibilities exists. 

Proteins exist in three states, defined by their hydrogen ion 
concentration, namely, (a) as non-ionogenic or isoelectric protein, 


26 HARVEY SOCIETY 


(b) metal proteinate (e. g., Na or Ca proteinate), and (c) protein- 
acid salts (e. g., protein chloride, protein sulfate, ete.). We will 
use gelatin as an illustration. At one definite hydrogen ion con- 
centration, namely 10°+7 N (or in Sérensen’s logarithmic symbol 
at pH—4.7), gelatin can combine practically with neither anion 
not cation of an electrolyte. At a pH>4.7 it can combine only 
with cations (forming metal gelatinate, e.g., Na gelatinate), at 
a pH<4.7 it combines with anions (forming gelatin chloride, 
ete.). This was proved in the following way: Doses of 
1 gm. of finely powdered commercial gelatin (going through 
sieve 60 but not through 80), which happened to have 
a pH of 7.0, were brought to a different hydrogen ion 
concentration by putting them for 1 hour at about 15° C. into 
100 e.c. of HNO, solutions varying in concentration from M/8192 
to M/8. After this they were put on a filter, the acid being al- 
lowed to drain off, and were washed once or twice with 25 e.c. 
of cold water (of 5° C. or less) to remove remnants of the acid 
between the granules of the powdered gelatin. These different 
doses of 1 gm. of gelatin now possessing a different pH were all 
put for 1 hour into beakers containing the same concentration, 
e. g., M/64, of silver nitrate at a temperature of 15°C. They 
were then put on a filter and washed 6 or 8 times each with 25 e.c. 
of ice cold water; the wash water must be cold since otherwise 
the particles will coalesce and the washing will be incomplete. 
This washing serves the purpose of removing the AgNO, held in 
solution between the granules, thus allowing us to ascertain where 
the Ag is in combination with gelatin and where it is not in 
combination, since the Ag not in combination with gelatin can be 
removed by the washing while the former can not, or at least only 
extremely slowly by altering the pH. After having removed the 
AgNO, not in combination with gelatin by washing with ice cold 
water we melt the gelatin by heating to 40° C., adding enough 
distilled water to bring the volume of each to 100 c.c., deter- 
mine the pH of each solution potentiometrically or colori- 
metrically, and expose the solutions in test-tubes to light, 
the previous manipulations having been earried out in a 
dark room (with the exception of the determination of pH, 


PROTEINS AND COLLOIDAL CHEMISTRY 27 


for which only part of the gelatin solution was used). In 
20 minutes all the gelatin solutions with a pH>4.7, i.e., from. 
pH 4.8 and above, become opaque and then black, while all the 
solutions of pH <4.7,7.¢., from 4.6 and below, remain transparent 
even when exposed to light for months or years. The solutions 
of pH 4.7 become opaque, but remain white, no matter how long 
they may have been exposed to light. At this pH—the isoelectric 
point—gelatin is not in combination with Ag, but it is insoluble. 
Hence the eation Ag is only in chemical combination with gelatin 
when the pH is>4.7. At pH 4.7 or below gelatin is not able to 
combine with Ag ionogenically. This statement was confirmed 
by volumetric analysis. 

The same tests can be made for any other cation the presence 
of which can be easily demonstrated. Thus when powdered gela- 
tin of different pH is treated with NiCl, and the NiCl, not in com- 
bination with gelatin be removed by washing with ice cold water, 
the presence of Ni can be demonstrated in all gelatin solutions with 
a pH >4.7 by using dimethylglyoxime as an indicator. All gela- 
tin solutions of pH of 4.8 or above assume a crimson color upon 
the addition of dimethylglyoxime, while all the others remain 
colorless. When we treat gelatin with copper acetate, and wash 
afterwards, the gelatin is blue and opaque when its pH is 4.8 or 
above, but is colorless and clear for pH<4.7. Most striking are 
the results with basic dyes, e. g., basic fuchsin or neutral red, after 
sufficient washing with cold water; only those gelatin solutions 
are red whose pH is above 4.7, while the others are colorless. 

On the acid side of the isoelectric point, 7.e., at pH <4.7, the 
gelatin is in combination with the anion of the salt used. This 
can be demonstrated in the same way by bringing different doses 
of powdered gelatin to different pH and treating them for one 
hour with a weak solution of a salt whose anion easily betrays 
itself, e. g.. M/128 K,Fe(CN),. If after this treatment the 
powdered gelatin is washed six times with cold water to remove 
the Fe(CN), not in chemical combination with gelatin and if 
1 per cent. solutions of these different samples of gelatin are made, 
it is found that when the pH is<4.7 the gelatin solution turns 
blue after a few days (due to the formation of ferric salt), while 


28 HARVEY SOCIETY 


solutions of gelatin with a pH of 4.7 or above remain perman- 
ently colorless. Hence gelatin enters into chemical combination 
with the anion Fe(CN), only when pH is <4.7. The same can 
be demonstrated through the addition of ferric salt when gelatin 
has been treated with NaCNS, the anion CNS being in combina- 
tion with gelatin only where the pH is<4.7. Acid dyes, like 
acid fuchsin, combine with gelatin only when pH is<4.7. 

In this way it can be shown that when the pH is<4.7 gelatin 
can combine only with cations; when the pH is >4.7 gelatin can 
combine only with anions, while at pH 4.7 (the isoelectric point) 
it can combine with neither anion nor cation. The idea that 
both ions influence a protein simultaneously is no longer tenable. 

It also follows that a protein solution is not adequately defined 
by its concentration of protein but that the hydrogen ion concen- 
tration must also be known, since each protein occurs in three 
different forms—possibly isomers—according to its hydrogen 
ion concentration. 

In the experiments just discussed it was necessary to wash 
the powdered gelatin to find out at which pH an ion was in com- 
bination with the gelatin. This has led some authors to the belief 
that in all my experiments the washing was a necessary part of 
the procedure. I therefore will call especial attention to the fact 
that the experiments to be described in the rest of the paper were 
carried out with isoelectric gelatin to which just enough acid or 
alkali was added to bring it to the hydrogen ion concentration 
required for the purpose of the experiment. 


III 


When a protein is in a salt solution, e. g., NaCl, it will combine 
with Na forming sodium proteinate as soon as the pH is higher 
than the isoelectric point of the protein; when, however, the pH 
falls below that of the isoelectric point of the protein the Na is 
given off and protein chloride is formed. 

Moreover, the writer has been able to show by volumetric 
analysis that the quantity of anion or cation in combination with 
the protein is an unequivocal function of the pH. When we add 
HCl to isoelectric gelatin and determine the pH we always find 


PROTEINS AND COLLOIDAL CHEMISTRY 29 


the same amount of Cl in combination with a given mass of orig- 
inally isoelectric gelatin for the same pH; so that if we know the 
pH and the concentration of originally isoelectric gelatin present 
we can also tell how much Cl is in combination with the protein 
for this pH. The same is true when we add an alkali to the iso- 
electric gelatin. For the same pH the amount of cation in com- 
bination is always the same. These facts have led the writer to 
propose the following theory. When we add an acid, e. g., HCl, 
to isoelectric gelatin (or any other isoelectric protein) an equili- 
brium is established between free HCl, protein chloride, and 
non-ionogenic or isoelectric protein; when we add alkali an equili- 
brium is established between metal proteinate, non-ionized pro- 
tein, and the hydrogen ions. Sorensen was led to a similar view 
on the basis of entirely different experiments. 


IV 


This fact that the hydrogen ion concentration of a protein 
solution determines the quantity of protein salt formed is the 
basis on which the following proof for the purely chemical char- 
acter of the combination between proteins and other bodies rests. 
The experiments mentioned thus far in this paper do not yet 
allow us to decide whether the ions are ‘‘adsorbed”’ or in chemical 
combination with the proteins. We will now show that acids 
and bases combine with proteins in the same way as they com- 
bine with crystalline compounds, namely by the purely chemical 
forces of primary valency. The combination between acids and 
proteins, is analogous to that between acids and NH,, and 
the combination between bases and proteins is analogous 
to that between CH,COOH and an alkali. This can be proved 
in the following way. We know that a weak dibasic or tribasic 
acid gives off one hydrogen ion more readily than both or all 
three; while in a strong dibasic acid, like H,SO,, both hydrogen 
ions are held with a sufficiently small electrostatic force to be 
easily removed. If the forces which determine the reaction 
between these acids and proteins are purely chemical it would 
follow that three times as many c.c. of 0.1N H,PO, are required 
to bring 100 c.c. of 1 per cent. solution of isoelectric gelatin to 


30 HARVEY SOCIETY 


a given pH, e. g., 3.0, as are required in the case of HNO, or HCl; 
while twice as many c.c. of 0.1N oxalic as of HNO, should be re- 
quired. On the other hand, it should require just as many c.c. 


| a 

HEEEEEEEEEEEE EE 

At ist | |) Uh aa 

—\-A\ 
| 


HHA ESE 
CEEEE EEE SSE 


pit 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 


Fic. I.—The or painates represent the c.c. of 0.1 N acid in 100 c.c. of r per cent. solution 

of isoelectric gelatin requ paced to bring the aatabaens to the pH indicated in the abscisse. e 

ine for 0.1 N He SO; and o.1 H NOs are ide aise al while the values for Piles: and oxalic 
differ, being approximately in the ratio of HNOs: oma ic acid: H3sPOu as 1:2:3 

of in IN H,SO, as HNO,. Fig. 1 ue that this is the case. The 

ordinates of ay figure are the c.c. of 0.1 N acid required to bring 


1 gm. of isoelectric gelatin to the pH indicated in the abscisse 


PROTEINS AND COLLOIDAL CHEMISTRY 31 


by the four acids mentioned, namely HNO,, H,SO,, oxalic, and 
phosphoric acids. The curves for H,SO, and HNO, are identical 
while, for the same pH, the value for H,PO, is always approxi- 
mately three times and the value for oxalic acid is always ap- 
proximately twice as high as for HNO,. 

On the basis of the same reasoning as applied to acids we 
should expect that equal numbers of c.c. of 0.1 N Ca(OH), and 
Ba(OH), as of LiOH, NaOH, and KOH should be required to 
bring 100 c.c. of a 1 per cent. solution of isoelectric gelatin to the 
same pH, and the writer was able to show that this is the ease. 


TABLE I 


C.c. of 0.01 N Acid in Combination with 10 c.c. of a 1 Per Cent. Gelatin 
Solution at Different pH 


Similar results were obtained with crystalline egg albumin. 

When we have a solution of a gelatin-acid salt of originally 
1 per cent. isoelectric gelatin and of a certain pH, e. g., 3.0, we 
have free acid in the solution and a certain amount of the anion 
of the acid in combination with gelatin. We can find out by 
volumetric analysis how much of the anion is in combination with 
the protein by making certain corrections discussed in former 
papers. In this way it can also be ascertained that all weak 
dibasic acids combine in molecular proportions with isoelectric 
protein, while strong dibasic acids and diacidie alkalies combine 
in equivalent proportions with proteins, as is shown by Table I. 
It follows from this table that for the same pH the amount of 
HNO,, oxalic, and phosphorie acids in combination with the same 
quantity of originally isoelectric gelatin is always in the pro- 
portion of 1 :2 :3. 

We can therefore state that the ratios in which ions combine 
with proteins are identical with the ratios in which the same ions 


32 HARVEY SOCIETY 


combine with erystalloids. Or in other words, the forces by 
which gelatin and egg albumin (and probably proteins in gen- 
eral) combine with acids or alkalies are the purely chemical 
forces of primary valency. 


We 


The most important fact for our purpose is that from the 
combining ratios just mentioned the influence of acids and bases 
on the physical properties of proteins can be predicted. This 
influence is altogether different from that stated in the so-called 
Hofmeister series of ions or by the ion series of Pauli and his 
collaborators, and this difference is due to the fact that these latter 
authors compared the effects of equal quantities of acids or 
alkalies while we found it necessary to compare the physical 
properties of solutions of proteins of the same hydrogen ion 
concentration. If this is done the following rule is found. All 
those acids whose anion combines as a monovalent ion raise the 
osmotie pressure, viscosity, swelling of protein about twice as 
much as the acids whose anion combines as a bivalent anion for 
the same pH. The same valency rule holds for the cations of 
different alkalies. 

We have seen that at the same pH three times as many e.c. 
of 0.1 NH,PO, as of HNO, are in combination with 1 gm. of 
originally isoelectric gelatin in 100 cc. of solution. It follows 
from this that the anion of gelatin phosphate is the monovalent 
ion H,PO, and not the trivalent anion PO,. It follows likewise 
from the combining ratios discussed that the anion of oxalic acid 
in combination with protein is the monovalent anion HC,O,. The 
same is true for all weak dibasic or tribasie acids, namely that 
they combine with proteins forming protein salts with monovalent 
anion. It follows also from the combining ratios that the salt 
of a protein with a strong dibasic acid, as H,SO,, however, must 
have a divalent anion, e. g., SO, If we compare the viscosity 
or osmotic pressure of 1 per cent. solutions of originally iso- 
electric gelatin with different acids of the same pH we find that 
these properties are identical for all gelatin salts with monovalent 
anion; in other words, 1 per cent. solutions of gelatin chloride, 


PROTEINS AND COLLOIDAL CHEMISTRY 33 


brontide, nitrate, tartrate, succinate, citrate, or phosphate have 
all the same viscosity, and the same osmotic pressure at the same 
pH. The same is true for the swelling (Fig. 2). If we plot 
the curves for these three properties with pH as abscisse and the 


Hho ee 
atu 
Bah 


Relative volume of 1qm of solid gelatin 


ott L ANN eee 5 6 
Fic. II.—Influence of different acids upon the swelling of gelatin when plotted over pH as 
abscisse. The curves show that nitric, trichloracetic, hydrochloric, phosphoric, oxalic, and 
citric acids cause approximately the same degree of swelling, while sulfuric acid causes only 
about one half the amount of swelling. In the case of gelatin sulfate the anion is divalent; 
in the case of the other acids used it is monovalent. According to the Hofmeister series the 
curves for phosphate, oxalate and citrate should coincide with that of sulfate instead of 
coinciding with that of coloride. 


values for osmotic pressure, viscosity, and swelling as ordinates, 
we get practically identical curves for gelatin chloride, bromide, 
nitrate, tartrate, succinate, citrate, and phosphate. The values 
for swelling are a minimum at pH 4.7 (the isoelectric point of 
gelatin) they rise rapidly with the fall of pH until they reach 
@ maximum at pH about 3.2, and then they drop again. Each 
curve is the expression of an individual experiment. The maxi- 
mum in the curves for gelatin chloride, bromide, nitrate, tartrate, 
succinate, citrate, and phosphate is practically identical, the vari- 
ations between the values for these acids lying within the limit 
3 


34 HARVEY SOCIETY 


of variation which we may expect if we plot six different experi- 
ments with the same acid. When, however, we plot the same 
eurves for gelatin sulfate, we get curves which are considerably 
lower, reaching a height of only one half (or a little less than) 
those of gelatin-acid salts with monovalent anions. It may be 
of interest to compare our curves with those expected on the basis 
of Pauli’s and Hofmeister’s ion series. According to the latter 
theory the curves for phosphates, oxalates, citrates, and tartrates 
should be in the region of the SO, curve but not in the region of 
the Cl curve. Those authors who observed such differences did 
not measure the hydrogen ion concentration, attributing the 
effects due to the difference in the hydrogen ion concentration of 
their gelatin solutions erroneously to a difference in the anion 
effect. These elementary errors form the basis of a number of 
speculations current in biology and pathology. 

When we compare monobasic acids of different strength, e. g., 
acetic, mono-, di-, and trichloracetic acids, we find that the 
weaker the acid the more acid must be contained in a 1 per cent. 
solution of originally isoelectric gelatin to bring it to the same 
pH. If we compare the effect of these four acids on the osmotic 
pressure of gelatin we find that it is (within the limits of accuracy - 
of these experiments) identical for the same pH. The curves 
for the influence of these four acids on the osmotic pressure of 
gelatin solution are practically identical when plotted over the 
pH as abscisse ; and, moreover, the curves are identical with the 
curves for HCl or H,PO, in Fig. 1. The explanation of this fact 
is that at the same pH the same mass of originally isoelectric 
gelatin is in combination with the same quantity of these four 
acids and since the anions of these four acids are all monovalent 
the curves must be identical. 

As far as the alkalies are concerned, we notice that the curve 
representing the effect of the weak base NH,OH on the physical 
properties of proteins is the same as that for the strong bases 
LiOH, NaOH, KOH when plotted over pH as abscisse, while 
the curves representing the effect of Ca(OH), or Ba(OH), on 
the same properties are considerably lower. 

It is obvious that the valency of the ion in combination with 


PROTEINS AND COLLOIDAL CHEMISTRY 35 


the protein has a noticeable influence on the properties of the 
protein salt formed, while the protein salts with ions of the same 
valency have all the same properties. The fact of the greatest 
importance is, however, that the influence of acids and bases on 
the physical properties of proteins is the expression of the com- 
bining ratios of the acids or bases with proteins so that we are 
able to predict the value of the physical properties from the 
combining ratios. This fact seems to give a final decision in 
favor of a purely chemical theory of these influences and against 
the colloidal theories as based on the Hofmeister or Pauli 
ion series. 

The behavior of the proteins therefore contradicts the idea 
that the chemistry of colloids differs from the chemistry 
of erystalloids. 


THE THEORIES OF BLOOD COAGULATION* 


PROFESSOR JULES BORDET 


Director of the Pasteur Institute of Brussels 


IRST of all, I beg you to excuse my imperfect knowledge of the 
English language and to accept my best thanks for the 
honor you have conferred upon me by inviting me to deliver 
the Harvey Lecture. I shall try to-night to give a brief resume 
of the chief theories which have been held concerning the mech- 
anism underlying blood coagulation. This phenomenon deserves 
our interest, not only because of its physiological importance, but 
also as a striking example of the resources of experimental anal- 
ysis. It can occur in vitro, and such is truly a very favorable 
condition for the success of investigation. Nevertheless, and al- 
though it has been the subject of innumerable researches, its 
mystery, up to the present time, has not been completely dis- 
closed. You will not expect me to attempt a detailed review 
of the whole subject. I shall give only such broad outlines as 
will serve to make clear the modern conceptions which, seeming 
to afford the best explanation of this complicated process, espec- 
ially deserve our attention. 

I do not think it necessary to recall that coagulation is nothing 
else but the aggregation into meshes of fibrin of particles of 
fibrinogen, a substance which, as Fredericq showed forty-three 
years ago, preexists as a dispersed colloid in the circulating 
plasma. When the blood is shed from a wound, the first determin- 
ing factor which, through successive modifications of the plasma, 
assures the solidification of fibrinogen, is, not infrequently, 
the mixture of the blood with very active principles liberated 
by the bruised tissue, or in other words, the addition to the 
blood of tissue extract. But such an influence is an additional 
one, foreign to the blood itself; and, limiting the problem, I 


* Delivered October 30, 1920. 
86 


THEORIES OF BLOOD COAGULATION 37 


shall consider here, exclusively, the coagulation that blood is 
capable of showing solely by means of its own substances. 

A most important, even decisive factor of this autonomic 
coagulation is the contact of a foreign solid body, which, such 
as glass, acts only physically by its presence, since it does not 
liberate any soluble substance. The contact, external factor, 
brings into activity the internal factors belonging to the blood, 
and that is the process through which the principle directly and 
immediately responsible for the coagulation, the fibrin-ferment 
or thrombin, is produced. In fact, the thrombin, which is found 
in large quantities in the clot or in the serum, does not exist, as 
Schmidt showed many years ago, in the circulating blood. Con- 
sequently, several stages are to be distinguished in the total 
process, the most important one being the period in which the 
thrombin appears; the fibrinogen itself playing merely a pass- 
ive role. Fibrinogen can be extracted by special methods and 
obtained in a rather pure condition; but it must be kept in 
mind that the essential problem requiring the attention of the 
physiologist, is the coagulation, not of pure fibrinogen, but of 
the blood considered as a whole, that is, of a very complex med- 
ium, cellular and plasmatic, having a definite reaction and def- 
inite osmotic pressure, containing numerous constituents and 
especially colloids which presumably are apt to influence each 
other through molecular adhesion. Coagulation could not be 
studied without taking into consideration every influence apt 
to interfere in the phenomenon. 

As a rule, the blood of mammalians clots promptly, and it 
was, therefore, essential to the success of investigation to find how 
the course of the process could be protracted and, moreover, how 
it could be stopped at the first period of its evolution, so as to 
make possible the separation of the cells from the still liquid 
plasma. Several methods have been devised in that direction; 
I shall only recall them briefly. 

Concentrated salts, magnesium sulphate for instance, hinder 
the coagulation. Common salt, being a normal constituent of 
the organism, especially answers the purpose. Blood that has 
been salted at three or five per cent. immediately after 


38 HARVEY SOCIETY 


withdrawal from an artery yields by centrifugalization a 
clear plasma which does not clot so long as the high saline con- 
centration is maintained, but which, diluted with distilled water 
added in sufficient proportion to reestablish the normal saline 
concentration, clots rather quickly. Decalcifying salts, the type 
of which is sodium oxalate, prevent wholly the coagulation, eal- 
cium salts being necessary to this phenomenon. By centrifugal- 
ization, a clear plasma is obtained, which is apt to clot when a 
calcium soluble salt, namely, chloride, is restored. 

Coagulation is also prevented if, to the active contact of glass 
a contact is substituted which is not, if we may say so, felt by 
the blood or the plasma. A liquid does not feel a wall, I mean 
does not react physically to it, unless capable of adhering to it. 
Freund was the first to show that blood flowing from the artery 
does not clot, or at least clots very slowly, when received in a 
vessel the inside of which is coated with oil or vaseline. Paraffin, 
forming a solid coating, is very suitable to such experiments, 
and frequently permits the separation of the cells and the plasma 
by centrifugalization. I saw with Gengou that thus a clear 
plasma might be obtained and be kept fluid during twenty-four 
hours, but the clotting soon occurred when the plasma was 
brought into contact with glass. This experiment shows that 
the contact of glass can bring about its effect without any presence 
of cells, that is, without any vital interference; we have, there- 
fore, to deal with a physicochemical phenomenon. 

The blood of certain animals, namely, birds and fishes, as 
Delezenne has shown, clots very slowly by its own means, ¢0- 
agulation being greatly hastened by addition even of traces of 
tissue extract. Without the help of decalcification or of paraffin 
coating, the blood of a bird will keep fluid for a long time and 
even yield by centrifugalization a permanently liquid plasma, 
if the utmost care has been taken not to let the tube inserted 
into the vessel touch the wound, so as to prevent any trace of 
tissue extract mixing with the blood. As a matter of fact, this 
precaution ought to be taken regularly, whatever may be the 
species of animal under experiment, as it is quite a general rule 
that tissue extract accelerates the coagulation; this auxiliary 


THEORIES OF BLOOD COAGULATION 39 


influence being particularly evidenced in the case of birds, be- 
eause the avian blood is not so capable of spontaneous coagulation 
as is the blood of mammalians. 

Thanks to such methods, the separation of the two constitu- 
ents, cells and plasma, can be performed before any coagulation 
begins; and, let us emphatically insist upon this essential fact, 
before the appearance of any of the coagulating principle throm- 
bin. There is no need to recall that serum yielded by coagula- 
tion contains thrombin. 

We must now try to go further and subject plasma and cells 
to a closer analysis. Let us consider first the plasma. Soluble 
galeium salts are necessary to coagulation. How do they act? 
Pekelharing and Hammarsten have shown the essential fact that 
these salts are not necessary to the transformation of fibrinogen 
into fibrin under the influence of thrombin, but are indispensable 
to the formation of the latter, that is, to the production of throm- 
bin from the mother-substances already present in the circulating 
blood. It is thus the production of thrombin which is prevented 
by the oxalate; but, on the other hand, the decalcification does 
not prevent the coagulation of fibrinogen by ready thrombin. 
Indeed, it has been proved that blood, oxalated immediately after 
withdrawal from the artery, remains permanently fluid, no 
thrombin being ever detected in it; whereas if serum yielded by 
normally clotted blood be oxalated, this oxalated serum, added 
to oxalated plasma, causes the coagulation of the latter. It fol- 
lows from these facts that oxalated plasma is a most suitable 
reagent for the detection of thrombin in a given liquid ; estimation 
of the coagulating power of such a liquid may then be made by 
- taking into consideration the quantity of oxalated plasma a cer- 
tain amount of this liquid is apt to coagulate, or the rapidity of 
the occurring coagulation. However, it must be borne in mind 
that, at least when present in serum, the activity of a given throm- 
bin depends not only upon its quantity but also upon its age. 
The capacity of fresh serum to coagulate oxalated plasma de- 
ereases very quickly, by a spontaneous attenuation of the throm- 
bin; and this fact affords a possibility of detecting whether a 
given thrombin has been produced quite recently or more 


40 HARVEY SOCIETY 


remotely. Several experiments, as we shall see, require such 
a determination. 

Contact is also necessary for coagulation. How does it 
operate? I showed with Gengou many years ago that contact 
suggests the same remark as calcium does, that is, that contact 
with a foreign solid body (paraffin of course excepted) is neces- 
sary for the appearance of thrombin, but is not requisite for the 
coagulating influence of the latter. When blood is received in 
a paraffin vessel, thrombin is not formed; when received in a 
glass vessel, thrombin is produced in the zone of contact; which 
fact explains why coagulation begins along the wall. But when 
serum yielded by previously clotted plasma is added to blood or 
plasma kept in a paraffined vessel, the entire mass rapidly solid- 
ifies; the paraffin no longer exerting any inhibiting influence. 
This experiment explains why blood freshly extracted and placed 
in a glass vessel coagulates in a mass much more rapidly 
when shaken. 

From whence does thrombin proceed? It does not exist as 
such in the circulating blood, although the latter contains every- 
thing requisite for its production. The circulating blood, there- 
fore, contains the mother substance, or mother-substances, of 
thrombin, which for convenience may be ecalied prothrombin, and 
which in the early stages of coagulation is converted into throm- 
bin. What then is prothrombin? 

Morawitz, sixteen years ago, made an important discovery 
concerning this subject. He found that if crushed tissue, muscu- 
lar tissue for example, is added to serum yielded by normal ¢o- 
agulation, the coagulating power of this serum towards oxalated 
plasma considerably increases. And still, the extract of tissue 
by itself does not contain any thrombin, not being capable of 
coagulating oxalated plasma without the help of serum. We 
are, therefore, forced to conclude that the tissue extract contains 
something which is not thrombin, but which reacts with the 
serum so as to produce this active principle. Then the hypoth- 
esis at once presents itself that thrombin is derived from the 
interaction of two different substances: the one furnished by the 
tissue cells; the other by the serum. Undoubtedly, even before 


THEORIES OF BLOOD COAGULATION © 41 


the introduction of the tissue extract, a certain amount of throm- 
bin existed in the serum ; but it seems as if this fluid contained also 
an excess of the mother substance, the latter being capable of 
reacting with the tissue extract so as to generate a fresh supply 
of thrombin. 

But the question immediately arises whether such an assump- 
tion, deduced from experiments in which tissue extract plays an 
important role, may be without any further inquiry applied to 
the autonomic coagulation of pure blood. As a matter of fact, 
it must be kept in mind that when injected into the circulation, 
the tissue extracts are highly toxic and cause sudden death due 
to intravascular coagulation. Undoubtedly, they contain some 
coagulating principle foreign to the blood itself. Because our 
task tonight is chiefly the study of the coagulation of pure blood, 
I shall dispense with discussing very fully the nature of this 
principle ; it is probably an albuminoid substance and is markedly 
thermolabil, found specially in the tissues and not in the blood; 
and cannot be considered as a real mother substance of thrombin. 
But we must immediately add that, beside this peculiar prin- 
ciple, the tissue cells nevertheless contain one of the two mother- 
substances of thrombin, which exists also in the blood cells, is of 
a lipoid nature and may receive the name of cytozym. The 
other mother-substance, called by us serozym, is furnished by 
the blood fluid and is present in the serum. But we have nat- 
urally to inquire how these conceptions have arisen. 

The assumption that the blood cells furnish one of the mother 
substances of thrombin is in perfect accordance with the results 
of experiments concerning the part played by those cells and 
chiefly by platelets in the coagulation. Platelets can be easily 
separated by a short centrifugalization of oxalated blood at a 
moderate speed; being very light, they remain in suspension 
whereas red and white corpuscles are deposited ; the turbid super- 
natant fluid pipetted off is very rich in platelets. Now if such 
a platelet-plasma is centrifugalized a long time at a very high 
speed, the platelets finally are sedimented and a clear plasma 
may be obtained from which the platelets have not been thor- 
oughly eliminated,—this being impossible,—but in which they 


42 HARVEY SOCIETY 


are present only insmall number. Comparing these two plasmas, 
the one very rich, the other very poor in platelets, Lesourd and 
Pagniez found that by recalcification the former clots rapidly, 
the latter slowly. Delange and I completed these experiments 
by comparing the coagulating influence, on oxalated plasma, of 
the two sera thus obtained, or in other words, by comparing 
the amount of thrombin they contain, and found that serum 
yielded by the coagulation of plasma rich in platelets contains 
a much larger quantity of thrombin than is found in serum 
yielded by plasma poor in platelets. Consequently, the platelets 
actively participate in the production of the coagulating prin- 
ciple. This fact can be proved more distinctly still by the fol- 
lowing experiment: a sediment constituted exclusively of these 
small cells is obtained by vigorously centrifugalizing oxalated 
plasma, previously carefully freed of its red and white cor- 
puscles, but containing still its platelets. This platelet deposit, 
thoroughly washed, is emulsified in physiological solution, and 
one drop of the turbid emulsion thus obtained is added to a 
certain quantity of a serum which, having been obtained by the 
slow coagulation of recalcified oxalated plasma previously freed 
of its own platelets, is by itself very poor in thrombin. In facet, 
the mixture becomes, within twenty or thirty seconds, capable 
of coagulating almost instantaneously a suitable amount of oxa- 
lated plasma; in other words, the reaction of serum with plate- 
lets generates plenty of thrombin. It must be pointed out that 
this experiment closely resembles that of Morawitz except that 
platelets, instead of tissue cells, are added to the serum. Tissue 
cells and platelets both contain, we shall insist further on this 
point, one of the generators of thrombin, which may be called 
eytozym; the second one, the serozym, exists in the serum. It 
ean be easily demonstrated that the reaction between serum and 
platelets, that is to say between serozym and cytozym, takes place 
only in the presence of soluble calcium salts, no thrombin appear- 
ing if the serum has been decalcified before the introduction of 
the platelets. Moreover, I shall further insist on the fact that the 
two substances unite, that is, they really consummate each other: 
indeed experience shows that when a serum has been treated a 


THEORIES OF BLOOD COAGULATION 43 


first time with platelets, and correlatively has already furnished 
thrombin, this serum is subsequently incapable of reacting with 
a new amount of platelets; its serozym having been exhausted 
by the first reaction. It follows that a serum produced by the 
coagulation of a plasma rich in platelets, and which of course 
contains much thrombin, is considerably less rich in serozym, 
henee, is considerably less capable of reacting with new platelets, 
than is a serum derived from a plasma deprived of most of its 
platelets. This is precisely what experience shows. It is, there- 
fore, highly advisable always to employ as serozym, a serum ob- 
tained by the coagulation of oxalated plasma which has been 
earefully freed of its platelets before recalcification. 

Serozym is a thermolabil substance, easily destroyed by heat; 
no thrombin is produced when platelets are added to serum that 
has been exposed to the temperature of about fifty-six degrees. 
On the contrary, cytozym, the active principle of platelets, may 
be heated up to one hundred degrees and even higher without los- 
ing its properties; cytozym is thermostable and, furthermore, 
can be easily extracted. 

A thick emulsion of platelets treated by a large excess of 
absolute alcohol gives an extract from which there is obtained 
by evaporation a residue soluble in alcohol, ether, toluol, chloro- 
form; but insoluble in aceton, thus exhibiting the characteristics 
of lipoids and specially of lecithin; and which acts as a very 
powerful cytozym. 

As we were able to show eight years ago, traces of this lipoid 
behave exactly like platelets, generating thrombin when added 
to serum, hastening the coagulation of recalcified oxalated plasma 
or causing the coagulation of spontaneously non-coagulable bird’s 
plasma. The same lipoid, possessing exactly the same properties, 
may be extracted from tissues, for example, from muscles. 

Such information being gathered about ecytozym, what is 
serozym? Serozym is certainly furnished by the plasma, not 
by the cells. Platelets contain cytozym, they give thrombin 
when mixed with serum, but they are never able to liberate 
thrombin when kept in physiological solution or in distilled 
water, even in the presence of calcium salts. They consequently 


. 


44 HARVEY SOCIETY 


contain only one of the mother-substances, not both of them. 
The lability of serozym towards heat allows us to presume this 
substance is of an albuminous nature. Its fragility would be a 
very serious hindrance to its isolation, but for one really fortunate 
property: the serozym shows a strong tendency to adhere to 
mineral precipitates, such as barium sulphate, or calcium fluoride. 
This is the reason why, as I discovered many years ago with 
Gengou, those precipitates, added to oxalated plasma, wholly 
suppress in the latter the property of coagulating by subsequent 
recalcification ; one of the mother-substances, the serozym which 
is absolutely requisite for the production of thrombin and con- 
sequently for coagulation, has been entirely removed. As I could 
ascertain more recently with Delange, tricalcic phosphate is 
especially powerful as an absorbent. When diluted in physi- 
ological solution this substance gives a rather gelatinous emulsion, 
a very slight quantity of which, added to blood flowing from the 
artery, prevents its coagulation. By centrifugalization and 
pipetting off, a clear plasma is obtained, which always keeps 
fluid, even when platelet emulsion, or tissue extract, or lipoidic 
cytozym is added. This is easily understood; both mother- 
substances, serozym and cytozym, are equally necessary to the 
production, of thrombin; it is of no use to add one of them if 
the other is absent. But such a plasma, which we may for sake 
of brevity call ‘‘ phosphate plasma’’ clots under the influence of 
ready thrombin or, which naturally is the same, when_ both 
mother-substances are added. It behaves as an excellent reagent 
for the detection of thrombin; its composition closely resembling 
that of the original plasma, it may be considered as being a 
fibrinogen dissolved in a normal medium. 

But tricaleic phosphate is endowed with a property which 
renders it remarkably available fer technical purposes. As is 
well known, it is capable of dissolving in physiological solution 
under the influence of a current of carbonic gas. Consequently, 
phosphate which, having been added to plasma, has absorbed the 
serozym can, after having been thoroughly washed, liberate, 
thanks to its own dissolution, the active principle it had with-| 
drawn. We succeeded thus, Delange and myself, in performing 


THEORIES OF BLOOD COAGULATION 45 


the isolation of serozym, which, on the addition of cytozym ex- 
tracted from platelets, gave plenty of thrombin, so that in the 
course of the whole experiment the determinism of coagulation 
is in reality subjected to an analysis followed by synthesis. 

As mentioned above, our assumption that serozym and cyto- 
zym. are the generators of thrombin involves the idea that those 
mother-substances really unite to form a compound, which is 
thrombin. This ought to be demonstrated also with regard to 
pure eytozym; I mean a cytozym in the condition of a lipoidal 
extracted matter. If the union truly occurs, we may anticipate 
that a given quantity of serozym which already has been mixed 
with a sufficient amount of cytozym, thrombin being thus en- 
gendered, will be correlatively exhausted; in other words, will 
be no more capable of giving fresh thrombin when a new amount 
of cytozym is added. Such is, indeed, the case. Serum yielded 
by coagulation of recalcified platelet-—free oxalated plasma is 
divided in two parts, lipoidal eytozym being added to one of them, 
the other portion being kept as it is. In the tube containing 
both serum and cytozym, thrombin appears, the activity of which, 
very strong at the outset, decreases very fast so as to become the 
following day quite attenuated. On this following day, lipoidal 
eytozym, and several minutes afterwards, oxalated plasma are 
added to both tubes; then, the tube which has the preceding day 
received cytozym. shows no clotting or only a very slow one, the 
tube to which cytozym has been just added for the first time, 
clots almost instantaneously. 

- There is no need to remark that such an experiment affords 
the possibility of ascertaining whether the same cytozym, en- 
dowed with the same binding properties as the pure lipoid, exists 
either in fresh or heated platelets, or in tissue juice such as ground 
muscle. Adequate experiments show that serum which has al- 
ready reacted with any one of such materials does not generate 
any more thrombin when subsequently brought into contact with 
any one of them. For example, serum to which lipoidal cytozym 
has been added no longer reacts either with the same lipoid, or 
with platelets, or with muscle juice, and conversely. 

Without entering into detail, I may add that the manner in 


46 HARVEY SOCIETY 


which the two substances unite, closely resembles the mode of 
union of toxins and antitoxins; namely, that the process is not 
governed by the law of strict and constant equivalents, but takes 
place in varying proportions, thus seeming to result, not from 
true chemical affinities, but from contact affinity or molecular 
adhesion. But another fact, more noteworthy for the knowledge 
of the underlying mechanism of coagulation is disclosed by the 
determination of the lapse of time required for the union of 
both substances. 

Serozym being found in serum may be assumed to exist also 
in the oxalated plasma from which this serum has been derived. 
Now if cytozym and serum are mixed, thrombin appears very 
quickly; in fact, in some seconds. But, and this fact is truly 
remarkable, if eytozym is added, not to serum yielded by coagula- 
tion of recalcified oxalated plasma, but to an identical oxalated 
plasma recalcified just before, that is at a moment when this 
plasma is still perfectly fluid, the appearance of thrombin is 
greatly delayed. In other words, serozym reacts with cytozym, 
quickly when present in serum, slowly when present in plasma. 
We thus reach the conclusion that the serozym does not exist in 
the same condition in plasma as in serum; that in plasma it is 
not still capable of reacting at once with cytozym. We may 
express the fact by saying that plasma contains proserozym in- 
stead of active serozym, one of the first phenomena of the whole 
process of coagulation being precisely the conversion of prosero- 
zym, unfit until transformed to unite with cytozym, into serozym 
capable of this reaction. , 

The idea that in original plasma or in circulating blood, 
serozym does not exist as such, I mean does not exhibit affinities 
towards cytozym, satisfactorily explains why intravascular in- 
jections of the latter substance are, as we ascertained, quite 
harmless. But the blood of such injected animals shows, when 
shed within about half an hour of the injection, a strikingly 
increased tendency to rapid coagulation ; this fact being probably, 
as we pointed out, available for therapeutic purposes in cases 
of hemorrhage. 

Is it now possible to investigate under what influence the 


THEORIES OF BLOOD COAGULATION 47 


proserozym is converted into serozym, or in other words, acquires 
the capacity of reacting with cytozym? 

To solve this problem, we have at our disposal a very adequate 
technic, based on the use of oxalated salt saturated plasma. 

I recalled to your attention, some minutes ago, the fact that 
when oxalated plasma is saturated with common salt, the fibrin- 
ogen precipitates completely. After strong centrifugalization, 
pipetting off, and elimination of the excess of salt by dialysis in 
the presence of physiological oxalated solution, the supernatant 
fluid represents exactly normal oxalated plasma, except that hav- 
ing lost all its fibrinogen, it is no longer capable of coagulation. 
Being oxalated it does not contain any trace of thrombin, but 
is still capable of producing plenty of thrombin on addition of 
calcium salt and cytozym. Now if calcium salt and cytozym are 
added thrombin appears in fact, but only after a rather important 
delay. Half an hour, sometimes more, must elapse before the 
mixture becomes capable of causing an almost instantaneous ¢o- 
agulation of a fibrinogen solution. Then the ability to react with 
cytozym, that is, the conversion of proserozym into serozym, 
requires a notable length of time. Now on the other hand, the 
aforesaid fluid without fibrinogen being recalcified, cytozym is 
only added one-or two hours later, then the thrombin appears 
almost instantaneously. This experiment clearly illustrates the 
essential assumption that the whole process of the production of 
thrombin, the first stage included, which is the conversion of 
proserozym into serozym henceforth capable of uniting to cyto- 
zym, takes its course without any participation of fibrinogen. 

Furthermore, the conversion of proserozym, which as we know 
cannot take place without calcium salts, is, and the fact is note- 
worthy, strikingly favored by the contact of glass. The eapa- 
city of reacting with cytozym appears only after a much longer 
lapse of time when the recalcified fluid is maintained in a vessel 
coated with paraffin. Consequently, the influence of contact, 
which is so obvious in coagulation, is not exerted through some 
interference of fibrinogen, but really acts without any help of 
the latter, as a factor of thrombin production. It is highly prob- 
able that contact, by way of absorption, frees the liquid of some 


HARVEY SOCIETY 


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THEORIES OF BLOOD COAGULATION 49 


antagonistic substance, most likely some protective colloid, which 
prevented the serozym from reacting with cytozym, that is, main- 
tained it in the inactive condition of proserozym. On the other 
hand, experiment shows that the presence of cytozym likewise 
facilitates such a liberation of serozym, owing to its strong affin- 
ities towards the latter principle. 

To sum up, we are now able to follow the scheme which indi- 
cates the order of succession of the phenomenon. 

I think the scheme symbolizes quite accurately the most prom- 
inent features of the whole process and distinctly shows the se- 
quence of events. But the mechanism underlying the coagulation 
as it occurs in the ordinary conditions is still somewhat more 
complicated, owing to a peculiar property of thrombin. Throm- 
bin results from the union of serozym and cytozym, but these 
two substances combine in variable proportions. The consequence 
is that a given complex, when rich in serozym, is able to capture 
an additional amount of cytozym, and, when rich in cytozym, 
which is ordinarily the case in the coagulation of total blood, 
shows a marked affinity towards a new amount of serozym. As 
a matter of fact, such an affinity is so strong that it causes 
thrombin to attract and to possess itself of serozym even when 
this principle is still present in a state of proserozym. Conse- 
quently, ready thrombin acts as it could bring about a remark- 
ably quick conversion of proserozym into serozym, the process 
preliminary to the genesis of fresh thrombin being thus greatly 
hastened. The consequence is that when thrombin is added to 
oxalated plasma which has been just recalcified, the total amount 
of thrombin this quantity of plasma is apt to furnish appears 
much more rapidly than it does when the same plasma is allowed 
to clot spontaneously without the impulse of thrombin. In fact, 
thrombin itself thus accelerates the formation of thrombin. Ow- 
ing to lack of time, I cannot report here in detail the experiments 
which have established this idea, and I think I may now consider 
briefly some views held by certain authors which are rather out 
of agreement with the ideas developed above. 

As is well known, my countryman, the physiologist Nolf, has 
adopted the rather unexpected theory of Wooldridge according 

4 


50 HARVEY SOCIETY 


to which, instead of being the immediate determining factor of 
coagulation, thrombin on the contrary, is generated as a con- 
sequence of the coagulation itself. According to Nolf, the trans- 
formation of fibrinogen into fibrin is not the effect, but the 
necessary condition of the appearance of thrombin. Much of 
the data I recorded above energetically contradicts such a con- 
ception. For example, I have but to recall the experiments 
showing the production of thrombin in fluids altogether devoid of 
fibrinogen, and thus proving unquestionably that fibrinogen does 
not play any role in the production of the coagulating principle. 

One important point has been and is still controverted; I 
mean the true significance of the lipoid to which we have so 
often alluded. Schmidt, who had already observed the acceler- 
ating influence, exerted by tissue alcoholic extracts on coagulation, 
believed that such lipoids made easier the production of thrombin, 
without assuming, as I do, that they really enter into its constitu- 
tion. One of the most distinguished among the writers who have 
devoted their skill to the study of coagulation, Prof. Howell, 
especially directed his attention towards the fact that the lipoid 
extracted for example from nervous tissue is capable of inducing 
the coagulation of pepton plasma and hirudin plasma which, as 
is well known, keep fluid because they contain an anticoagulating 
substance called antithrombin. Contrary to our assumption, 
Howell thinks that the lipoid is not a constituent of thrombin, 
but acts because capable of neutralizing the antithrombin, which 
hindered the spontaneous conversion of prothrombin into throm- 
bin. The real existence of antithrombin is, of course, unquestion- 
able; and it is undoubtedly proven that antithrombin may be 
neutralized by thrombin, the two substances being, in all prob- 
ability, capable of forming a compound. Now the question arises 
whether, when lipoid is added to pepton or hirudin plasma, the 
removal of the antithrombin function is due, as Howell claims, 
to the direct neutralization of antithrombin by this lipoid, or 
to a neutralization of antithrombin by thrombin generated under 
the influence of the same lipoid, the latter reacting with the 
serozym or proserozym also contained in the aforesaid plasma. 
In other words, according to this second interpretation, the 


THEORIES OF BLOOD COAGULATION 51 


neutralization of antithrombin by the lipoid would be merely 
apparent or at least indirect, the direct agent of this neutraliza- 
tion being the thrombin the lipoid has caused to appear. I think 
such is in reality the conclusion forced upon us by recent and 
careful experiments of Gratia. Without the necessity of entering 
into the somewhat complicated details, those experiments have 
shown that the lipoid does not at all neutralize the antithrombin 
when the serozym or proserozym is previously removed, that is, 
when the production of thrombin is made impossible. Even 
when the lipoid is added in large excess, the abolition of the 
antithrombin function only occurs in proportion to the amount 
of serozym present, that is, in proportion merely to the quantity 
of thrombin that can be generated. Consequently, a direct in- 
fluence of the lipoid on the antithrombin cannot be admitted. 
Furthermore, Howell’s view could hardly be brought into 

harmony with a very essential fact, mentioned above. Were his. 
assumption correct, it should be admitted that serum yielded by 
the coagulation of recalcified oxalated plasma deprived of its 
platelets contains a large amount of antithrombin, since the ad- 
dition of lipoid to such a serum, by itself poor in thrombin, pro- 
duces in this fluid plenty of the latter principle. Upon the whole 
the serum should, in this respect, resemble very much the plasma 
from which it is derived. But, such being the case, it would be 
very difficult to understand why the lipoid neutralizes the anti- 
thrombin very quickly when added to serum, and very slowly 

when added to plasma. I think the only possible explanation 
of such a difference is that, in serum but not in plasma, as was 
said before, the serozym is capable of reacting very rapidly with 
eytozym to generate thrombin. However, the question as to the 
relation of cytozym with the antagonistic function is one of the 
most delicate in the whole study of coagulation: I fully realize 
that different views may still be upheld. As I told you when 
beginning, coagulation has been studied years and years by many 
investigators; none of them could presume that the problem is 
solved ; every one of them merely induges in the hope of gather- 
ing some complementary data, a little more information. 


URAEMIA* 


DR. NELLIS B. FOSTER 
Assistant Professor of Medicine, Cornell University Medical College. 


N his Harvey Lecture on Nephritis, Theodore Janeway stated 
three problems, the solution of which are necessary for a 
clearer conception of the symptoms of renal diseases. The prob- 
lems were cedema, vascular hypertension and uremia. At that 
time, 1913, we were studying uremia in the belief that the solu- 
tion of this question might aid materially in solving the others 
and possibly throw light on the essentially most significant prob- 
lem, namely—the mode of production of nephritis generally. 

By uremia we understand an intoxication manifested my 
psycho-motor disorders, which is apt to supervene in nephritis. 
The term takes origin in the fact disclosed by the first chemical 
studies of body fluids of nephritics—the increase of urea in 
the blood and cerebro-spinal fluid, detected by Christison and 
Babbington. It was quite a natural inference that the retention 
in the body of considerable amounts of substances known to be 
waste products, since they were present in normal urine, should 
be considered responsible for the conspicuous symptom of epilep- 
tiform convulsions. The initial error in this deduction was the 
ancient enemy of medical science—faulty logic; and it required 
the energies of some of the best minds for the next half century 
to correct the conception. Owen Rees, it is true, objected to the 
current theory on the ground that larger amounts of urea were 
recovered from the blood of a case of obstructive anuria than 
had been noted in any case of Bright’s disease; yet there had 
been in his case no nervous disturbances, no convulsive seizures. 
Subsequent results of animal experimentation cast a shadow of 
doubt on the theory which, however, was but slightly altered since 


* Delivered November 20, 1920. 
52 


URZEMIA 53 


ammonium carbonate, the supposed precursor of urea, focussed 
attention (Frerichs) for a generation, until Oppler, under 
Hoppe-Seyler’s direction, finally disproved the hypothesis. 

The attention of students with a chemical bent turned to 
the extractives; but as theories based upon the idea of the toxic 
nature of uremia weakened, the morbid anatomists advanced 
other theories based upon supposed changes in the central nervous 
system ; e. g., inflammation of the arachnoid, edema of the brain, 
general or local. Traube’s attention was arrested by the fre- 
quency of serous effusions in nephritis; and this fact, together 
with cardiac hypertrophy and the increased arterial pressure, led 
him into a complex mechanical explanation of cerebral cedema. 

The history of these early investigations is here merely out- 
lined, because no abiding truth was revealed, no principle of 
wider application determined. This history is also an exception 
in medicine, since not here, as has so often happened, did the 
clinician separate out of chaotic disorder the several disease 
entities and state clearly the problem for solution. Toa confusion 
of clinical entities must be ascribed the barren results of carefully 
done work. For example, the intimate relation between cardiac 
disorders and renal disease or their similarities, could not have 
been duly appreciated till a later date, nor the types of cerebral 
accident that might result. 

Now, while the term uremia may be inexact, yet it has won 
a general usage as descriptive of several symptom complexes 
accompanying nephritis. These symptoms fall roughly into 
groups; thus headache, vomiting, diarrhcea and amaurosis are 
styled toxic; then there are psychic symptoms; hallucinatory- 
parnoid states, stupor and coma, and motor symptoms ;—transient 
paralyses, paresis and hemiplegia and convulsions. Careful 
clinical studies have shown that of these symptoms some are apt 
to occur together, while others are more or less fortuitous. And 
so there has grown up a conception of types of uremia: (1) the 
convulsive or epileptiform type being the earliest one recognized 
in Bright’s time; with this epileptiform uremia headache and 
sudden amaurosis are often precursors and coma a sequel. The 
convulsive seizures and not infrequently recovery are the striking 


54 HARVEY SOCIETY 


features. (2) A second type never displays a sudden onset, but is 
marked by gradually deepening coma, unaccompanied by psychie 
disorder or signs of motor irritation. (3) A third type shows 
visual disturbances only when demonstrable lesions of the eye 
are present (hemorrhages, exudate, neuritis, which is in contrast 
to the blindness of the first type of uremia); and is prone to 
gastro-intestinal and psychic disorders, of which the latter are 
commonly hallucinations and paranoid delusions. Convulsions 
do not occur, lethargy and somnolence are the rule, and coma 
is terminal. 

The association of symptoms into groups is not alone because 
they seem most commonly thus associated in disease, but also be- 
cause each of these symptoms complexes appears often as a result 
of certain disturbances in renal function ; and, furthermore, these 
uremic types have each a more or less clearly defined disorder of 
metabolism. It will be my endeavor to present to you the evidence 
for these statements. 

It has doubtless been a great handicap to study that path- 
ology has not been able to discover in uremia lesions of the 
central nervous system with sufficient constancy to correct clinical 
judgment. The diagnosis of uremia can only be suspected from 
the character of organic change found post mortem. Aside from 
the lesions in the kidney and occasionally ulceration in the lower 
gastro-intestinal tract, uremia leaves inconstant signs. Since 
the symptoms are so largely those related to the central nervous 
system, attention has been given chiefly to search for cellular 
alteration in the brain and cord. 

It is well known that some increase of fluid in the ventricles 
and meninges post mortem is but an expression of the agonal 
transudation that occurs in all serous lined cavities, and is 
therefore of slight significance. This explains the edema of the 
brain noted so constantly by early students, notably Rees. The 
question of cerebral edema must be approached with due caution 
because the problem has never received adequate attention, Very 
nice considerations are involved in any attempt to explain an 
increase of fluid in a closed chamber such as the cranial cavity. 
Suffice it here to say that the larger problem is not comprehended 


URZEMIA 55 


and in many instances where the increase of fluid is but moderate 
we can not be sure of cerebral edema unless there be an accom- 
panying disorder, such as hyperemia, to explain it. Roughly, 
there is differentiated an active and a passive cedema; and, 
although the weight of Traube’s name focussed attention on 
cedema of the brain as an explanation for uremia, the part played 
by the general circulation in this edema, and hence by myocardial 
disease, was not appreciated till the work of von Recklinghausen. 
We recognize now that edema may be due to circulatory dis- 
orders and that in nephritis there is especially apt to supervene 
as a late complication an edema resultant upon myocardial 
insufficiency. This fact, now appreciated, often confused elini- 
cians of the last century. 

Quite different in causation probably is the edema associated 
with the lesion styled serous encephalitis. Not confined to the 
meninges, the cedema of the central nervous system in uremia 
has more similarity to serous encephalitis than to purely passive 
edema. But with our knowledge of serous transudation, agonal 
or post mortem, this observation can not be forced. The question 
of cedema generally is an unsolved problem and one that might 
profitably be attacked by physico-chemical methods. 

In its highest severity edema of the brain appears with 
constancy in but one type or uremia; that type where stupor and 
coma, without convulsion, without psychic or motor disorder, is 
the prominent nervous symptom. The clinical picture, in so far 
as referable to the nervous system, and the neuro-pathology are 
then in similarity with that of chronic alcoholism. That this 
cedema of the brain may bear a causal relation to stupor or coma 
is suggested at least, by the transient clearing of the mental state 
following removal of cerebro-spinal fluid, which in this type of 
uremia is usually under increased tension. Cerebral cedema seems 
in these cases only a part of the general anasarca which is the 
prominent clinical symptom. 

Definite cerebral hyperemia we have observed in only one type 
of uremia. Difficult to estimate and therefore uncertain in mild 
degrees, this hyperemia is in some cases beyond doubt, and in 
several instances it has been accompanied by numerous pinpoint 


56 HARVEY SOCIETY 


hemorrhages seattered generally throughout the brain substance. 
There was also at times cedema, the nature of which is uncertain. 
In brief, these lesions are not to be differentiated from those seen 
in morphine poisoning. Now the interesting fact to us was that, 
while this picture was not seen with constancy, it was the sig- 
nificant lesion in some cases dead of convulsive uremia and was 
not observed in other types. Oedema in slight degree might or 
might not be present, often quite absent, and then the neuro- 
pathology of epileptiform uremia stood, in some measure at 
least, differentiated from that of other types or uremia. A 
conservative deduction from these observations is that two types 
of lesions are notable in the central nervous system and in their 
extreme degrees these lesions appear to be associated with definite 
groups of symptoms. Only in so far do they suggest differences 
in causal factors. 

Since its recognition as a sequel to nephritis uremia has been 
regarded generally as an intoxication and efforts directed to 
determine the cause were largely made by chemical methods. 
Down to the time of Bouchard it was believed that urine is 
poisonous, or contains a poison. And since the epileptiform 
type of uremia was so easily differentiated, little attempt was 
made to discover variations in the clinical complex or to hunt for 
more than one immediate cause, all alike being a result of renal 
disease. Today we recognize that disorder of the functions of 
the kidneys may take several forms and conceivably some vari- 
ability in nervous symptomatology might be expected. It is 
generally accepted that nephritis may be characterized by imper- 
fect nitrogen excretion, or in other cases by defect in salt and 
water excretion. And we observe cases where the former condition 
prevails without evidence of the latter, hence when the two occur 
together we recognize not a third type, but a mixed complex, at 
least from a physiological aspect. 

The older ideas held some truth buried, nevertheless, in a maze 
of misconceptions. It has been known for ages that persistent 
anuria leads to death. Rees objected to Christison’s theory of 
urea poisoning on the ground that anuria due to stone did not 
induce convulsions, although fatal. This observation has been 


URZMIA 57 


repeatedly confirmed. It matters not whether anuria be due to 
obstruction of ureters, renal arteries or veins, or removal of both 
kidneys, the symptoms resulting are alike ; the most notable being 
progressive weakness and an increasing somnolence, nausea, 
headache, stupor, terminating in death. None of the classical 
symptoms of epileptiform uremia are noted; amaurosis, palsies, 
and convulsions are absent. The renal arteries or veins, or 
ureters, were ligated in a number of dogs, which were observed 
carefully by us, but there was no clinical resemblance to a uremic 
picture of the convulsive type. I studied with the greatest care 
from day to day three individuals who had been deprived of the 
only functioning kidney by emergency operations. In none of 
these were there the slightest evidence of irritability of the 
motor nervous system, nor impairment of the psychic functions 
until the last days of life. None had amaurosis, muscle spasms, 
paralysis, nor convulsions. All alike experienced first weakness, 
slight vertigo, mental dulness, then, a tendency to sleep which 
lapsed into coma, with death on the ninth to eleventh day after 
the operation. The blood in all of these cases showed a higher 
concentration of nitrogen and urea than usually occurs with 
uremic patients. Similar symptoms were experienced by Hewlett 
and his two assistants following the ingestion of large amounts of 
urea. In one experiment enough urea was taken to raise the 
blood-urea up to 240 mg. per cent. All suffered from the same 
symptoms, differing only in degree; nausea, headache, vertigo, 
mental irritability, apathy and somnolence. 

It is our conception that one type of uremia is due chiefly 
to the retention in the body of substances normally excreted in the 
urine. The conditions leading to anuria induce symptoms 
resembling in certain respects (weakness, somnolence, etc.) 
asthenic uremia, but there is not a complete reproduction of the 
complex. At first glance it would seem that these conditions of 
anuria are exactly and perfectly analogous to those of nephritis 
since they effect an extreme nitrogen retention. That this is not 
entirely true will appear on further examination of the problem. 

A number of years ago Voit studied the toxicity of urea and 


58 HARVEY SOCIETY 


several other urine elements and found that he could feed dogs 
large amounts of urea in their food without apparent injurious 
result, provided the animals were permitted as much water as 
they desired. If, however, the water were limited to very small 
amounts, or withheld, symptoms such as vomiting, lethargy and 
ataxia developed. This observation contains a principle which 
is applicable to the conditions observed in chronic nephritis with 
nitrogen retention. This principle I must. explain. We have been 
able to show in our studies of cases of chronic nephritis with 
nitrogen retention that the amount of nitrogen excreted in the 
urine bears a relation to the volume of urine. This fact was 
determined in this way: Cases with no defect in water execretion 
were given diets containing a definite known amount of nitrogen, 
the only variable being water; and it was then observed that if 
we gave much water no nitrogen was retained in the body, all 
being excreted; but if water were limited to less than a liter 
per day, nitrogen was retained and after a period the blood 
analysis showed an increasing amount of urea and non-protein 
nitrogen, in other words, an accumulation of nitrogenous waste. 
This is experimental confirmation of a well established clinical 
doctrine, namely, that these cases of chronic nephritis with 
nitrogen retention require much water in order to eliminate the 
nitrogenous waste, because the diseased kidney can execrete only 
at a low level of concentration of urea. Senator warned of the 
danger of uremic symptoms if water be withheld. 

It now becomes evident that the comparison of the metabolism 
of a patient with anuria on the one hand and one with nephritis 
and nitrogen retention on the other hand reveals an important 
difference. Both alike lose a definite amount of water through 
the lungs, but the patient with anuria loses no water through 
the kidney, consequently, even though nitrogenous substances are 
retained, water also is retained and the concentration of nitrogen 
in the tisswes is thus relieved for some time. Furthermore, in 
nephritis the kidney excretes selectively, some substances with 
relative ease, others with increasing difficulty, so there results in 
disease selective concentration. All the nitrogen components 
of urine are not retained in equal degree, but. some more than 


URZMIA 59 


others. This fact defines a contrast in the kind of nitrogen reten- 
tion of nephritis to that of anuria. With anuria all the substances 
normally excreted in the urine are held back in the body; with 
nephritis, on the contrary, some are retained more than others. 
Now does the examination of blood in these two conditions accord 
with theory? In nephrectomized dogs we noted that urea formed 
60 per cent. or over of the non-protein nitrogen. In the anuria 
of mercury poisoning the urea ran as high as 90. per cent of the 
non-protein nitrogen in some cases and was generally high. With 
uremia, however, while both urea and non-protein nitrogen may 
be high, the urea nitrogen forms a smaller percentage of the total 
than with anuria—seldom over 65 per cent. and often below 50 
per cent. of the total. We find then just the difference we should 
expect theoretically. In chronic interstitial nephritis this 
process of heaping up nitrogen waste is gradual and the cells 
become tolerant to abnormal amounts of these urinary elements. 
An excellent example of the effects of retention in the body of 
nitrogenous waste products consequent to desiccation is observed 
in cholera; a uremic syndrome is one of the late complications of 
cholera, although the accompanying nephritis is not of severe de- 
gree. Here the extreme loss of water from the body in the stools 
results in actual desiccation ; the specific gravity of the blood may 
rise to 1060. Accompanying this there is also an increase of 
nitrogen waste due to an increased katabolism of protein conse- 
quent to the infection. <A similar condition of affairs I have 
observed in diphtheria; anuria due to desiccation leading to 
asthenie uremia and at autopsy no significant lesion being demon- 
strable in the kidneys. The dryness of the tissues in these cases 
is well known. 

But the best illustration of the relation which water excretion 
bears to the onset of uremic symptoms in nephritis with nitrogen 
retention is offered by the effects of diuresis. Addison remarked 
that uremia resulted when certain cases of Bright’s disease with 
cedema developed diuresis and the edema subsided. This is now 
a common observation; and uremia may be not only a conse- 
quence of water loss through the kidneys but may also follow 
diaphoresis or restriction of the fluid ingested. All of these 


60 HARVEY SOCIETY 


conditions, diuresis, diaphoresis, or restricted fluid ingesta, result 
in a concentration of waste products in blood and tissues in eases 
of nephritis. There is then not the perfect analogy between 
anuria and the nitrogen retention of nephritis which has 
been supposed. 

The chemistry of the blood has been well studied in asthenic 
uremia because this is the most common type. It is now well 
known that all of the nitrogenous bodies found in urine are 
generally increased in the blood; some bodies more than others. 
In addition, we have observed that the amounts of nitrogen 
retained in the body by very sick patients (the difference between 
the nitrogen ingested in food and that excreted in the urine, 
feces, ete.) could not be accounted for by the non-protein nitrogen 
of the total blood in the body. These two facts led us to analysis 
of tissues post mortem. In brief, it has been quite definitely 
learned, I think, that the tissues retain more of these katabolic 
products than does the blood. In fact, there is some ground for 
the opinion that the excess in blood expresses a super-saturation 
of tissues; but this is not demonstrated. 

In the range of problems yet unsolved is the question of the 
physical state of these organic compounds in the body fluids. 
Are they merely in solution or are they in combination with 
colloids? Although yet not determined, the latter state seems, 
however, more probable, and these colloidal compounds would 
then be directly influenced by various conditions, such as H-ion 
concentration. It will be recalled that the acidosis theory of 
uremia has repeatedly been advanced at first by Senator, and 
while acidosis is often detectable it is usually significent in degree 
only in the terminal period of life. But exceptionally acidosis 
may be a prominent factor (V. C. Myers), and it is of interest 
that appropriate alkaline therapy then ameliorates or quite 
relieves the uremic symptoms. This is an unusual manifestation. 

We see then that asthenic uremia is a complex syndrome, the 
chief components of which I have attempted only to indicate. The 
objection to the hypothesis of intoxication by excretory com- 
pounds loses force on careful serutiny, since nephritis is com- 
parable to anuria only in certain aspects: In one ease, anuria, we 
observe the effects of a sudden overwhelming dosage; in the other 


UREMIA 61 


ease, asthenic uremia, we observe the results of slow cumulative 
poisoning from the same elements but in different proportions. 
There is as much correspondence of symptoms in the two condi- 
tions as we should expect, more similarity, in fact, than exists 
between the clinical effects of large toxic doses of known poisons 
and the slow cumulative effects of that poison. There is also 
found the difference in chemical composition of body fluids which 
we should theoretically expect to find. 

For a generation after Bright the term uremia was applied 
chiefly to a symptom complex characterized by epileptiform con- 
vulsions. The extension of the definition to cover the various 
types of intoxications which we have been discussing was of later 
development. The striking features of the epileptiform type of 
uremia in some respects seems to differentiate a separate and 
peculiar entity. Without premonitory symptoms in many cases 
there occur sudden and violent convulsive seizures, transient 
palsies and hemiplegia and a peculiar form of blindness unasso- 
ciated with detectable cause in retina or nerve; a recovery and 
return to health in some instances, as Addison observed—these 
symptoms are in such sharp contrast to asthenie uremia that they 
suggested the effects of a peculiar toxin. The disorder has always 
been regarded as an intoxication. The explosive character of 
the symptoms aided correct diagnosis and study, in contrast to 
the insidious onset of other types of uremia easily confused with 
various cerebral accidents. 

From time to time attempts have been made to demonstrate 
the presence of a toxic substance in the blood from eases of 
convulsive uremia, but none met with convincing results; nor has 
it been shown that urine from these patients is either less toxic 
or more toxic than normal. Each one of the organic substances 
excreted in urine was tested for its toxic properties a generation 
ago, but with no result, unless one consider the experiment of 
Landois, who applied creatinine to the brain cortex and elicited 
convulsive seizures. 

If convulsive uremia be an intoxication, as the older students 
conjectured, then the toxin is probably recoverable from the blood 
or tissues. 

When urine is subjected to fractional analysis we find that 


62 HARVEY SOCIETY 


the various bodies composing the non-colloidal nitrogen are 
known down to a small per cent. Thus 75 to 85 per cent. is urea, 
the remainder ammonia, uric acid, creatinine, ete., and an insig- 
nificant fraction only is in doubt. Now, turning to blood, the 
non-protein nitrogen or filtrate nitrogen is composed of known 
elements only in part. The sum of the known bodies totals, at 
most, only about 80 per cent. of the total filtrate nitrogen, and 
this sum may fall to less than 50 per cent. of the total non-protein 
nitrogen of blood. Much less is known concerning the erystalloids 
of blood than of urine. Since we observed that the unknown 
fraction was large, not only in nephritis, but in the blood of 
healthy individuals generally, our first suspicion was that amino- 
acids made up a considerable part of this unknown nitrogen. But 
this idea proved to be incorrect. The amino-acid fraction varies 
but little and is not appreciably increased in nephritis with nitro- 
gen retention. This fact, nevertheless, had considerable interest 
to us, because since this undetermined nitrogen is not composed 
of amino-acids, then it is probably not destined for cellular 
nutrition, but, on the contrary, is a katabolie product, a precursor | 
of some known urinary element. The definite fact gained from 
our studies in fractional blood analysis was that a large fraction 
of the non-colloidal nitrogen of blood consists of substances not 
found in the urine. This fact opened certain possibilities for 
study which had seemed useless so long as the search for a uremic 
toxin was restricted to the well-known ingredients of urine. From 
this time our energies were directed toward the isolation of 
various organic substances from the blood of patients suffering 
from convulsive uremia and testing these substances on animals. 
This is not the time to discuss intricate chemical methods em- 
ployed for fractioning the blood, since they have been reported 
elsewhere. Suffice it to say that in analysis of blood two dif- 
ficulties must be surmounted: First, to separate all protein 
without affecting any chemical change in the protein molecule 
that might produce cleavage products, and for this only colloidal 
methods are suitable and the second difficulty to be met is the 
ever-present possibility of altering some non-toxic substance into 
a toxic one through chemical reagents. It is also to be remembered 


UREMIA 63 


that chemical reagents might likewise transform a toxic body 
into one relatively harmless. 

By employing colloidal methods all protein can be separated 
from blood and a water clear filtrate secured which gives no 
reaction for protein by any test. In general, the methods em- 
ployed in our work were, with slight changes, those commonly 
used by Bio-chemists for the separation of alkaloidal bases. An 
alcoholic solution of the hydrochloride is finally secured from 
which a erystalline salt separates on the addition of gold or 
platinum chloride. These crystals may be purified by recrystal- 
lization, broken up with hydrogen sulphide and the pure base 
recovered for tests on animals. 

Considering the relative body weight of man and guinea-pig 
there should be sufficient toxin in 200 ¢.e. of blood from an 
uremic patient to produce definite symptoms in the guinea pig. 
This we employed as our standard. The amount of toxin in 
200 c.c. of blood is a fraction of a milligram. The base was dis- 
solved in one cubic centimetre of normal salt solution and injected 
into the peritoneal cavity. This in outline was our method. We 
had now examined samples of blood from twenty-two cases of 
epileptiform uremia and from over twice as many controls. For 
controls we used blood from other types of urswmia and eases 
of anuria, epilepsy and also normal individuals. From none 
of these control samples has a toxic substance been isolated. 
When, however, the solution of the base from the blood of cases 
of epileptiform uremia was injected into a guinea pig the result 
has been uniformly fatal. The first symptoms usually appear 
about five minutes following the injection. There was rapid 
breathing and muscular twitching; this often followed by a 
series of convulsive seizures, terminating in death in a few min- 
utes. In other cases the animals showed paresis of the hind 
legs, and had frequent bowel movements before convulsions 
develop. A few did not have definite convulsions, but severe 
twitching movements accompanying a stuporous state terminat- 
ing in death. The result of our investigations seemed to indicate 
that the blood of patients with epileptiform uremic contains an 
organic base which is toxic. Usually not more than a few hun- 


64 HARVEY SOCIETY 


dred cubic centimetres of blood can be taken from uremic pa- 
tients, and from his blood but a very small amount of the base can 
be recovered, the most recovered was weighed in milligrams. 

The question then arose, had we perhaps made this organic 
poison by our chemical procedures? The possibility remained 
that the blood of uremic patients may contain some substance 
not present in blood normally, nor in other diseases, and that our 
chemical manipulation so altered the nature of this substance 
that it became toxic. To determine this possibility we dialized 
blood from cases of convulsive uremia against distilled water, 
then this diffusate was reduced to a small volume at low tempera- 
ture and tested on animals. These diffusates are of course a 
mixture of all the non-colloids of blood. The interesting fact is 
that those samples from uremic patients were usually quite 
toxic, while other samples were inert. 

The substance isolated is basic in its properties and forms 
crystalline salts with platinum and gold. Of its chemical nature 
we know next to nothing because we have never been able to 
collect a sufficient quantity for analysis. Probably our chemical 
methods are quite imperfect and we either lose or destroy much in 
preparation. And in criticism of the work it is necessary to state 
that the existence of a toxin in uremic blood will not have been 
demonstrated until its chemical identity is known. That is the 
only assurance against the effect of reagents upon unknown and 
possibly labile organic compounds. Apparently we are dealing 
with a substance as poisonous as strychnine, the amount of which 
in the body at any one time being possibly but a small fraction 
of a gram. We can easily conjecture several sources of such 
a poison in the precursors of known organic extractives. Espe- 
cially inviting is the idea of reversible reactions in this connection, 
whereby the accumulaton in the body fluids of a katabolic product 
results in the increase also of its immediate precursor, which is 
often toxic but normally present in only the minutest amounts. 

Uremia presents a complex and intricate problem; and I do 
not wish to leave the impression that we now understand the 
clinical manifestations and their immediate causation. My 
thesis has been to indicate some of the more important 


| ae 


UREMIA 


components in uremic states and the probable origin of 


these individual factors. 


As in nephritis we conceive of 


specific renal functions and that the disorder of each alone or 
in combinations produces various symptoms, so in uremia our 
conception is of several simple types, each a resultant upon a 


peculiar metabolic defect. 


These simple components or types, 


frequently merging in various combinations, effect the varied 
syndromes we name uremia. 


Ascoli. 
Foster. 


Herter. 
Hewlett. 
Landois. 
Letche. 
Myers. 


Neubauer. 


Peabody. 
Reiss 
Voit. 


Vorlesungen u Uraemie. 
Arch. Int. Med. 


Jour. Amer. Med. Assa 
Am. Jour. Med. Sci. 
Montreal Med. Jour. 
Arch. Int. Med. 

Die Uremie. 

Ziet. f. Physiol. Chem 
Jour. Am. Med. Asso. 
Munch. Med. Woch. 
Arch. Int. Med. 

Zeit. f. Klin. Med. 
Zeitachr. f. Biol. 


Jena, 1903. 
1913, 13, 452. 


‘1915, 15, 356 & 754. 


1919, 24, 242. 
1916, 67, 927. 
1916, 151, 49 
1898, 27, 321. 
1916, 18, 636. 
Wien, 1891. 
1909, 53, 31. 
1920, 74, 641. 
1914, 61, 857. 
1914, 14, 236, 
1914, 80, 87 & 425 
1868, 4, 140. 


THE PRESENT STATUS OF CARDIO- 
DYNAMIC STUDIES ON NORMAL 
AND PATHOLOGICAL HEARTS* 


DR. CARL J. WIGGERS 


Professor of Physiology, Western Reserve University 


HE experimental or clinical investigator who essays to study 
circulatory problems that directly concern vital phases of 
medicine is frequently handicapped because certain fundamental 
data, which are the key to the interpretation of these problems, 
are not included in our stock of general information. It is de- 
sirable, therefore, first to review briefly some recent experiments 
which, I believe, help to clarify our understanding of the normal 
contraction processes in the heart. This accomplished, the laws 
which govern cardiac behavior will be analyzed. Finally, an 
effort will be made to see how far these laws may be applied in 
the interpretation of pathologic conditions with which we are 
confronted in the clinic. 


I. THE FUNDAMENTAL MECHANISMS OF THE HEART RATE 


The Physiology of Auricular Systolé-—The cardiac cycle is 
generally described as consisting of auricular systole, followed 
promptly by ventricular systole and diastole. It has long been 
known that certain quantitative differences exist between the 
contraction of the auricular and ventricular musculature. Thus, 
the greater capacity of the ventricles for performing work and 
their longer contraction period are generally emphasized, even 
in elementary physiology. Recently, evidence has been adduced 
which indicates that qualitative differences also exist. The 
ventricles receive their impulses through the His-Tawara system 
in such an ordered manner that all parts of the ventricular myo- 


* Delivered December 11, 1920. 
66 


CARDIO-DYNAMIC STUDIES 67 


eardium are virtually excited at the same time (Garten'; Lewis 
and Rothschild?). Consequently, we may assume that the entire 
bulk of the ventricular musculature begins and ends its contrac- 
tion at practically the same moment. 

It is different in the case of the auricular contraction. A few 
years ago, Lewis and his associates demonstrated that the im- 
pulses developed rhythmically in the sinus node, spread eccentric- 
ally over the arterial muscular tissues, exciting in succession each 
fractionate portion of auricular tissue. In this way, the more 
distal portions receive their excitation later than those portions 
more proximal to the cardiac pacemaker. 

In 1916, I presented experiments’ which led to the conclusion 
that, a short interval after receiving an excitation, each unit of 
auricular tissue undergoes a brief fractionate contraction lasting 
about 0.05 second and then relaxes—an interpretation that has 
recently been confirmed by Lewis and his co-workers.* Auricular 
systole begins with the first fractionate contractions near the 
sinus node, and ends when a balance of the fractionate relaxa- 
tions and contractions causes no further decrease in the length 
of the entire auricle. Since the fractionate units excited first 
begin to relax during mid-systole, the pressure in the auricles 
and large veins rises only during the early half and decreases 
during the latter half of auricular systole. We may therefore 
divide auricular systole into (a) a dynamic phase, during which 
blood is injected into the ventricles and (b) an inflow phase, 
during which some blood actually flows into the auricles from 
the central veins. 

The Consecutive Phases of the Ventricular Cycle.—In order to 
interpret the dynamic mechanisms of the ventricles, it is some- 
times desirable to subdivide their periods of systole and diastole 
into shorter phases. In doing this, synchronous pressure curves 
recorded by optical manometers from the cardiac chambers 


*Garten: Skand. Arch. Physiol. 29: 114, 1913; Ztachr. f. Biol. 66: 23, 
83, 1915. 

? Lewis and Rothschild: Phil. Tr. Roy. Soc. London 206: 181, 1915. 

* Wiggers: Am. J. Physiol. 42: 133, 1916; 40: 218, 1916. 

*Lewis, Feil and Stroud: Heart 7: 131, 1920. 


68 HARVEY SOCIETY 


and aorta, together with ventricular volume curves, are of 
great assistance. 

While it would be tedious to describe, even superficially, the 
apparatus and technic required for recording pressure and vol- 
ume changes accurately, the principles of such apparatus can be 
outlined in a few words. 

Suppose (Fig. 1) that small chambers, A, B and C, filled with 
fluid and covered by very tensely drawn rubber membranes, are 
inserted through the auricular and ventricular walls and into 
the aorta. Each membrane will then respond to every pressure 
variation by a microscopic movement. This can be magnified 
and rendered visible by reflecting a narrow band of light from a 
small mirror fastened to the rubber. By allowing these beams 
to focus on a film (D) moving in a specially constructed camera, 
a true picture of the pressure variations can be recorded. 

In order to record the volume changes of the ventricles, they 
are slipped as far as their a-v junctions into a glass oncometer 
covered by a rubber diaphragm in which an opening, correspond- 
ing in shape and size to the a-v ring, has been cut. This onco- 
metre is connected with a large recording tambour. When blood 
is expelled and the ventricular volume decreases, the volume of 
air in the tambour is reduced by a corresponding amount, and 
the tambour lever falls. When the volume of the ventricles, on 
the other hand, increases as blood flows in during diastole, the 
lever rises. By connecting the interior of the large tambour with 
an optical segment capsule, the very slight pressure variations 
which correspond to the volume changes may be projected and 
recorded optically (Henderson®; Wiggers®). 

While the conformation of such volume and pressure curves 
alters under different experimental conditions and varies also 
in different animals examined, their general character and the 
time relations are represented fairly well by the curves shown 
in Figure 2. A careful study of many kilometers of such records 
obtained from over 200 dogs under a large variety of experi- 


5 Henderson and Collaborators: Am. J. Physiol. 16: 325, 1906; 23: 
345, 1909. 

* Wiggers: Circulation in Health and Disease, 1915, Phil., Lea 
and Febiger. 


CARDIO-DYNAMIC STUDIES 69 


mental conditions, together with a careful consideration of similar 
dynamic studies carried out by Garten,t Piper, Straub’ and 
C. Tigerstedt, have led me to interpret and subdivide the ventri- 
cular cycle as follows: At the onset of ventricular systole (Fig. 
2, 1) the pressures within the auricle and ventricle are approxi- 
mately equal. At this time, as indicated by the experiments of 


Fic. I.—Schematic representation of principles employed to record pressure curves optically 
from auricles (A), ventricles (C) and aorta (B). D, sensitive photographic surface. Des- 
cription in text. 


Dean,® the a-v valves are in the act of floating into apposition. 
As Henderson and Johnson® suggest, this movement probably 
of the pressure rise (I) until the opening of the semilunar valves 
is initiated by the sudden cessation of the jet when the peak of 
the presystolic auricular wave is reached. The first elevation 
of intraventricular pressure firmly closes these valves, and the 
ventricles then contract in an absolutely isometric fashion. This 
first phase of ventricular systole, extending from the beginning 


*Dean: Am. J. Physiol. 40: 206, 1916. 
® Henderson and Johnson: Heart 4: 69, 1912. 


70 HARVEY SOCIETY 


of the pressure rise (1) until the opening of the semilunar valves 
(II), is preferably designated as the isometric contraction phase. 

As soon as intraventricular pressure exceeds intra-aortic pres- 
sure, the semilunar valves open and a comparatively large vol- 


VENTRICLE 


AURICLE 


1 HE IVV WE VIE VID 


Fic. II.—Superimposed curves of pressure changes in ventricle (heavy line), aorta (upper 
dotted line), and auricle (lower dotted line) together with volume changes in two ventricles 
(lower solid line)- I-IV, systole; IV-VIII, diastole. Detailed phases of each discussed in text. 


ume of blood per unit time is ejected. As long as the volume 
ejected remains greater than the outflow from the peripheral 
arterioles the aortic and intraventricular pressures continue to 
rise. This summit (III) marks the end of a second phase of 
systole which I have designated as the maximum ejection phase. 
As soon, however, as the volume of the systolic discharge decreases 


CARDIO-DYNAMIC STUDIES 71 


to such an extent that it no longer equals the peripheral outflow, 
the aortic and intraventricular pressures begin to decline. This 
third phase (extending to IV) may be designated as a phase of 
reduced ejection. It terminates the period of systole. 

At the onset of ventricular relaxation, aorta and ventricle 
are still in communication. The first event, viz., the approxima- 
tion of the semilunar valves, is signaled by a sharp drop in 
both aortic and intraventricular pressures (IV-V), designated 
as the incisura. This marks a fourth or protodiastolic phase of 
the ventricular cycle. Following the closure of the semilunar 
valves (interpreted as taking place at V) and until the a-v valves 
have opened, the ventricle relaxes without any flow of blood either 
from or into its cavity. This phase (extending from V to VI) 
may be designated as the isometric relaxation phase. With the 
opening of the a-v valves (VI), a rapid ventricular inflow 
begins. This continues until an equalization of pressure between 
the auricle and ventricle has taken place (VII), or until a 
subsequent systole interrupts the filling. This is the sixth phase, 
which may be designated as the early diastolic inflow phase. In 
long cycles, and when auricular pressure is normal, a period of 
reduced filling or approximate stasis is indicated in the volume : 
eurve (VII and after), which may be designated, after Hender- 
son’s suggestion, as the phase of diastasis. Finally, there may 
be added an eighth phase during which the dynamic interval 
of auricular systole (VIII) affects the filling or pressure of the 
ventricles. This summary of the dynamic events occurring 
during ventricular systole and diastole and the suggested sub- 
division of the periods of systole and diastole into shorter phases 
is schematically indicated in Figure 3. On the diagrams are 
also indicated the average duration of these consecutive phases 
recently found in animals in which the thorax remained intact. 


i. THE LAWS GOVERNING CARDIAC BEHAVIOR UNDER NORMAL 
AND ABNORMAL CONDITIONS 


Under a variety of physiologic, pharmacodynamic and _ path- 
ologic conditions, the heart must adapt itself to an altered venous 
return and changes in arterial resistance. In association with 
or quite independent of these, changes in rate and rhythm may 


72 HARVEY SOCIETY 


take place. Again, the inherent functions of cardiac irritability 
and contractability may be stimulated or depressed. 

When such a combination of influences unites to modify the 
cardiac mechanisms, it may become quite perplexing, if not hope- 
less, to analyze the factors responsible for the resulting cardiac 
behavior. It is quite probable that this accounts for the observa- 


Bo OPESOPIETRA Come D matinun vce D Reou.ee srecton 


VENTA AR 
PRESSURE SToLts 


TR PROTO-Brayroun AELas VY tsomeran eves 


Zz 
Ai, 


Fic. III.—Series of pictorials illustrating the consecutive phases of the cardiac cycle estab- 

lished from pressure and volume curves. The extent of the ventricular pressure variations 

that have been completed at the end of each phase are also indicated. Upper series, phases 
of systole; lower series, phases of diastole. 


tions (1) that ‘‘clinical hearts’’ do not always seem to conform to 
the laws and reactions established by laboratory experiments, and 
(2) that they do not always react to drugs as do the hearts of 
experimental animals. 

It is important, therefore, that the laboratory investigations 
concern themselves primarily with the alteration produced in 
cardiac behavior when, as nearly as possible, only one of these 
variable influences operates at a time. The history of such re- 
searches has been the history of all investigations involving the 
use of complicated apparatus to unravel the mysteries of complex 
functions. One investigator demonstrates a series of striking 


CARDIO-DYNAMIC STUDIES 73 


facts; their uniformity suggests that they are grounded on a 
common factor or principle; a theory or law of cardiac behavior 
is formulated. Another investigator discovers certain facts 
which it is difficult or quite impossible to harmonize with such 
a conception. The older law is apt to be considered disproven 
and a new one is formulated. Rebuttal and countercharges sup- 
ported by new and still newer experimental facts fill many pages 
of scientific literature until he who follows every development 
cannot always decide what to believe either in his own work or 
in the experiments of others. 

With the many differences of opinion regarding the funda- 
mental laws controlling the functions of the heart beat, it is 
possible to keep from falling into this hopeless mental state only 
by bearing in mind that the disapproval of certain interpretations 
does not necessitate the discard of all experimental facts arrayed 
in its support. On the other hand, an investigator may have 
established a broad principle and yet have failed to realize the 
limitation of its applicability. We must admit, I believe, that 
while each new series of experiments has contributed its building 
stone, there still remains to be hewn out of unknown facts the 
keystone to that group of laws which regulates the heart beat 
under diverse conditions of circulation. 

The Heart Rate as a Factor in Controlling Cardiac Efficiency 
and the Law of Uniformity of Behavior—In a large series of 
experiments, Henderson and his co-workers® have contributed 
greatly to our understanding of the cardiac mechanism. They 
have demonstrated by experiments, that to me seem not to be 
negatived by apparently contradictory results of other investi- 
gators, that the ventricular filling occurs chiefly during the earlier 
portion of diastole, and that, in slowly beating hearts, there exists 
a phase of diastasis during which a very gradual filling of the 
ventricle takes place. They have done much toward demonstrat- 
ing that the blood volume received by the ventricle during diastole 
also determines the amount discharged during systole. They 
have analyzed how variations in ventricular tonus can modify 
both filling and systolic discharge. They have demonstrated 
how, as the heart accelerates and the cycle shortens, the succeed- 


74 HARVEY SOCIETY 


ing diastolic filling is encroached on more and more until the 
diastolic inflow is abbreviated and systolic discharge is greatly 
affected. That this tendency of the systolic filling to be de- 
creased as the heart accelerates is one of the fundamental com- 
pensatory mechanisms which prevents an excessive minute volume 
from being discharged during rapid heart action, cannot be 
questioned. Henderson and his collaborators maintain further, 
however, that both under normal conditions of venous return as 
well as during states of increased venous pressure, the systolic 
discharge cannot be further affected by the venous pressure 
change or volume of venous return, but hold that it is determined 
solely by the duration of the cardiac diastole. They found that 
the volume curves of the ventricle, at any heart rate, are prac- 
tically superimposable on portions of a standard curve obtained 
during a slow beat. This led them to formulate the ‘‘law of 
uniformity of cardiac behavior,’’ according to which the systolic 
volume discharged is entirely a function of heart rate as long 
as the venous pressure is at or above normal. 

The strict operation of this law has been questioned by sub- 
sequent investigators because it does not appear to square with 
other experimental evidence. In 1914, [°° found that systolic and 
diastolic blood pressures in man vary, independently of heart 
rate, which was interpreted to indicate that the rate of ventricular 
filling in man must alter during normal inspiration and expira- 
tion. Henderson and Haggard" have subsequently attempted to 
nullify these experiments by showing that systolic and diastolic 
pressures, measured by the sphygmomanometer method in man, 
failed to increase when a person is tilted on a board from a hori- 
zontal to a head-down position—a procedure obviously increasing 
the venous return and auricular pressure. Such experiments 
cannot be regarded as crucial, however, for, even if it be admitted 
that the ordinary methods of estimating human blood pressure 
are sufficiently delicate to detect small variations, the fact that 
their experiments were always attended by heart rate changes, 


4 Henderson and Haggard: J. Pharmacol. and Exper. Therap. 11: 
189, 1918. 


CARDIO-DYNAMIC STUDIES 75 


make it quite impossible to lend much significance to the pulse 
pressure change that occurred. On the basis of subsequent work, 
I am quite ready to admit, however, that my interpretation of 
pulse pressure changes during inspiration and expiration are 
more probably explained by a direct effect of the changing nega- 
tive pressure on the aorta itself. 

The view that the systolic discharge is unable to vary inde- 
pendently of heart rate when venous pressure is increased has 
been disputed by the results of Krogh,'* Plesch'* and Zuntz;"* 
for it is difficult to explain the greatly augmented blood flow 
through the lungs during exercise in any other way than by 
assuming that the systolic discharge increases above normal even 
when the heart is very rapid. Krogh endeavored to show, fur- 
thermore, that such results may be harmonized with Henderson’s 
volume curves if one or two assumptions is made, namely, either 
that the venous supply is normally inadequate, or that some 
myocardial factor increases the vigor of systole. Henderson and 
Barringer’ again investigated the question as to whether the 
accelerator nerves can effect the amplitude of systolic discharge 
independent of rate—with negative results. Subsequently, Star- 
ling and his collaborators'® re-investigated the subject by means 
of their ‘‘heart-lung preparation’’ and concluded that the ventri- 
cular volume curves are not superimposable. Their volume 
curves indicated to them that when venous pressure increases 
above normal, the systolic stroke is greatly increased without 
any change in heart rate. Similar conclusions have also been 
reached by Straub’ and Socin." 

We may inquire what changes must necessarily take place 
if the systolic discharge increases at the same time that the heart 
accelerates. Obviously, such a condition is made possible only 


* Krogh: Skand. Arch. Physiol. 27:126, 1912. 

*Plesch: Centralbl. f. Physiol. 26:90, 1912. 

* Zuntz: Ztschr. f. klin. med. 74:347, 1912. 

* Henderson and Barringer: Am. J. Physiol. 31:228, 352, 1913. 


* Starling and Collaborators: J. Physiol. 44:206, 1912; 47:275, 286, 
1913; 348, 357, 465, 1914. 


*Socin: Arch. f. d. ges Physiol. 160:132, 1914. 


76 HARVEY SOCIETY 


by an increase in the expulsion rate or by lengthening of the 
ejection phase. Recent experiments in which I measured the 
duration of systole after saline infusion indicate that this causes 
a definite prolongation of the ejection phase, quite independent 
of diastole length. 

On the basis of recent experimental work, Katz and I** have 
found it necessary to conclude also that, even under quite normal 
conditions, the systolic discharge of the heart may not be regu- 
lated by changes in the duration of cycle alone. Our evidence 
is based on the following considerations: Although emphasis 
has not been laid specifically on the fact by Henderson and 
his co-workers, it is evidently a corollary of the ‘‘uniformity of 
behavior law’’ that the duration of systole is fixedly related to 
cycle lengths under all conditions which normally produce a 
change in heart rate. As the cycle shortens from a very long 
to a very short cycle, the phase of systolic ejection must, at first, 
be very little affected but becomes progressively shorter. By 
determining the theoretical systole and cycle lengths and express- 
ing this as a systole: cycle ratio, it was found possible to construct 
a curve of theoretical s/e ratios. To this curve, the actual 
s/e ratios at different heart rates should conform if the law of 
superimposability holds good. It was found, however, that, 
while the actual s/e ratios obtained during normal rates and 
during vagus beats coincided reasonably well, the ratios were 
very much below this curve when the heart rate increased during 
stimulation of the accelerator nerve. 

In carrying this work still further, Katz and I, working in- 
dependently and by different methods, have obtained other evi- 
dence which indicates that during vagus slowing the periods of 
systole and diastole are also not strictly related to the length of 
previous diastole. When, for example, the peripheral end of a 
vagus nerve is stimulated with a current producing moderate 
slowing, systole increases in length for several succeeding beats, 
becoming stationary only when a new equilibrium has been 
established. This occurs regardless of previous diastole lengths 
and often contrary to them. After reflex slowing induced by 
central vagus stimulation, the duration of systole in a few experi- 


** Wiggers and Katz: Am. J. Physiol. 53:49, 1920. 


CARDIO-DYNAMIC STUDIES iid 


ments was longer than in peripheral vagus stimulation, even 
though a much greater slowing was produced by previous peri- 
pheral stimulation. When partial asphyxia produces cardiac 
slowing, the periods of systole may remain unchanged or even 
become abbreviated.® 

Such results indicate that while a constant relation between 


Fic. IV.—Diagram showing arrangement of muscle activating a work adder, with attach- 

ments for photographically recording tension changes and length changes optically. S, 

spring; m, small mirrors reflecting light beam to photographic film; P. Further description 
in text. 


systole and diastole lengths, such as complete superimposability 
of beats demands, approximately obtains when a stable equili- 
brium has once been produced after direct vagus stimulation, 
there are other factors at work which more than counterbalance 
such a control of systole length. 

On the basis of all these investigations, we must conclude that, 
while the systolic discharge is mechanically determined by the 
heart rate when other factors are unchanged, the simultaneous 
variations of, these factors even under normal conditions prevent 
the beats from being superimposable. 

The Response of thé Heart to Changes in Venous Return and 


” For subsequent extension of this work cf. Wiggers and Katz: Amer. 
Journ. Phys., 58, 439, 1922. 


78 HARVEY SOCIETY 


Arterial Resistance.—The response of the normal heart to changes 
in venous return and alterations in arterial resistance have been 
studied by recording both the volume curves of the two ventricles, 
and the pressure curves from the separate ventricles. While 
such methods have their difficulties and drawbacks, their use has 
served to advance our understanding of an important phase of 
eariodynamies. In order to grasp the significance of such investi- 
gations in their fullest, however, it is necessary to recall the 
nature of the contraction processes in a skeletal muscle which 
operates in a manner similar to the heart. 

It has been pointed out by Henderson that, with certain 
reservations, the heart contracts as a skeletal muscle operating 
a work-adder. In such an arrangement (Fig. 4) the weight 
(W,) which the muscle is required to lift is supported by the 
ratchet (R,,) and, consequently, weights the muscle only during 
contraction. During the rest period, as well as during the pro- 
cess of relaxation, the muscle is stretched by a smaller weight W,. 
Obviously, the greater this weight becomes, the greater the length 
of the resting muscle. This resting length of the muscle is 
referred to as its initial length. When this weight increases, 
the muscle fibers are not only lengthened more but are also placed 
under a greater tension, referred to as its initial tension. 
Changes in this initial tension may be recorded graphically and 
evaluated by attaching the upper end of the muscle to a stiff 
spring, the very slight movements of which can be greatly mag- 
nified and projected (Fig. 4). A muscle so arranged is said to 
be ‘‘after-loaded.’’ Before it can shorten, its tension must be 
increased sufficiently to overcome the load W,, i. e., it first con- 
tracts isometrically. Such a tension variation will be recorded by 
the upper lever a short interval before the lower lever begins 
to register a decrease in length. This accomplished, the ratchet 
R, engages and the weight is raised during the remainder of the 
contraction phase. Inasmuch as the tension during this phase 
of contraction does not alter appreciably, it is said to contract in 
an isotonic manner. At the onset of relaxation, the ratchet 
lever R, engages and the relaxation process is assisted by the 
small weight W,. 


CARDIO-DYNAMIC STUDIES 79 


In the normally beating heart, the venous pressure represents 
the distending load (W.) and determines the initial tension as 
well as the initial length of the ventricular muscle fibers, while 
the arterial pressure corresponds to the lifted load (W,). It is 
clear, therefore, that changes in initial tension as well as the 
tension changes during contraction and relaxation may be con- 
veniently followed by recording optically the intraventricular 
pressures. Changes in the length of muscle fibres, as Frank, 
Patterson, Piper and Starling and others have pointed out, may 
be evaluated most satisfactorily by studying the changes in the 
ventricular volume during consecutive phases of the heart cycle. 

In 1914, I reported® experiments which seemed to demonstrate 
that every increase or decrease in the volume of blood returning to 
the right auricle affects simultaneously the initial tension, height, 
and contour of the right intraventricular curve. These experi- 
ments were the first to demonstrate that the laws derived by 
Frank from a study of the frog’s heart apply also to the naturally 
contracting mammalian ventricle. . In brief, the conclusion 
seemed justified that the gradient of the isometric pressure rise 
as well as the systolic pressure-maximum are determined by the 
imtial tension as long as marked changes in arterial resistance or 
alterations in the inherent contractility of the heart are not 
produced. At the same time, it was shown that any increase 
in pulmonary arterial resistance is also capable of altering the 
pressure-maximum in the right ventricle under conditions of 
unchanged venous inflow. Finally, it was pointed out that inde- 
pendent of, or coincident with these factors the pressure-maxi- 
mum may be determined by the inherent contractility or irrita- 
bility of the heart itself. 

Shortly after the publication of this work, a series of investi- 
gations were published which apparently analyzed the reactions 
of the heart to increased venous return and increased arterial 
resistance in a much more fundamental manner. This was ac- 
complished by limiting the circulation to the heart and lungs 
and controlling independently the venous inflow and the arterial 
resistance. With such a ‘“‘heart-lung’’ preparation dynamic 
experiments were carried out in London, by Starling,'® working 


80 HARVEY SOCIETY 


at various times in association with Knowlton, Markwalder, Pat- 
terson and Piper, and contemporaneously. by Straub’ in Munich. 
Subsequently Gessell*® in this country, has utilized a similar 
method of experimentation. 

The first investigations of Starling and his associates showed 
that the systolic discharge of the ventricle at any constant rate 
is unaltered by very considerable change in arterial resistance 
as long as the inflow is kept constant. On the other hand, they 
found that, within wide limits, the heart is able to increase its 


A 
3 ¢ 
Fic. V.—Diagrammatic representation of ventricular volumes (upper curves) and pressure 
changes in left ventricle (lower curves), according to results of Patterson, Piper and Starling. 
D, diastolic volume; S, sytolic volume; D-S sytolic discharge; I, initial pressure; M, pressure- 
maximum. A, normal controls; B, after increased arterial resistance—initial pressure (I) 
unchanged, initial volume (D) increased, pressure-maximum (M) higher, sytolic discharge 
(D-S) unaltered. C, after increased venous iniow—initial pressure (I) decreased, initial dia- 
stolic volume (D) increased, sytolic discharge (D-S) and pressure-maximum (M) increased. 


output in direct proportion to the venous inflow. Similar results 
were obtained by Socin’ and de Heer.*? 

In studying the cardiac reactions more in detail, Patterson, 
Piper and Starling obtained results which are diagrammatically 
illustrated in Figure 5. Their records show that when the venous 
inflow increases, the ventricles are more distended in diastole 
and the systolic discharge increases (Fig. 5, A and C). The 
initial tension in the left ventricle, however, may not increase, 
but, on the contrary, may actually be lower. Nevertheless, the 
intraventricular pressure-maximum appears to rise. 

When arterial resistance alone was raised, they again found 
an increased diastolic volume due to retention of blood during 
the first few beats. Their tracing indicates that once dilated to 

” Gesell: Am. J. Physiol. 39:239, 1916; 40: 267, 1916. 

* de Heer: Arch. f. d. ges Physiol. 148:45, 1912. 


CARDIO-DYNAMIC STUDIES 81 


a stable capacity, the heart expels at least as large a systolic 
volume as before the increase in resistance (Fig. 5, A, B). In 
studying the intraventricular pressure changes accompanying 
such reactions, it was also found that the left intraventricular 
pressure-maximum increases, that the pressure gradient rises 
steeper and that the duration of the period of systole is increased. 
In some cases, however, the noteworthy observation was made 
that the initial tension is scarcely affected in the left ventricle. 
These results, together with observations on the isometric con- 


A 8 ¢ 


Fic. VI.—Diagrammatic representation of pressure changes in right (lower) and left (upper) 

ventricles according to Straub’s results. A, normal control curves; B, after increased arterial 

resistance—initial pressure (I) increased in left ventricle, unaltered in right, pressure-maximum 

(M) higher in left ventricle, lower in the right. C, after increased venous inflow—initial 

pressure (I) increased in right but not in left ventricle, pressure-maximum (M) increased 
markedly in right and vero slightly in left ventricle. 


traction curves obtained from the terrapin heart, led them to 
conclude that ‘‘in the reaction of the heart to increased venous 
inflow and increased resistance, the only factor which constantly 
varies with the response of the ventricles is the volume of the 
heart, i. e., the length of its muscle fibers.’’ They believe, on 
the basis of such experiments, that we are justified in ascribing 
the increased energy of the cardiac contractions under conditions 
of increased inflow or augmented resistance entirely to alterations 
in the length of the muscle fibers and not to change in tension 
on the fibers, which, as they interpret it, may or may not be 
present at the same time. 

The contemporaneous experiments of Straub’ led on the whole 
to similar, yet in some vital respects, different conclusions. He 
also found that, under a constant venous inflow, increased arterial 

6 


82 HARVEY SOCIETY 


resistance leads to a systolic retention both in systolie and dia- 
stolie distension. The systolic discharge remained unaffected. 
His optical pressure curves indicated, moreover, that, in the left 
ventricle, not only the maximum pressure, but also, the initial 
pressure increases (Fig. 6, of A and B). Such results, contrary 
to those reported by Starling and his co-workers, would indicate 
that an increased pressure-maximum is constantly associated with, 
if not fundamentally due to, an increased initial pressure. In 
the right ventricle, however, he found no increase in height nor 
elevation of the initial tension ; in fact, in some cases, the pressure- 
maximum seemed to be reduced. These results, it will be recalled, 
are quite contrary to those previously reported by Fiihner and 
Starling’® who found that a ‘‘ backing up’’ of blood always occurs 
when the left heart works against an increased resistance. In 
attempting to harmonize these discrepancies, Straub pointed out 
that he also was able to obtain such ‘‘back pressure’’ effects 
when the arterial pressure at the start was low and the coronary 
supply therefore insufficient to maintain the heart in prime con- 
dition. Straub considered the latter reaction as one of a hypo- 
dynamic and uncompensating heart; Fihner and Starling 
considered it the reaction of a normal heart. We shall revert to 
a discussion of this question later. When the inflow rate was in- 
creased but the arterial resistance kept constant, Straub found, 
similar to Starling and his co-workers, that the two ventricles 
dilate somewhat and expel larger systolic volumes. The intra- 
ventricular pressure curves taken from the two ventricles again 
showed differences (Fig. 6, A and C). In the right ventricle, 
changes similar to those reported by myself were constantly 
observed, i. e., increased diastolic filling always occasions an 
increased initial tension and a higher pressure-maximum. In 
the left ventricle and in confirmation of Starling’s results, no 
changes in initial tension occur although the pressure curves did 
become somewhat higher. According to these results, the in- 
creased discharge of the right ventricle is unable to affect the 
diastolic filling of the left sufficiently to cause an elevation of 
initial tension. While Straub interprets his results as indicating 
that initial tension is the primary factor in determining ventri- 


CARDIO-DYNAMIC STUDIES 83 


cular efficiency, the increased systolic discharge of the left ven- 
tricle must, in such eases, be assigned to changes in initial length 
or initial volume rather than initial tension. 

In investigating the importance of auricular systole in the 
dynamics of the ventricle, Gesell,’® was compelled to consider the 
broader question as to whether initial length or initial tension 
primarily determine ventricular efficiency. In the auricle of the 
river turtle, which shows rythmice fluctuations in tonus, he found 
it possible to study the effect of changes in tension and length 
independently. His results indicated that in the auricle of the 
turtle, increased strength of contraction may accompany either 
increased length of fiber while initial tension remains constant, 
or increased tension while initial length remains the same. Fur- 
ther experiments on a mammalian heart-lung preparation led him 
to conclude that this also applies to the mammalian ventricles. 
The latter experiments may not be regarded as quite conclusive, 
however, because the method employed to record variations in 
tension and length do not appear to be quite adequate for the 
study of the mammalian circulation. As a result of his work, 
Gesell suggests that, while both initial length and initial tension 
may determine ventricular efficiency, the surface-volume relations 
are also concerned. 

With these conflicting views before us it seems desirable to 
re-investigate whether measurable differences of initial tension 
fail to accompany such experimental procedures as have been 
definitely shown to increase initial volume. This, I have recently 
attempted in intact animals. At once we may anticipate the 
loud objections that experiments carried out on intact animals can, 
of course, not prove valid either the one contention or the other. 

Extensive experience has convinced me that it is not so difficult 
to control or evaluate the separate factors in intact circulation 
experiments as has been claimed. If the vagi nerves have pre- 
viously been severed, variations in heart rate are no more exten- 
sive than those which occur in perfused hearts. The venous 
return may readily be reduced by compression of the vena cava 
and increased by the injection of innocuous normal saline. In 
neither event is arterial resistance altered appreciably. In- 


84 HARVEY SOCIETY 


creased resistance may be induced either peripherally by vaso- 
constriction or more centrally by mechanical compression of the 
aorta. If carried out for intervals which are short but quite long 
enough to obtain observations, the venous return is either not 
sufficiently affected or, if modified, can be evaluated in interpret- 
ing the reactions. 

Are the experimental conditions in the heart-lung preparation 
better or more controllable? The very fact for which these ex- 
periments are lauded, viz., that each factor—venous inflow, arter- 
ial resistance and rate—may be controlled at will, makes them a 
source of trouble. In such schemes, it is the first duty of the 
experimenter so to adjust the artificial factors (the controllable 
factors) that the heart beats after a fashion which he interprets 
as normal. What criterion other than instinct can guide him? 
We have already pointed out that the adjustment of the artificial 
resistance to the inflow volume apparently determines whether or 
not a ‘‘back pressure’’ effect takes place on raising the arterial 
resistance. Each experimenter will be ready to admit that his 
adjustment approximates normal. Fiihner and Starling find 
‘“back pressure effects’’ as far back as the right auricle on inereas- 
ing artificial resistance; Straub finds that the pressure in the 
right ventricle decreases. Both results cannot apply to the intact 
normal circulation. Who shall judge between them? I have 
been able to show in similar heart preparations that, with constant 
arterial resistance, an increased systolic discharge may cause 
either an increased or decreased pulse pressure in the arteries, 
depending on whether the arterial resistance during the so-called 
‘‘normal’’ is relatively great or small, as compared with the 
venous inflow. Both reactions cannot be characteristic of the 
intact circulation. The fact that mean arterial pressure approx- 
imates the normal found in animals of course means nothing 
whatsoever. In short, I believe that in many instances it is 
possible to set the ‘‘normal’’ so that absolutely diverse proposi- 
tions may be clearly (!) demonstrated with equal facility. 

Aside from the judgment of the experimenter, we have pos- 
sible alterations in the physiological condition of the perfused 
heart to deal with. Does it react as the heart in the intact cir- 


CARDIO-DYNAMIC STUDIES 85 


culation? Always, it is separated from all nerve control—not 
without its effects on the duration and strength of ventricular 
contraction. Usually, also, the pericardium is opened—causing, 
as has been shown in Starling’s own laboratory by Kuno, im- 
portant changes in the distension of the ventricles. Commonly 
also, the capacity of the rubber tube substituted for the aorta is 
too small to accommodate, in a natural manner, the ejected blood, 
so that the entire systolic volume must each time be forced 
through a small cannula tied into the narrow lumen of the 
innominate artery. In the heart-lung preparation, the blood 
supply of the heart also changes in a manner which is quite 
abnormal, whenever the resistance increases. If the aortic re- 
sistance increases in the natural circulation, short circuits are 
always available through which an excess of blood may flow. In 
the heart-lung preparation the only short circuit is the coronary 
system which then apparently allows exorbitant volumes of fluid 
to flow through it. A few direct observations may be interesting : 
If we use the figures of Patterson, Piper and Starling, we can 
only conclude that normally from 25 to 35 per cent. of the entire 
systolic discharge passes through the coronary system, a volume 
which if correct represents a most abnormal state of the coronary 
circulation which certainly does not conform to the intact heart. 
Straub found that after compression of the aorta, the coronary 
blood flow increases so greatly that right auricular pressure is 
thereby augmented—a condition just the reverse of that obtaining 
in the intact circulation. Frequently also, the heart is supplied 
with a blood-saline mixture of unnatural composition. In 
Straub’s experiments, for example, the deficiency of carbon di- 
oxid in the blood, according to his own interpretation, caused the 
hearts to beat at the excessive rate of 300 per minute. Finally, 
it seems very doubtful whether the preparation accomplishes 
the task for which it is specifically employed. I question, for 
example, whether it is possible to alter any one factor—e.g.,— 
heart rate, venous pressure or arterial resistance—without at the 
same time affecting some other factor. Thus, it appears both 
from the records of Patterson, Piper and Starling and those of 
Straub that, whenever the arterial resistance increases consider- 


86 HARVEY SOCIETY 


ably, the filling pressure in the right auricle also augments. 
Again, I have found it exceedingly difficult in similar experi- 
ments to dissociate changes in temperature from changes in ven- 
ous inflow; the two seem intimately interdependent. Whenever 
the inflow rate is increased, a tendency exists to increase the 
temperature of the heart muscle; when it is reduced, the reverse 
tendency exists. The temperature change may be only 0.5 C.; 
but what changes in inherent irritability and contractibility may 
not this induce! How can the influence of this factor be sep- 
arated from that produced by augmented inflow itself? On the 
whole, who dares to say that the heart in such preparations reacts 
as would an intact heart or that every factor can be per- 
fectly controlled? 

I cite these objections not to condemn the method, nor to 
discourage its employment in the analysis of the cardiae mech- 
anisms. On the contrary, I am of the opinion that its employ- 
ment has greatly enhanced our knowledge of the fundamental 
laws according to which the heart can react. I merely wish to 
emphasize the possibility that such laws may apply only to special 
conditions and must always be transferred to the intact circula- 
tion with the greatest reserve and caution. 

With such reflections in mind, I have recently investigated 
the ventricular pressure and volume changes during conditions of 
altered arterial resistance and venous inflow on intact animals, 
for, in such experiments, in contrast to studies on the heart-lung 
preparation, it is possible to study what probably does happen 
when the heart reacts to different influences. Both right and left 
intraventricular pressures were simultaneously recorded by opti- 
cal manometers. In some experiments the volume changes were 
also recorded; in others, volume curves were omitted in order 
to test the same procedures in animals in which the natural 
pericardial support of the ventricles was maintained. 

In seventeen experiments, so far completed, it was found, 
without exception, that any sudden increase in venous return 
which increases also the volumes of the ventricles, always 
promptly elevates the initial tension and pressure-maximum in 
the right as well as left ventricle. This is illustrated by the 


CARDIO-DYNAMIC STUDIES 87 


im 
1 
4 
1 
1 
FN 
C214, mir 
a 
a 
0214, ‘ ~ 1 es 
243 C2/4,3- C2/4,E¥ 


Fic. VII.—Superimposed tracings of right (lower) and left (upper) intraventricular pressure 

curves, after experiments of author. I, normal as compared with effects during asphyxia; 

II, normal as compared with saline infusion effects; VIII, normal as compared with decreased 

venous return after vena cava compression; IV, normal as compared with effects of vaso- 

constriction; X, as compared with effects of aortic compression; XV, normal as compared 
with effects of chloral (2) and strophanthin (3). 


records shown in Figure 7, II. Curves ‘‘1’’ are normal controls. 
Fifty ¢.c. of warm saline solution was then allowed to flow into 
the external jugular vein in twelve seconds. In other experi- 


88 HARVEY SOCIETY 


ments, this had been shown to increase definitely the diastolic 
volume of the ventricles and augment the systolic discharge in 
from 2 to 3 seconds. Four seconds after, curves ‘‘2’’ were 
recorded. Both intraventricular pressure curves show an eleva- 
tion of initial, as well as maximum pressure. Toward the end of 
the infusion, the third series of curves were taken; a further 
elevation of initial and maximum pressures in both ventricles 
is obvious. 

Reduction of the venous inflow produced by clamping the 
inferior vena cava has precisely the reverse effects on initial and 
maximum pressure in the two ventricles. This is shown in 
records labeled as observation VIII. Such changes in initial 
pressure occur with great promptness when the volume of fluid 
returned is either decreased or increased. Thus, in observation 
VIII, ‘‘1’’ shows the normal control, ‘‘2,’’ ‘‘3’’ and ‘‘4’’ illus- 
trate the changes taking place during the second, fourth or sixth 
beats after compression of the vena cava. 

When arterial resistance increases either through intense vaso- 
constriction or mechanical compression of the aorta, the initial 
pressure is always elevated when it is of sufficient degree to 
cause a dilation of the ventricles. The details of these changes 
are illustrated in the series of records shown in IV and X. Ob- 
servation IV indicates the final results during intense vaso- 
constriction reflexly induced by stimulating the central end of 
a divided vagus nerve. Curves ‘‘1’’ are normal controls. While 
arterial pressure (recorded supplementary) was on the ascent, 
curves ‘‘2’’ were recorded. At the height of the pressure reaction 
curves ‘‘3’’ were taken. In both, a considerable elevation of 
initial pressure is indicated in the left ventricle pressure curves 
and a relatively smaller increase is discernible in the right ven- 
tricle. In observation X are noted the immediate effects of rais- 
ing the arterial resistance through mechanical compression of the 
thoracic aorta. Curves ‘‘1’’ are normal, curves “‘2’’ represent 
the pressure changes during the first beat following compression. 
The pressures in the right ventricle are unaffected. The pressure- 
maximum increased by virtue of the higher resistance and pres- 
sure existing during the contraction process, The initial pressure 


CARDIO-DYNAMIC STUDIES 89 


has not elevated. Curves ‘‘3’’ show the changes in the third 
beat after compression. Increased initial tension and pressure- 
maximum occur in the left ventricle, the pressure in the right 
still remaining unchanged. Curves ‘‘4’’ represent the fifth beat 
after compression. Initial pressure and pressure-maximum are 
further elevated in the left and, for the first time, in the right 
ventricle also. 

Experiments of another order have also been carried out. In 
these, the ventricular volume curves were recorded on a slowly 
moving smoked paper; the two intraventricular pressure curves, 
as before. At the first indication of an increase in diastolic volume 
(initial length) after slow saline infusion, optical pressure curves 
were at once recorded. Comparison with normal curves showed 
that the initial pressure-increase in the right ventricle was never 
dissociated from an alteration in initial diastolic volume. 

This state of affairs obviously holds good only as long as the 
inherent functions of the cardiac muscle are not excited or de- 
pressed. There are many evidences of deviations from this rule; 
both in the literature emanating from other laboratories and my 
own. Thus, when the initial pressure becomes elevated to an 
excessive degree, the intraventricular pressure-maximum no 
longer increases but becomes lower at the same time that the 
systolic discharge lessens. So also, when the heart is long dis- 
tended by a great inflow or is required to react against a very 
high arterial resistance for a long time its subsequent power of 
response is reduced. The irritability of the heart may also be 
depressed or stimulated by chemical agents, in which case the 
pressure-maximum and systolic discharge are not related to the 
initial pressure. This is illustrated in observation XV, in which 
curves ‘‘1’’ again show normal controls. Curves ‘‘2’’ are repre- 
sentatives of pressure changes following the use of chloral hyd- 
rate. Initial pressure is greatly elevated in the right, very slightly 
in the left ventricle. In spite of this, the pressure-maximum is 
lower in both ventricles. The heart was obviously dilated. 
Neither increased initial pressure nor increased initial length de- 
termines the vigor of the ventricle when the myocardium is de- 
pressed. Curves ‘‘3’’ were obtained after subsequent use of 


90 HARVEY SOCIETY 


strophanthin. The tension maximum increased above normal 
in both ventricles—the initial tension remaining unaltered in the 
left and decreased in the right. 

Viewing all the experimental evidence in the light of the more 
fundamental work of Blix, Hill and others on skeletal muscle, 
we must be ready to admit that the dynamic efficiency of the 
ventricle may be fundamentally determined by such factors as 
initial length, and diastolic surface-volume relations. It is not 
so evident, however, (except, perhaps, under conditions of very 
small venous inflow, or where the ventricle has lost its tonus 
completely) how any increase in diastolic volume (and initial 
length) can take place otherwise than by the force of an increased 
initial tension. The ventricles are filled to capacity even under 
very low auricular pressures. It. would seem that any additional 
increase in volume must necessitate a stretching of the elastic 
and tonie walls of the ventricle. This requires an increased 
auricular and increased initial pressure. The pressure required 
to stretch the walls sufficiently to admit a definite volume increase 
need not be great, if the tonus is low; but must be considerable, 
if it is high. The pressure increase is not proportional to the 
volume increase; but an increase must exist. We may reiterate: 
While initial length of ventricular fibers and diastolic surface- 
volume relations may fundamentally determine myocardial effic- 
iency, it is difficult to picture how these factors can be increased 
except through an increase in initial tension. 


Ill. THE DYNAMICS OF THE CIRCULATION IN HEART 
DISEASE 


The signs and symptoms arising from acute or chronic cardiac 
disease are the expressions of dynamic consequences which occur 
when the normal valvular mechanism is impaired or the functional 
capacity of the ventricular myocardium is affected. As the latter 
are always concerned more or less in valvular effects, it seems 
desirable to analyze on the basis of experimental results, how 
the myocardium becomes abnormal in its function, to consider 
the factors of safety that are at once called into play, to analyze 


CARDIO-DYNAMIC STUDIES 91 


how additional compensatory mechanisms gradually develop, and 
finally, to attempt an answer as to why these mechanisms ulti- 
mately fail to accomplish the task for which they were developed. 

The Hypodynamic or Inherently Weakened Heart.—Under 
this heading I mean to catalogue cardiac conditions in which the 
working capacity of the ventricles has been reduced. It is, I 
believe, the condition which so frequently follows or terminates 
severe febrile or infectious processes. Clinically, it is recognized 
chiefly by the feeble heart sounds (particularly the first) and the 
small pulse amplitude. The latter has definitely been proven to 
be caused by the decreased systolic discharge; the enfeeblement 
of the first sound I** have recently shown to be related to and 
diagnostic of a reduction in intraventricular tension, 

It is probable, therefore, that we have, in this hypodynamic 
heart of the clinic, a condition not unlike that produced by de- 
pressant drugs such as chloral, chloroform, ete., and consequently, 
we may venture an interpretation of the cardiodynamiecs on the 
basis of experimental results obtained from the use of such drugs. 

The capacity of the ventricle for work is, of course, a function 


both of pressure and volume, as well as time. O. Frank has ex- 
Ti 


pressed it by the integral, A= ay P. V. dx in which A repre- 
sents the work; P, pressure; V, volume; T,, time of opening of 
semilunar valves; T,, the time of closure of the semilunars. Ow- 
ing to the facts that the volume curves of each ventricle cannot 
be separately recorded and that initial tension is a function both 
of aortic resistance and venous filling, it has not been found pos- 
sible to apply this formula in estimating the working capacity 
of the mammalian heart beating under different conditions. A 
separate study of the changes in the volume and pressure curves 
of the ventricles has given us, however, a clue to the essential 
changes taking place in the hypodynamic heart. Socin,'!? who 
studied the volume changes, systolic discharge and minute volume 
of the heart depressed by chloroform, found that such depression 
expresses itself primarily by a decreased systolic discharge and, 
in consequence of the inefficient discharge, by a dilation. The 


™ Wiggers: Ach. Int. Med. 24:471, Sept., 1919. 


92 HARVEY SOCIETY 


depressed heart retains only to a lesser degree its power of re- 
sponding to changes in venous inflow or arterial resistance. If, 
for example, the arterial resistance is increased, the systolic dis- 
charge is not maintained as in the normal heart but continues 
reduced foralongtime. This leads to dilation. Again, when the 
venous pressure is increased, it does not respond with an increased 
output as the normal heart, but the discharge remains unaffected. 

Similar evidences of its inability to respond to increased re- 
quirements are shown by studies of the pressure curves. Experi- 
ments, not yet completed but well under way, point to the 
conclusion that, when the heart is acutely depressed by such 
agents as chloroform, chloral, alcohol, etc., the intraventricular 
pressure progressively rises less abruptly and to a lower level in 
spite of the fact that the initial pressure is elevated and the dia- 
stolic ventricular volume, to judge from volume curves, is actu- 
ally greater. 

The heart gradually recovers from such effects. This, we are 
accustomed to attribute to the fact that the chemical action grad- 
ually wears off. Pressure curves indicate, however, that this 
‘‘wearing off’’ effect is not entirely due to the cessation of a toxic 
action but involves rather a process of compensation. This seems 
to occur as follows: As a small quantity of blood is retained 
during successive systoles, the initial tension and initial distension 
of the ventricles is greater. When this has gone sufficiently far, 
the hypodynamic heart reacts to the higher initial tension and 
the amplitude of the pressure curve again increases. In these 
depressed hearts, the impression is clearly gained that initial 
tension fundamentally determines the pressure relations; and 
present one instance as to why the analysis of the relative im- 
portance of initial length, and initial tension, in determining 
cardiac efficiency is of more than academic interest. 

If cardiac depression is more severe, the ventricular pressure 
is not elevated to normal even if the initial pressure itself is 
considerably higher. By virtue of the higher initial pressure, 
the ventricle dilates more and more and the pressures in the left 
auricle and entire pulmonary circulation have a tendency to 
become elevated. Marked pulmonary congestion is probably 


. am ies - 


CARDIO-DYNAMIC STUDIES 93 


avoided because the output of the depressed right ventricle is 
diminished by an amount nearly equal to that of the left. Stag- 
nation of blood in the veins and liver without pulmonary conges- 
tion can thus be explained in a logical manner. 

If the influences depressing the contractile power of the ven- 
tricles are removed, or if they are neutralized by suitable cardiac 
stimulation, gradual recovery may take place. Such experiments 
favor the use of such stimulating drugs as digitalis and strophan- 
thin in purely myocardial types of depression. 

Cardiac Strain and Fatigue.—Cardiac strain begins when the 
normal or hypodynamic heart is required to eject its blood against 
a greater arterial resistance, or, what amounts to the same thing, 
a higher diastolic pressure. The reactions correspond to those 
previously analyzed when the arterial resistance is increased ex- 
perimentally. Asa result of the greater load, a small increment 
of blood remains behind, at once distending the ventricle. As 
long as the elastic and tonic resistance of the myocardium is not 
impaired, however, it at once elevates the initial tension. This 
safety mechanism causes a larger pressure elevation and a restor- 
ation of the discharge to normal. The earlier phases of this 
reaction are undoubtedly beneficial. With the higher pressure 
developed during the isometric phase goes an intensification of 
the first sound; and with the closure of the semilunar valves at 
a higher diastolic level, we get, as has been experimentally demon- 
strated, an accentuated second sound. As long, therefore, as both 
sounds remain intensified, the heart is responding by adequate 
safety mechanisms. 

If the factors increasing diastolic pressure operate too rapidly, 
or if the elevation is continued too long, a second phase of cardiac 
strain develops. During this stage, as Bruns** has shown in the 
frog’s heart, the inherent contractility suffers. In the mam- 
malian hearts, the intraventricular pressure curves do not mount 
so high and the isometric slope become more gradual, even though 
there is a progressive dilatation of the ventricle and an increased 
initial pressure. When this occurs, the second sounds may re- 
main intensified, while the first sound vibrations become reduced 


* Bruns: Deutsch. Arch. f. klin. Med. 113:179, 1913. 


94 HARVEY SOCIETY 


in amplitude. Since the tonic contraction of the cardiac muscle 
and its elastic resistance is unable for long periods of time to 
resist the gradually increasing strain, the heart begins to weaken 
and finally gives way (Bruns). The ventricle then dilates enor- 
mously. This marks the onset of cardiac fatigue. Straub’s ex- 
periments indicate that when this occurs the pressures in the left 
auricle become greatly elevated and the lungs markedly distended. 
The right ventricle, in consequence, is compelled to contract 
against a greater load; it then passes through the same phases 
of cardiac strain as the left. During the time that dilation of the 


JIAS TOLIe 
VOLUME 


SYSTOUR 
VOLuNe 


OrAsroLK 
voLUMe 


. y 
SisroLic — _—_ —— ee 
vorvme 


Fic. VIII.—A, upper curves, series of diagrammatic volume curves showing mechanical de- 
crease in diastolic volume when the heart accelerates, according to conceptions of Henderson. B, 
lower curve showing effect of increasing diastolic volume due to increased venous inflow when 


tonus remains normal (dotted lines) and when it is reduced (solid lines). Result, is a larger 
systolic volume in the former, and unaltered discharge in the latter instance. 


left ventricle is backing blood into the pulmonary circuit, the 
efficiently contracting right ventricle adds normal volumes of 
blood to the pulmonary side, consequently, pulmonary congestion 
cannot fail to supervene during the second stage of cardiac strain, 
while there may be no evidence of venous congestion. 

Either one of two sequels must follow: the right ventricle may 
pass to the stage of dilation causing the venous pressure to rise 
and pulmonary pressure to fall, or new compensatory mechanisms 
may come into play which help to reestablish normal relations. 

Tonus and Dilatation.—These terms are constantly employed 
by physiologists and clinicians alike, without always a clear con- 
ception of what they really imply. When the exposed heart ap- 
pears large and distended during diastole, we speak of a dilated 
heart or one having a low tonus. If, on the other hand, the 
diastolic volume is small, we are apt to speak of tonus as being 
high. As Patterson, Piper and Starling point out, the state of 


CARDIO-DYNAMIC STUDIES 95 
distension and tone are not necessarily related ‘‘for the volume 
may be merely determined by the amount of blood entering from 
the veins.’’ Henderson has shown that the diastolic volume of 
a heart distended by high venous inflow is necessarily greater than 
that of a heart which receives only a small venous inflow. Obvi- 
ously, the diastolic volume of the heart is usually passively deter- 
mined and in such cases the more dilated hearts are the more 
efficient ; both because the initial and maximum intraventricular 
pressures are higher, and because the systolic discharge is greater 
(Fig. 8, A). For the sake of differentiating, let us speak of this 
as a physiologic dilatation (tonogenie dilatation of Moritz). 

Clinically, the term ‘‘dilatation’’ is applied to a condition in 
which the heart is dilated during diastole while the systolic dis- 
charge is diminished; or, perhaps, more precisely stated, when 
the dilation is not accompanied by a larger discharge. In other 
words, the heart is dilated during systole as well as diastole; 
a relation that may be expressed by the volume curves diagram- 
matically shown in Figure 8, B. Let us hereafter refer to this 
type as pathological dilatation (myogenic dilatation of Moritz). 

Pathologic dilatation is frequently attributed to a failure of 
eardiae tonus; the physiologic type, to a passive distension in 
which tonus persists. According to such conceptions, Patterson, 
Piper and Stdrling consider the term tonus ‘‘as synonymous with 
the physiological condition or fitness of the muscle fibers and its 
measure is the energy set free per unit length of muscle fiber at 
each contraction of the heart.’’ A heart with good tonus will 
carry on a large circulation and nearly empty itself at each con- 
traction, a heart with defective tonus can eject the same systolic 
volumes, only when its fibres are lengthened (Fig. 8, B). This 
is also essentially the conception formulated by Moritz.** 

While this expresses the end effects of tonus changes, and re- 
lates the importance of tonus to cardiac efficiency very well, it 
does not clearly define the nature of tonus itself, nor does it 
analyze the mechanisms through which tonus governs cardiac 
efficiency. To the physiologist, the term ‘‘tonus’’ has come to 
signify a sort of a sustained partial contraction of muscle tissue 


* Moritz: Deutsch. Arch. f. klin. Med. 66:349, 1899. 


96 HARVEY SOCIETY 


by virtue of which the muscle fibers resist stretching more than 
they would by virtue of the inherent elasticity alone. According 
to this conception, the ventricular tonus varies directly as the 
volume-elasticity coefficient of the relaxed heart, i. e., the ratio 


of the pressure increase to the volume increase, De 


This relation may be studied after the fadnes edhenia teats 
illustrated in Fig. 9. Let us suppose that, in such a preparation, 


Onarivas 
¢ Gotme 


HIGH Torus 


Fic. IX.—Diagram illustrating principle of measuring volume—elasticity coefficient of relaxed 
ventricles. Lower curves illustrate distention curves in heart with high and low tonus, each 
step representing an equal increment of intraventricular pressure. 


sufficient fluid is admitted into the ventricle to raise the intra- 
ventricular pressure by eight equal increments. The volume 
changes corresponding to each of, say eight, such pressure eleva- 
tions may then be plotted in steplike fashion. Comparison of 
curves from ventricles under varying conditions of tonus make 
it quite obvious that when tonus is low, a much greater increase 
in volume accompanies a given pressure increase than when tonus 
is high; or, stated in the reverse, the same volume change is 
associated with a much greater pressure change when tonus is 
high than when it is low. 

We may now again examine into the reasons why a heart 


CARDIO-DYNAMIC STUDIES 97 


with deficient tonus is less effective than the normal. Two hearts, 
distended to equal volumes, would have equal initial lengths. If 
this is the dominant or only factor determining the power of 
the heart to respond, we can only assign the decreased working 
capacity to an impairment of the muscular ability itself. Such 
is apparently the conception of Starling and his associates. If, 
however, initial tension is primarily concerned in determining 
the working capacity of the heart, then the reduced working 
capacity of the ventricle during atonia may be accounted for by 
the fact that, at equivalent initial volumes, the initial pressure 
is lower in the atonic than in the normal heart. 

The factors which may modify cardiac tonus have not all 
been definitely established on an experimental basis. Thus, from 
the experiments of Socin,’ it could not be definitely ascertained 
whether in cardiae depression from chloroform, tonus was also 
reduced. Bruns,!* however, was able to show definitely that 
tonus in the frog’s ventricle is reduced when for long periods of 
time the heart is made to beat a very rapid rate, or compelled to 
work against increased resistance. 

Compensation and Decompensation.—It is the dynamic func- 
tion of the heart so to adjust its mechanisms that it, at all times, 
pumps the venous blood received into the systemic system under 
sufficient pressure to insure a continued capillary flow. As long 
as the heart does this, the circulation is compensated; when it 
fails to do so, decompensation occurs. The power of compensa- 
tion is a physiological attribute of normal muscle tissues and is 
not necessarily linked with subsequent cardiac hypertrophy. 
This phase of the compensatory phenomenon may be well illus- 
trated by reference to the acute production of a severe experi- 
mental lesion in animals. If, for example, the aortic valves are 
suddenly rendered incompetent, it will be found that the aortic 
diastolic-pressure not only falls at once, but that the systolic 
pressure remains normal or rises above normal with the very next 
beat. The mechanisms through which this is accomplished oper- 
ate somewhat as follows: With the first diastole, a small volume 
of blood regurgitates back into the ventricles. This not only 
distends the ventricles but elevates the initial tension. Conse- 

/ 


98 HARVEY SOCIETY 


quently, during the next and every subsequent beat, not only the 
tension-maximum, but also the volumes ejected during systole are 
greater. Compensation for valvular defects then resolves itself 
into an increase in diastolic volume and initial tension which 
causes the heart to react, at once, by larger pressure curves and 
larger output. 

Under what conditions does such immediate compensation fail 
to take place? Twosuggest themselves: (1) If the tonus of the 
heart muscle, as defined, is low, augmented volumes may be ac- 
commodated within the ventricle without a proper elevation of 
initial tension. When this happens, the pressure-maximum 
reached within the ventricles and aorta are both lower and the 
discharge is actually decreased. (2) If the reserve power of the 
normal ventricle is exceeded, or if, through depressing agents, 
the normal reserve power is reduced, then also, decompensation 
supervenes. This necessitates an interpretation in more precise 
physiologic terms of the phrase ‘‘reserve power.”’ 

We have seen that every increase in diastolic volume and 
initial tension causes not only a larger systolic discharge but a 
higher pressure-maximum within the ventricles as well (Fig. 7). 
To this, as it has been experimentally shown, there is, however, 
a limit, for, if the initial pressure increases more and more, there 
comes a time when the pressure-maximum begins to decrease. 
Then the systolic discharge also decreases. The initial pressure 
at which this turning point occurs may be taken as the index of 
the reserve power of the ventricles. Whenever, therefore, the 
increase in initial pressure occasioned by a valvular defect rises 
above this point, the efficiency of ventricular contraction dimin- 
ishes and decompensation begins. This safety mechanism 
whereby the ventricle is capable of responding at any moment’s 
notice to larger initial tension, undoubtedly explains why decom- 
pensation does not, as a rule, occur in valvular lesions for many 
years, and that patients remain quite unaware of valvular dis- 
turbances which may be very marked. 

The initial pressure at which the heart no longer responds with 
more vigorous beats and normal systolic discharge varies, not 
only in different animals, but in the same heart, e.g., when its 


CARDIO-DYNAMIC STUDIES 99 


blood supply is altered or when the heart muscle has been sub- 
mitted to toxic depression or long continued stain. We have in 
this a clear explanation as to just how the condition of the myo- 
eardium finally determines whether compensation or decompensa- 
tion takes place. For years, experiments on artificial circulation 
machines (Marey,‘ Moritz,”° ete.) had demonstrated that, when- 
ever left heart valvular lesions occur, there is always a physical 
tendency for blood to dam back toward the right side, thus in- 
ereasing pulmonary and right ventricular pressures. On the 
basis of such physical experiments, clinicians have long explained 
the pulmonary congestion and venous stasis observed in cardiac 
eases on the so-called ‘‘back pressure theory.’’ It was, therefore, 
surprising that practically all experimental investigations of the 
various heart lesions (MacCallum and McClure,** Straub,’ ete.) 
show that ‘‘back pressure effects’’ occur very seldom in lesions 
acutely produced in normal hearts. How are these observations 
to be interpreted? The physics of the body circulation is not 
different from that of artificial circulation machines. Back pres- 
sure effects should be and, as a matter of fact, would be produced, 
were it not for the immediate compensatory reactions called into 
play. When, in animals or in patients, this compensatory 
mechanism (i. e., the ability to respond to increased initial ten- 
sion and volume by equal discharge and higher pressure- 
maximum) is lost, decompensation sets in. Then, and then only, 
‘‘back pressure effects’’ take place. 
*® Marey: La Circulation du Sang 16:136, 710. 


MacCallum and McClure: Johns Hopkins Hosp. Bull. 17:260, 1906; 
22:197, 1911. 


NEWER ASPECTS OF SOME NUTRI- 
TIONAL DISORDERS* 


DR. ALFRED F. HESS 


Professor of Clinical Pediatrics, New York University and Bellevue 
Hospital Medical College 


NE of the most novel medical conceptions is that serious 
diseases or functional disorder may be occasioned by a mere 
lack of certain constituents in the dietary. Until recently we 
were wont to associate tissue damage or functional disturbance 
solely with the introduction of some harmful foreign substance— 
chemical or bacterial—into the body. It is not only remarkable 
but also creditable that a concept so revolutionary should have 
gained wide acceptance in so short a time, not only among the 
medical and scientific world, but among the public at large. The 
first to bring forward convincing evidence in favor of this view 
was Kijkman! who noted in the course of his experiments in Java 
that fowl fed on decorticated rice became paralyzed and developed 
symptoms resembling beriberi, which disappeared when rice 
polishings or their alcoholic extract were added. The subject 
slumbered for some fifteen years when, less than a decade ago, 
Hopkins? established it on a scientific basis by demonstrating 
that animals were unable to live on a dietary composed of casein, 
starch, lard, water and a mixture of inorganic salts, after these 
ingredients had been carefully purified, but that this diet could 
be rendered adequate merely by adding a small amount of a 
natural food—a few cubic centimetres of milk. It will be noted 
that the new path was blazed as the result of empiric observation 
as well as carefully planned scientific investigation, and further- 
* Delivered January 15, 1921. 
* Hijkman, C.: Eine beriberi aehnliche Krankheit der Huehner, Virchows 
Arch. f. path. Anat. 148:523, 1897. 


? Hopkins, F. G.: Feeding Experiments Illustrating the Importance of 
Aceessory Factors in Normal Dietaries, J. Physiol. 44: 425, 1912. 


100 


NUTRITIONAL DISORDERS 101 


more, that as has happened so frequently in the past, alert em- 
piricism outran and prepared the way for the more carefully 
planned laboratory experiment. Today the fact that there are 
deficiency diseases is taught to children in the schools, and vita- 
mins are bandied about in the advertising pages of the daily 
papers, and are the proper concern of the up-to-date mother. 
This rapid diffusion of scientific knowledge, despite the inter- 
ruption of the war, furnishes a striking illustration of present- 
day alertness in connection with topics affecting personal health 
and vigor. 

No doubt the disorders brought about by a deficiency of the 
vitamins or accessory food factors have occurred for centuries. 
To a considerable extent, however, they must be regarded as 
typically modern disorders. Viewed as a group they are a con- 
sequence of our unnatural mode of life and peculiar civilization, 
of the growth of immense cities housing millions of people, who 
are dependent on perishable foodstuffs transported from a great 
distance. To even a greater extent they are the product of 
countless ingenious methods devised mainly to render food stable 
—drying, heating, the addition of preservatives—most of which 
accomplish their objects, but incidentally rob the food of one or 
more of its essential constituents. In a measure these nutritional 
disturbane¢es are a consequence of the supreme domination of the 
bacterial point of view, of the ever present dread of infection 
and solicitude to protect ourselves against contaminated food- 
stuffs. This fear has led to the demand for a more or less com- 
plete sterilization of foods, and to a preference of foodstuffs whose 
unsullied whiteness lends them the appearance of purity— as in 
the case of polished rice, and highly milled flour. 

The current view associates deficiencies of the various vitamins 
with specific disorders, for example, with beriberi or with scurvy. 
Now, although it is quite true that such diseases demonstrate 
conclusively the absolute necessity of certain constituents in our 
dietary, it is likewise true that clear-cut disorders should not be 
regarded as the most common or important result of food defi- 
ciencies. It should be realized that a lack of these essential 
food factors generally does not bring about typical pathologic 


102 HARVEY SOCIETY 


states, but obscure alterations of nutrition, ill defined functional 
disabilities, which cannot be characterized or even recognized as 
disease. It is such incomplete, larval forms of the deficiency 
disorders to which physicians will have to address themselves. 

Nor should the domain of the deficiency disease be restricted 
to the narrow confines of disturbances brought about by a lack 
of vitamins. In a broader sense it includes malnutrition due 
to an insufficiency of any food constituent which is essential to 
normal metabolism. The peoples of the Central Empires, for 
example, as the result of a great lack of meat, milk, cheese and 
eggs, were compelled to subsist during the war on a dietary 
which was deficient in phosphoric acid as well as in one or more 
of the vitamins. 

Many observations lead to the conclusion that these disorders 
are not limited to man, but to a large extent affect the animals 
which man uses for food. It has been found in Victoria, for 
example, that cattle raised on certain pastures develop paralysis 
and other infirmities which can be cured by fertilization of the 
soil. In the United States in some areas it is impossible to main- 
tain cattle in good condition until the forage is improved by 
mineral or animal fertilizers, which illustrates that a deficiency 
in plant tissues leads to nutritional disorder in animals. Recently 
Hart, Steenbock and Humphrey* have confirmed these observa- 
tions by careful experiments which showed how the mere addition 
of calcium to the fodder of cows prevented the birth of premature, 
weak or dead calves. Indeed, the extensive investigations of 
Forbes showing that cows producing large amounts of milk, and 
fed common winter rations, undergo constant losses of calcium, 
magnesium and phosphorus from their skeletons, suggest that 
large numbers of milch cows are suffering from a deficiency 
disease. These chemical analyses recall Hanau’s report* of 
almost thirty years ago, to the effect that the bones of pregnant 
women, who had enjoyed apparent health, frequently were the 

3’ Hart, E. B.; Steenbock, H., and Humphrey, G. C.: Influence of Rations 
Restricted to the Oat Plant on Reproduction in Cattle, Research Bull. 49, 
Agric. Exper. Station, Univ. Wisconsin, 1920. 

*Hanau, A.: Ueber Knochenveraenderungen in der Schwangerschaft, 
Fortschr. d. Med. 10: 237, 1892. 


NUTRITIONAL DISORDERS 103 


site of lesions resembling osteomalacia—an interesting observation 
that might be substantiated during life by means of roentgen- 
ologic examinations. 


SCURVY 


The most clear-cut and sharply defined deficiency disease is 
seurvy. In fact, it is the only nutritional disorder brought about 
by inadequacy of diet—whether of vitamin, of a definite chemical 
substance, or of calories—which is associated with characteristic 
pathologie alteration. For we must bear in mind that the nerve 
degenerations of beriberi are not typical or diagnostic as are the 
bone lesions of scurvy. The latter disorder, therefore, is pre- 
eminently qualified to serve as the prototype of this class of 
diseases. The clinical picture usually called to mind by the word 
‘‘seurvy’’ is that of an individual afflicted with a severe, acute 
disease; either an adult with bleeding, fungous gums, hemor- 
rhagic eruption and painful gait, or a pale, unhappy infant, with 
gingival hemorrhages, and tenderness or swelling of one or both 
lower extremities. This is the classic text-book picture, which 
should not, however, be regarded as the ordinary or prevalent 
type of scurvy, either in adult or infant. The more common form 
is far more subtle in its manifestations, as is true of other nutri- 
tional disorders. In the adult it is evidenced by a lack of physical 
or mental vigor, vague pains suggesting rheumatism, an increased 
susceptibility to infection—conditions often impossible to diag- 
nose when occurring sporadically, but conclusive when scurvy 
pervades a large group of individuals. Such seurvy was noted 
during the War of the Rebellion among the Northern troops, 
being referred to as a ‘‘scorbutic taint,’’ and is mentioned in the 
recent report of the British troops in Mesopotamia. It has been 
described by me in relation to infants,> and during the war by 
physicians in Vienna who had charge of child-caring institutions.°® 
They noted, in addition to infants suffering from manifest scurvy, 
a far larger number of what may be termed ‘‘subacute’’ or 


*Hess, A. F.: Subacute and Latent Scurvy: The Cardiorespiratory 
Syndrome, J. A. M. A. 68: 235 (Jan. 27) 1917. 
°Tobler, W.: Der Skorbut in Kindersalter., Ztschr. f. Kinderh. 


104 HARVEY SOCIETY 


‘“latent’’ cases with the characteristic muddy complexion, lack 
of appetite, stationary weight and fretful disposition. That this 
syndrome is truly scorbutic has been proved repeatedly by the 
miraculous improvement which follows the addition of an anti- 
scorbutie to the dietary. From our knowledge that about six 
months of the inadequate diet is required to bring about definite 
clinical manifestations, it follows that there must be a mild or 
latent type of scurvy and that this form must comprise the ma- 
jority of the cases. 

I shall not weary you with a review of the sypmtomatology 
of scurvy, but rather consider briefly the tissues and bodily 
functions which are particularly affected when the antiscorbutic 
food factor is lacking in the dietary. This vitamin is probably 
needed for the normal functioning of all the cells of the body— 
if we may interpret in this sense the general loss of mental and 
physical vigor—however its lack is evidenced in particular 
directions; in a failure of the integrity of the endothelium of the 
blood vessels; in a disintegration of the structure of the bones; 
in various disturbances of the circulatory system. It may be of 
interest to discuss briefly these three conditions, as their occur- 
rence must be closely associated with the function of the anti- 
scorbutia vitamin. 

The lesion of the lining of the blood vessels is one of the most 
characteristic signs of scurvy; it is the cause of the hemorrhage 
of the gums, of the petechie in the skin, of the subperiosteal 
hemorrhage, the hematuria, and all the other hemorrhagic mani- 
festations which have frequently led to the inclusion of scurvy 
among the group of hemorrhagic diseases. The coagulability of 
the blood is almost normal in this disorder, the escape of the blood 
from the vessels being due to a weakening of their walls, or to a 
lesion of the endothelial cells or their cement substance. Apply- 
ing a tourniquet to the upper arm (the ‘‘capillary resistance 
test’’), thus subjecting the vessel walls to additional strain, will 
generally demonstrate this weakness, causing the appearance of 
numerous petechie on the forearm. A similar weakness of the 
vessel walls does not occur in beriberi, or in any clinical condition 
attributed to a lack of vitamin. 


NUTRITIONAL DISORDERS 105 


It is unnecessary to dwell on the fact that the bones are par- 
ticularly vulnerable to a lack of the antiscorbutic factor. For 
decades attention was centered to such a degree on the bones 
that clinicians as well as pathologists gave little heed to mani- 
festations occurring in other organs. 

The association of circulatory disturbances with ‘‘latent’’ or 
‘‘subacute’’ scurvy is of particular interest as, until recently, 
these symptoms have been overlooked. They furnish a clinical 
link between scurvy and beriberi, the deficiency disease attributed 
to the lack of the so-called water-soluble vitamin. Frequently 
one of the earliest signs is tachycardia, a heart beat of 140 or 150 
in an infant. But a still more noticeable and characteristic sign 
is the marked instability of the pulse rate, an increase of 20, 30 
or 40 beats to the minute on the least exertion or from a slight 
rise in temperature. This tachycardia is similar to that of exoph- 
thalmie goiter, the electrocardiogram showing merely an exagger- 
ated T-wave. Accompanying this tachycardia there is generally 
a polypnea—respirations mounting to 40, 50 or 60 to the minute. 
These symptoms may be termed ‘‘the cardiorespiratory phenom- 
enon’’ of scurvy. That it is truly scorbutic may be deduced from 
the fact that it yields promptly to antiscorbutic treatment. Its 
occurrence points to an involvement of the nervous system, and 
at least to a functional relationship between this vitamin and 
nerve tissue, thus illustrating the inaccuracy of the appellation 
‘*antineuritic vitamin’’ as applied to the beriberi vitamin. 

Another scorbutic symptom is enlargement of the heart, espec- 
ially of the right heart, a lesion which has been considered typical 
of beriberi. For many years this lesion was overlooked in scurvy, 
owing to the fact, as stated, that attention was narrowly focused 
on the bones, an oversight which is strikingly evident in reviewing 
necropsy protocols. It may be noted that Erdheim’ of Vienna 
recently published a paper with the significant title of ‘‘Das 
Barlowherz,’’ in which he describes thirty-one necropsies of in- 
fantile scurvy in which the heart was found enlarged in almost 
every instance. 


™Erdheim, J.: Ueber das Barlowherz, Wien. klin. Wehnschr., 1918, 
p. 1293. 


106 HARVEY SOCIETY 


In coneluding this summary of the relation of scurvy and its 
vitamin to the circulatory system, passing attention should be 
called to oliguria, the diminished secretion of urine in the course 
of scurvy, a symptom at once alleviated on administering an 
antiscorbutic. This sign is still more common in beriberi. 


NATURE OF VITAMINS 


As is well known, the exact chemical structure of a vitamin 
isasyetamystery. This lack of knowledge has led to skepticism, 
even to the point of doubting the very existence of the vitamins. 
This attitude is strange, in view of the fact that for almost a 
generation we have become quite accustomed to conceding the 
existence of factors which we are unable to isolate chemically. 
We know quite as much about the chemical nature of the vitamins 
as we do of complement, hemolysin or immune bodies—substances 
which have gained general recognition and are admitted to the 
select company of scientifically established entities. Not only the 
nature of the vitamine but also their mode of action is unknown: 
whether they exert their effect directly on the tissues, or indirectly, 
as has been suggested, through a hormone action. It seems clear 
that man cannot manufacture them, or at most can do so to a 
limited extent—insignificant from the standpoint of his well- 
being. We are therefore entirely dependent on our food supply 
for these essential factors. Nor has it been shown that any other 
of the higher animals possess this ability. Lower forms of animal 
life, seem to be able to elaborate vitamin, and plant cells such 
as the yeast cell, possess this faculty to a high degree. Not only 
are we unable to manufacture these vitamins, but it is probable 
that we are unable to store them to any great extent. A series 
of experiments planned to investigate this question, and described 
in detail elsewhere,* led to the conclusion that at least guinea-pigs 
are unable to store the antiscorbutie vitamin. In other words, 
we are leading a precarious hand-to-mouth existence in regard to 
food factors which are essential not only to our health but also 
to our lives. 


® Hess, A. F.: Scurvy, Past and Present, Philadelphia, J. B. Lippincott 
Company, 1920. 


NUTRITIONAL DISORDERS 107 
ANTISCORBUTIC VEGETABLES 


It is hardly an exaggeration to state that in the temperate 
zones the development or nondevelopment of scurvy depends 
largely on the potato crop. In Ireland, when the potato has 
failed, seurvy has developed. The same thing has been true in 
Norway. To a minor degree this happened in 1914 in various 
localities in the United States, when the potato crop was inade- 
quate. This is attributable in part to the fact that the potato 
is an excellent antiscorbutic, but to a greater extent because 
it is consumed during the winter in amounts that exceed the 
combined total of all other vegetables. The great nutritional 
value of the potato has not been explained. Its protein is 
stated to be of inferior quality, and it is poor in the water- 
soluble and in the fat-soluble vitamins. Nevertheless, the 
practical dietic experience of nations and the prolonged investi- 
gations of Hinhede prove that it is a food of exceptional value. 

One of the recent advances in the study of scurvy has been a 
more exact appreciation of the antiscorbutic value of foods, an 
appraisal of vegetable and animal foodstuffs from a quantitative 
standpoint.. This has led to some surprises; for example; that 
the lime, which has been time honored as the most potent of 
antiscorbutics, is not comparable in this respect. to the lemon or 
the orange. We have learned also to appreciate the value of the 
swede and of the tomato. But of still greater importance is the 
realization that any categorical statement of the relative value of 
antiscorbutic foods must be accepted with qualifications. Foods 
should not be considered as chemical entities. A lack of under- 
standing of this fact has led to nutritional disease in man, and 
to confusion in investigations on animals. For example, a veg- 
etable such as the carrot may possess moderate or very little 
antiscorbutic power, depending on attendant circumstanees. If 
it is old, it is poor in the antiscorbutic vitamin, whereas if it is 
young and succulent, it is far richer in this factor. We had a 
surprising experience some years ago when guinea-pigs developed 
scurvy in spite of a ration which included large amounts of 
carrots such as are ordinarily fed laboratory animals. Experi- 
ment readily showed that 35 gm. a day per capita of these carrots 


108 HARVEY SOCIETY 


was insufficient to protect a guinea-pig, whereas the same quantity 
of a young earrot sufficed. Furthermore, it is not immaterial 
whether the vegetables are freshly plucked or whether they are 
stale, and it is quite possible that antiscorbutie potency depends 
to a certain extent on the composition of the soil; in other words, 
that the vegetable may in turn suffer from a vitamin deficiency 
disease. Such being the case, the influence attributed to climate 
in the causation of seurvy—for, as is well known, certain coun- 
tries have always been associated with seurvy—may be due partly 
to the effect of the soil on the vegetation. Therefore, in ration- 
ing individuals or groups, the quality as well as the quantity of 
antiscorbutie foodstuffs must be considered. 


ANIMAL FOODS 


Similar qualifications exist in regard to animal foods. For 
some years there has been marked divergence of opinion as to the 
antiscorbutie value of milk. This is an important question, as 
milk constitutes the basal diet of infants during the first year of 
life, and constitutes frequently their sole antiscorbutie supply. 
The conflicting opinions of various investigators have been recon- 
ciled recently and the results of those who believed milk to be 
poor as well as those who believed it rich in this vitamin have 
been substantiated. Its potency depends almost entirely upon 
the fodder of the cow. We should long ago have established this 
fact, fortified by our knowledge that animals are unable to syn- 
thesize the vitamins. Hart, Steenbock and Ellis,*° Dutcher and 
his associates,?° and Hess, Unger and Supplee™ have all reported 
similar results. In our experiment, cows that had been for a 
period of three weeks on fodder, which was almost completely 
Antiscorbutic Potency of Milk, J. Biol. Chem. 42: 383 (July) 1920 

* Dutcher, R. A.; Eckles, C. H.; Dohle, C. D.; Mead, S. W., and 
Schefer, O. G.: The Influence of Diet of the Cow upon the Nutritive and 
Antiscorbutiec Properties of Cow’s Milk, J. Biol. Chem. 45: 119, 1920. 

“Hess, A. F.; Unger, L. J., and Supplee, G. C.: Relation of Fodder 
to the Antiscorbutic Potency and Salt Content of Milk, J. Biol. Chem. 
45: 229, 1920. 


NUTRITIONAL DISORDERS 109 


devoid of antiscorbutic vitamin, produced a milk that was almost 
devoid of this factor, although of normal caloric value and ade- 
quate in its fat, protein and carbohydrate content. Such results 
may well have far reaching dietetic significance; they raise the 
question whether ‘‘winter milk’’ supplied by stall-fed cows is a 
well balanced and complete food. It is quite possible that it 
may become part of dairy inspection to note the adequacy of the 
fodder as well as the sanitary conditions. Human milk no doubt 
also varies according to the nature of the woman’s food, and in 
some instances is deficient in antiscorbutic vitamin, owing to 
eccentricities of diet or to poverty. During the winter months 
this may at times exert its influence on the nutrition of the child. 
In closing this brief consideration of the intrinsic variations of 
vitamin in animal tissues, I should lke to suggest that the blood 
from which the milk is elaborated may also vary in its antiscor- 
butiec content, and that from this standpoint it should not be 
regarded as a chemical entity. 


FACTORS TENDING TO DESTROY THE VITAMIN 


To understand the etiology of scorbutic malnutrition it is 
important to know the antiscorbutic value of natural foodstuffs ; 
but it is equally important to appraise correctly the factors that 
tend to destroy the vitamin in these foodstuffs. Until recently 
this problem seemed very simple. The subject was summed up by 
the statement that foods which have been dried, heated to a high 
degree, or canned, lose their vitamin content and induce scurvy. 
The ravages of scurvy in the mercantile marine and in the navy, 
in the days of sailing vessels, seemed a convincing demonstration 
of the deleterious effect of preserved food. The matter, however, 
is not so simple, and recent investigations have proved the fallacy 
of these generalizations. In regard to the effect of heat, it has 
been shown that the duration of the heating process is of greater 
importance than the degree of temperature to which the food is 
subjected. For example, milk that has been heated to a temper- 
ature of 145 F. for thirty minutes has lost more of its antiscor- 
butie potency than milk that has been raised to 212 F. for a few 


110 HARVEY SOCIETY 


minutes. This result confirms clinical experience that scurvy 
oceurs more frequently on a diet of pasteurized than on one of 
boiled milk. It has been shown also that the reaction of the 
medium is of importance in regard to resistance to heating—that 
substances which are acid, such as orange juice or tomato juice, 
retain their potency in spite of subjection to high temperatures. 

Our views on the effect of the dehydration of foods have swung 
back and forth on insufficient evidence. For centuries it was 
known empirically that dried vegetables possessed practically no 
antiscorbutie virtue, as demonstrated in many wars, including 
our War of the Rebellion. Nevertheless, in the recent World 
War dried vegetables were again relied on as antiscorbuties. 
They proved to be the greatest cause of scurvy in the Central 
Empires. In this country the conception that dried vegetables 
are the nutritional equivalent of the fresh nearly led to their ex- 
tended use and general adoption for our army. But although 
vegetables have not yet been dried by a process which enables 
them to retain their antiscorbutie vitamin, we must not infer 
that desiccation per se destroys this factor, as dried orange juice 
or tomato juice retains almost all of its antiscorbutie value. Nor 
is this resistance dependent solely on the acid reaction of these 
foods, for milk, dried by the Just roller process (by which it is 
subjected to 230 F. for a few seconds) loses little of its potency. 
Evidently, drying does not necessarily destroy the sensitive anti- 
scorbutie factor. 

We should also maintain an attitude of open-mindedness in 
regard to the effect of canning, commonly regarded as absolutely 
destructive of this vitamin. In general, this view is sound; but 
animal experiments as well as clinical tests have proved that this 
rule has exceptions—that tomatoes may be canned and that milk 
may be both dried and canned, and yet preserve its antiscorbutic 
quality. Indeed, we found this to be true of dried milk which had 
been canned and kept for over a year at room temperature; an 
astonishing result, considering that such treatment involves sub- 
jection to almost all the influences commonly associated with the 
destruction of this vitamin—drying, heating to a temperature 
above the boiling point in a neutral or slightly alkaline medium, 


NUTRITIONAL DISORDERS 111 


canning, and finally the deteriorating influence of age.’* In view 
of these experiences, the statement of the British Medical Re- 
search Committee to the effect that foods lose their antiscorbutic 
vitamin after having been dried or tinned requires qualification. 
The stability of dried milk cannot be attributed, as we at first 
supposed, to its low moisture content (less than 3 per cent.), as 
sweetened condensed milk, containing more than three times as 
much water, was found also to retain the larger part of its anti- 
scorbutie factor. 


EFFECT OF OXIDATION 


Such irregular and contradictory results suggested the action 
of some other destructive agent. We were led to believe that 
oxidation might be a harmful factor, and undertook experiments 
to investigate this question. 


A Typical Test—Four cubic centimetres of a normal solution of 
hydrogen peroxid was added to a liter of raw milk, which was then placed 
in the incubator over night. Eighty cubic centimetres per capita daily, 
in addition to oats and straw, was fed to a series of guinea-pigs. The 
animals promptly developed scurvy. Indeed, they manifested signs of this 
disorder as quickly as when fed milk that had been autoclaved for one hour 
at 115 C. Cure was accomplished by adding orange juice to the dietary. 
Evidently the antiscorbutic vitamin was almost completely destroyed by 
this small amount of hydrogen peroxid. Another experiment showed that 
orange juice subjected to oxygen had lost a definite degree of its potency, 
so that an increased quantity was required to cure scorbutic guinea-pigs. 


These investigations indicate that oxidation destroys the 
antiscorbutic vitamin and must be considered in the etiology 
of scurvy.** 


4In this respect, however, it should be borne in mind that there is 
an essential difference between a food which is of an alkaline or neutral 
reaction in its natural state, and one which has been rendered so artificially ; 
for instance, orange juice rapidly loses its antiscorbutic vitamin after it 
has been made faintly alkaline, whereas the potato, in spite of its natural 
alkaline medium, retains this vitamin throughout the winter. 

*% These results were referred to in a discussion of the vitamins at 
the meeting of the British Medical Association (Cambridge, July 1, 1920). 
At this session Hopkins also reported that the fat-soluble vitamin is 
destroyed by oxidation. 


112 HARVEY SOCIETY 


Let us in a few words reconsider the antiscorbutie value of 
milk from this point of view. Dried milk may retain its anti- 
scorbutie virtue, in spite of drying, canning and aging, owing 
to the fact that it is well packed and hermetically sealed. It 
loses its potency after it is exposed to the air. When we refer 
to the deleterious effect of aging—a vague term—we may well 
be alluding to oxidation. Sweetened condensed milk, which we 
found to contain antiscorbutie vitamin, is zealously protected 
from access of air in the course of its manufacture, not for fear 
of oxidation or destruction of any of its food constituents, but to 
avoid the danger of bacterial contamination. It is probable that 
oxidation plays a réle in the partial destruction of this vitamin 
in the pasteurization of milk; this seems the explanation of an 
experience referred to in 1915: the decided difference in the 
production of scurvy between milk which had been pasteurized 
in the home and that which had been pasteurized commercially. 
It may also account for the clinical results of Variot and others, 
who have repeatedly stated that they fed thousands, indeed, 
tens of thousands of infants on sterilized milk, and never en- 
countered cases of scurvy; their milk was sterilized in hermetic- 
ally sealed bottles. Bearing the factor of oxidation in mind 
may make it possible so to alter the process of manfacture or 
of the preservation of foods as to increase their antiscorbutic 
content, and render them more nearly the equivalent of the 
fresh food. 

The deleterious influence of apparently unimportant processes 
in industrial methods warns us to proceed cautiously in the 
handling of foods, and not to concentrate our attention too 
narrowly on the bacterial dangers, for even some slight mechan- 
ical manipulation may damage and denature. 


RICKETS 


We are all aware of a renewed interest in another nutritional 
disorder affecting primarily the health of children, namely, 
rickets. This awakening closely followed the recent activity in 
the study of securvy—always regarded as a closely allied disorder 


NUTRITIONAL DISORDERS 113 


—and has been further stimulated by the remarkable outbreaks 
of rickets and osteomalacia in the Central Empires. Today we 
find clinicians and laboratory investigators in England, Germany, 
Austria and the United States endeavoring to shed light on the 
etiology of this disorder, which Glisson described so vividly 
more than 250 years ago. Rickets is the most common nutritional 


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Jan. Agril July Oct 


Cuart I.—Result of microscopic study of the bones of 386 consecutive necropsies on infants: 
marked decrease of active rickets accompanied by marked increase of healing rickets 
during the summer months. 
disease Occurring among the children of the temperate zone, 
fully three fourths of the infants in the great cities, such as 
New York, showing rachitic signs in some degree. Schmorl’s 
pathological studies present evidence that this percentage is 
still higher when we include eases of latent rickets which can 
be diagnosed only by the microscope. Furthermore, rickets has 
the distinction of being the most frequently overlooked disorder 
of childhood—an important omission, in view of the fact that 

we possess an efficient agent for its cure. 
Broadly considered, there are two main theories as to the 
8 


114 HARVEY SOCIETY 


etiology of rickets: the dietetic and the hygienic. It would lead 
too far afield to discuss the respective merits of these theories. 
It is my opinion that rickets is primarily a dietetic disorder, but 
that hygienic factors, such as lack of sunlight, poor ventilation, 
crowded quarters, and infection, are important contributory in- 
fluences, far more important than in the ease of scurvy. That 
climate is not the determining etiologic factor is amply proved 
by the recent experiences of Europe, where rickets developed 
during the war in almost epidemic form. For example, Dalyell’ 
reported from Vienna that, in one community which included 
many breast-fed infants, rickets was diagnosed in 50 per eent. of 
the infants at 5 months, and in 100 per cent. at 9 months of age. 
Davidsohn’> has emphasized the great increase of severe cases in 
Berlin during the year following the armistice. This increment 
occurred despite the fact, shown by an analysis of some thousands 
of cases, that at the beginning of the war 40 per cent. of the babies 
were nursed for more than two months, whereas in 1918 more 
than 50 per cent. were nursed for a similar period. 

I believe that I may safely state that today attention is 
centered on the role of the vitamins in relation to the etiology 
of rickets, and specifically on the fat-soluble vitamin. As the 
result of the investigation of Mellanby on dogs and the acceptance 
of his results by the Medical Research Committee of Great 
Britain, many regard it as an established fact that the fat-soluble 
vitamin is synonymous with the antirachitie vitamin. About a 
year ago Dr. Unger and I expressed the opinion that although 
this vitamin may be a factor in the etiology of rickets, it is not 
the dominant factor in its pathogenesis.‘° The conclusion was 
based on a clinical study carried out in an institution for child- 
ren. As this theory of etiology is the paramount one at the 
present time, I shall waive other aspects and discuss it in the 
Medicine, Brit. M. J., July 31, 1920. 

1 Davidsohn, H.: Die Wirkung der Aushungerung Deutschlands auf 
die Berliner Kinder, Ztschr. f. Kinderh. 21: 349, 1919. 


16 Hess, A. F., and Unger, L. J.: The Clinical Role of the Fat-soluble 
Vitamin: Its Relation to Rickets, J.A.M.A. 74: 217 (Jan. 24) 1920. 


NUTRITIONAL DISORDERS 115 


light of my experience, which embraces a period of two and a 
half years, and a careful observation of about 150 cases. My 
opportunity for a clinical study has been exceptional, as the 
children were in a model institution, where the diet was pre- 
pared in a central kitchen, and all the conditions were uniform 
and capable of control. Furthermore, I was sure that the in- 
fants received a diet adequate in calories and in other food 
factors. It is only under similar conditions that studies on 
chronic nutritional disorders can be carried out. 

Time will not allow a detailed review of these observations, 
which will be reported at another time. It may, however, be 
of interest to summarize the results of two groups of cases, one 
which received a ‘‘fat-soluble minimal’’ diet and the other a 
full quota of milk.17 Among six infants who were given a diet 
which was generous in every respect excepting in fat-soluble 
vitamin, a diet comprising adequate calorific value, a full amount 
of the water-soluble and antiscorbutie vitamins, and an adequate 
salt mixture, after a period of more than six months only one 
showed rachitie signs by physical examination or by the roéent- 
genray. For, as many no doubt know, the course of this disorder 
can be studied by means of rdentgenograms, and its development 
or cure thus visualized. R6entgenography, which has been em- 
ployed extensively abroad, and by Phemister’® and by Howland 
and Park’® in this country, has formed part of our monthly 
routine examination for the last year.*° This procedure has 
great value in the investigation of rickets, and no doubt will aid in 
elucidating some of its perplexities. As stated, one of these six 
infants receiving a minimal amount of fat-soluble vitamin in 

“The “fat-soluble minimal” diet consisted of 60 gm. of dried skimmed 
milk, 30 gm. of sucrose, 30 c.c. of cottonseed oil, orange juice, autolyzed 
yeast and wheat cereal. In some cases the oil was discontinued for over 
six months, and an increased quantity of cereal substituted. 

* Phemister, D. B.: The Effect of Phosphorus on Growing, Normal and 
Diseased Bones, J.A.M.A. 70: 1737 (June 8) 1918. 

* Howland, J., and Park, S. A.: Some Observations on Rickets, Arch. 
Pediat. 37: 411, 1920. 


» Hess, A. F., and Unger, L. J.: Dietaries of Infants in Relation to the 
Development of Rickets, Proc. Soc. Txper. Biol. & Med. 17: 220, 1920. 


116 HARVEY SOCIETY 


the dietary—only so much as was included in the equivalent of 
20 ounces of a dried skimmed milk—showed signs of rickets 
after a long period of observation. In one case, which was 
observed for eighteen months, rickets existed at the onset and 
disappeared on this diet. 

At the same time the development of rickets was followed in 
infants who were receiving daily from 24 to 32 ounces of raw 
or pasteurized milk. Surely this amount should suffice to pro- 
tect against a disorder, were its occurrence dependent on the 
fat-soluble vitamin. Among this group, numbering twelve, who 
were receiving a dietary rendered adequate by the addition of 
orange juice, autolyzed yeast, and cereal (for babies over 6 months 
of age), six developed rickets. That this disorder was truly 
rickets was proved by its rapid subsidence on the administration 
of cod liver oil, as shown by physical and réentgen-ray examina- 
tion. The inference would seem to be that cod liver oil, which 
is regarded as the prototype of the fat-soluble vitamin, must 
differ not merely quantitatively but also qualitatively from milk 
fat. This view is strengthened by metabolism experiments of 
Schabad, Orgler*! and others, which show that although cod liver 
oil almost invariably causes calcium retention in cases of rickets, 
the substitution of large amounts of milk in the dietary leads 
to a negative calcium balance. Evidently the fat-soluble vita- 
min, as it exists in milk, is not the antirachitic factor; neither 
will a large amount of milk protect against rickets, nor a small 
amount lead to its development. 

In passing, it may be of interest to refer to an investigation 
of the diet of the negro mother carried out a few years ago by 
Dr. Unger and myself? in a negro district of New York. As is 
well known, rickets is far more frequent among negro infants 
in the large cities of the North than among those of any other 
race, occurring in marked degree in fully one third that are 
breast-fed. We came to the conclusion that the main defect and 


*"QOrgler, A.: Zur Theorie der Lebertranwirkung, Jahrb. f. Kinderh. 
37: 459, 1918. 

™ Hess, A. F., and Unger, L. J.: The Diet of the Negro Mother in New 
York City, J. A. M. A. 70: 900 (March 30) 1918. 


NUTRITIONAL DISORDERS iy 


the chief variation in the dietary, compared to what they had 
been accustomed to at home in the West Indies, was a lack of 
fresh vegetables and fruits, and an excess of carbohydrates. 
Last spring and fall Dr. Gertrude McCann earried out a similar 
investigation in this district and came to the same conclusion. 
This deficiency of fresh vegetable food, accompanied by a high 
incidence of rickets, is worth noting. 


THE EFFECT OF ‘‘SEASON’”’ 


A remarkable phenomenon noted by Kassowitz years ago, and 
one which has not been sufficiently emphasized, is the marked 
seasonal incidence of rickets; its increased occurrence and in- 
tensity in the spring, and tendency to fall to its lowest level 
in the late summer or autumn. In the course of two years’ 
observations, this fact stood out both winter and summer in 
bold relief ; in August and September, rickets almost disappeared 
in the institution. Not only the clinician, but also the path- 
ologist, is well aware of this seasonal augmentation and diminu- 
tion ; Schmor]’s?* study of some 386 eases brings it out admirably. 
So definite is this occurrence that any theory which attempts to 
explain rickets must satisfactorily interpret this remarkable 
seasonal variation in its incidence. Pellagra, tetany, kerato- 
malacia, and to a less extent beriberi, are associated with a 
similar variation. The marked increment of rickets in the spring 
was attributed by Kassowitz to prolonged indoor confinement of 
the infants throughout the winter, and was the basis of his 
‘‘domestication’’ theory. It may, however, be due to a change 
in diet, not that the infants are given different food, but that the 
milk in the late spring and summer, when the cows are on pasture 
and no longer stall-fed, differs from that of the winter. The 
nature of this difference is obscure. This interpretation does 
not exclude the beneficent effect of the improved hygienic condi- 
tions which come about in the late spring. 


* Schmorl, G.: Die pathologische Anatomie der rachitischen Knochener- 
krankung, Ergebn. d. inn. Med. u. Kinderh. 13: 403, 1914. 


118 HARVEY SOCIETY 
COD LIVER OIL 


Happily, we have a drug which, if given in sufficient amount, 
eures rickets. Cod liver oil has been used therapeutically for 
almost 100 years, but even today it has not been accorded its 
proper place in therapy. It is recognized as a drug which bene- 
fits nutrition, but the fact that it has unequaled value in the 
prevention and cure of rickets is hardly realized. Some three 


Without 
CalseOnl 


Low High 
Milk Fat|Milk Fat 


Case 
0.175 
PS +0.157 
+ 0.143 
2 -—0 014 $0.519 
! £0,073 | +0303, +0.038 | ~0.034 


+ 0.0435 


+0.037 | 0.267 


Cuart II.—An aspect of the calcium metabolism in rickets. The favorable effect of cod liver 
oil on the calcium balance and the unfavorable effect of an abundance of milk-fat. 


years ago a study of the effect of cod liver oil on negro children 
in a district of New York showed that it was of decided value 
in 80 per cent. of the cases. This test was carried out during 
the winter and early spring. Since this time, réentgen-ray 
examinations month by month im a series of cases have shown 
objectively the benefit of this therapeutic agent. It is quite 
remarkable how rapid is the deposition of calcium under 
this treatment. 

It is possible to rid New York, or any locality, of rickets by 


NUTRITIONAL DISORDERS 119 


means of the use of cod liver oil. There are approximately 
125,000 children in New York City between the ages of 3 and 15 
months, the period of greatest susceptibility to rickets. If we 
estimate generously that the families of one third to one quarter 
of these children are unable to purchase cod liver oil, and if we 
agree that the development of rickets may be prevented by giving 
a teaspoonful three times a day, then, at the present cost, rickets 
could be practically abolished in this city by the expenditure of 
about $100,000 a year. This is merely one of many instances 
in which the community does not get the full benefit of our medical 
knowledge. A similar example exists in connection with the 
prevention of beriberi. As is well known, this disease is the 
main factor in the exceedingly high infant mortality in the 
Philippines, leading to a death rate in the city of Manila of 430 
out of every thousand infants under 1 year of age. The pre- 
ventive of beriberi is the water-soluble vitamin, which is fur- 
nished in high concentration in brewers’ yeast, a by-product of 
the brewing industry. Yet this high mortality is allowed to 
continue unabated in spite of the fact that the country is under 
a stable, civilized government. 


MALNUTRITION NOT TYPICAL DISEASE 


The harmful effects of food deficiencies should not be associ- 
ated in our minds, essentially or chiefly, with specific diseases 
such as scurvy or rickets, but rather as disorders of nutrition 
producing slight and manifold disturbances of function. This 
is probably quite as true of rachitic as of scorbutic malnutrition. 
It is probable that every organ or system in the body may be 
affected by faulty nutrition, so that the deficiency diseases must 
engage the attention of every physician, whatever his particular 
interest or specialty. For example, involvement of the eyes 
may lead to impaired vision or night-blindness; or, on the other 
hand, neuritis, cardiac enlargement, disturbances of the circula- 
tory system, atrophic disorders of the skin, nails or hair, caries 
of the teeth, or unaccountable lack of appetite and constipation, 
may each in turn be the earliest symptom. A more careful 
inquiry into the dietary of patients will result in bringing to light 


120 HARVEY SOCIETY 


many cases in which vague and ill defined symptoms can be 
remedied simply by rendering the diet adequate. 

The fat-soluble vitamin has been termed the ‘‘growth-vita- 
min.’’ The designation is unfortunate, not only because this 
vitamin canot be credited with this specific faculty, but also be- 
cause no single food constituent deserves such distinction, or is 
endowed with this all-important function. It is probably true 
that if the fat-soluble vitamin is deficient, growth will not 
progress normally. This is certainly the case with rats, which 
are particularly sensitive to a lack of this vitamin, but which 
require a very small amount to render their diet adequate. 
Similar observations have not, however, been made on infants, 
so that we do not know, even approximately, how much fat- 
soluble vitamin food is needed for normal growth. The stunt- 
ing effect of a lack of antiscorbutie vitamin on infants has been 
definitely shown, so that with equal justice this might be termed 
the growth vitamin. The sounder physiologic view, however, 
would be to regard no food constituent as entitled to be styled 
the growth vitamin or factor. If an essential amino-acid, vita- 
min or inorganic salt is lacking in this dietary, this inadequate 
factor—whatever its chemical nature—must be regarded as and 
will prove to be the growth factor. In other words, for adequate 
gerowth the diet must be complete; and when it is incomplete— 
whatever the nature of the inadequacy, or however minimal its 
amount—growth will suffer. 


INTERRELATIONSHIP OF NUTRITION AND INFECTION 


Studies of the deficiency diseases have served to illustrate in 
a most convincing manner the intimate relationship of nutrition 
to infection, and have led our attributing increased significance 
to the former. Indeed, the chief clinical importance of disorders 
of nutrition seems to be associated with the fact that they bring 
about an abnormal condition of the tissues which renders them 
more susceptible to the invasion of bacteria or their products. 
This relationship was exemplified in 1913, when, as a result of a 
dietary of pasteurized milk, latent scurvy developed among a 
group of infants under our care, This ‘‘scorbutie taint’’ was 


NUTRITIONAL DISORDERS 121 


followed by a widespread grip infection, with hemorrhagic skin 
manifestations, which disappeared on the administration of 
orange juice. For some years I was uncertain how to interpret 
this peculiar clinical picture, whether to regard the epidemic 
as due to scurvy or to infection. As the result of subsequent 
experience I realized that it was due to both causes, the result 
of a primary nutritional disturbance and a secondary bacterial 
invasion. Another illustration of the interrelationship of dis- 
ordered nutrition and infection is furnished by the frequent co- 
incidence of nasal diphtheria and latent or subacute scurvy. 
This concurrence is so suggestive that when a large number of 
eases of nasal diphtheria develop, suspicion should be aroused 
that the infection was implanted on tisues rendered susceptible 
by scorbutie or other nutritional disorder. This view holds true 
for animals as well as for man. Veterinarians and farmers are 
well aware that faulty nutrition leads to fatal infections. The 
so-called ‘‘snuffles’’ of hogs is recognized as a disorder of this 
twofold nature. It is probable that plants which have been 
poorly nourished, owing to an inadequacy of the soil, also react 
by diminished resistance, and that this is a factor in the infectious 
diseases of plant life. This ‘‘nutritional-infectious’’ aspect has 
been convincingly illustrated on a large scale among the peoples 
of the Central Empires, who during the many years of the war 
suffered from various forms of malnutrition. The general im- 
pairment of health was most strikingly manifested both in adults 
and in children by the great spread of tuberculosis and its in- 
creased mortality. Davidsohn** has reported that in Berlin there 
was a marked increase in infection with tubercle bacilli in 
children under the age of 5 years, and that they had been infected 
earlier in life than formerly ; whereas in 1913, 30 per cent. gave 
a positive reaction at 414 years, in 1919 this percentage was 
reached at 214 years. The mortality of children from tuber- 
culosis showed a similar diffcrence in the year previous to the 
war compared to that of the year succeeding the armistice, the 
figures being thirty-two as compared to about forty-eight deaths 
among children under 6 years of age, on the basis of 10,000 
living individuals. 

Clinical investigations in the domain of the deficiency diseases 


122 HARVEY SOCIETY 


have, as a rule, differed essentially from laboratory experiments. 
The latter, if accurately planned and correctly executed, study 
but one deficiency at a time; whereas the clinician investigating 
the dietary inadequacies of an individual or of a group, is neces- 
sarily confronted by a lack of more than one food factor. For 
example, an analysis of the cases of xerophthalmia or kerato- 
malacia—a disorder ascribed to a lack of the fat-soluble vitamin 
—reported by Block of Copenhagen shows that many of the 
infants were receiving an insufficient quota not only of this vita- 
min but also of the antiscorbutic vitamin and of calorie food 
equivalents. Furthermore, in many localities where there was 
prolonged subnutrition during the recent war, there was a lack 
of vitamin, of adequate salts, of other essential substances and 
of calories. This confusion renders it impossible to unravel 
the clinical phenomena or to asign the various food factors their 
respective roles. This criticism applies to the study of war or 
hunger edema which in 1917 spread through Poland and other 
countries, and which probably was the result of partial starva- 
tion combined with an unbalanced diet.** For this reason it is 
questionable whether we shall derive much increased knowledge 
from subsequent detailed reports concerning this vast experi- 
ence of human suffering. On the other hand, a great deal will 
be learned in the future from clinical studies of nutrition when 
the diets are carefully controlled so that the results are capable 
of exact interpretation. We may expect such investigations 
to be undertaken more frequently and more intensively 
than heretofore. 

On the other hand, for the laboratory worker there is the 
temptation to draw sweeping deductions from animal experi- 
ments, and to apply them en masse to the deficiency diseases of 
man. It should be remembered that the results of animal ex- 
periments are provisional and require the confirmation of clinical 


* The experiences in the Central Empires during the war render it 
improbable that pellagra is due merely to a lack of adequate protein. 
Adequate protein was lacking to a marked degree—milk, cheese, eggs, meat 
were all unavailable. Nevertheless there was no prevalence of pellagra 
throughout these years, 


NUTRITIONAL DISORDERS 123 


experience. Only too often has it been found that laboratory 
conclusions which at the time seemed open to but one interpreta- 
tion were later explained by unsuspected and entirely different 
factors. The pitfalls in dietary experiments on animals are 
especially numerous on account of the varying reactions of the 
different species, and because the artificial diet—in spite of the 
greatest care—may be incomplete in more than one particular. 
In vitamin experiments there is especial danger of attributing 
failure of growth and nutrition solely to a deficiency of this 
factor, on which the attention of the investigator is focussed, 
taking it for granted that the dietary is adequate beyond question 
in salts, protein and all other constituents. It is quite possible 
that this inconsistency will be found to invalidate some experi- 
ments that have seemed conclusive. 

The disorders of nutrition have always presented a preemi- 
nent opportunity for collaboration between the laboratory and 
the clinic. It will be remembered that at one time the concep- 
tion of rickets embraced a motley crew—congenital syphilis, 
scurvy, true rickets, achondroplasia and osteopsathyrosis, and 
that one by one these diseases were differentiated by the combined 
investigation of laboratory worker and clinician. The same op- 
portunity exists today. The group of deficiency diseases fur- 
nishes urgent problems for the chemist, for the experimental 
biologist, the pathologic anatomist, the réentgenographer, and 
last, but above all, for the trained clinician. The subject is so 
complex that advance will be along various paths, each worker 
furthering and checking the work of the other, so that progress 
may not leap beyond the bounds of well-founded experimental 
or clinical evidence. 


NATIONAL CHANGES IN HEALTH 
AND LONGEVITY 


By SIR ARTHUR NEWSHOLME, K.C.B., M.D.* 


Resident Lecturer in Charge of Public Health Administration, School 
of Hygiene and Public Health, Johns Hopkins University. 


HE subject roughly indicated in the title as announced, 
evidently cannot be even outlined in an hour’s address; 
and my remarks will deal chiefly with some of the changes in 
longevity in England, and, so far as they are ascertainable, in 
this country. After a more general introduction, I propose 
to confine my review to men, merely indicating now that im- 
provements in the male have in nearly every instance been 
exceeded in the female. As will be seen shortly, I propose 
furthermore, to limit my comparisons chiefly to the period be- 
yond the 40th year of human life. 

The object of Preventive Medicine may be stated to be to secure 
long life with enhanced health. The mere desire for long life 
may, from a certain angle, be regarded as including some 
ignoble elements. There is a sense which we must agree with 
the Wisdom of Solomon: 

“ Honorable age is not that which standeth in length of time, nor is 


measured by number of years. He being made perfect in a short time 
fulfilled a long time” 


(Apocrypha, Wisdom of Solomon, Chap. IV. 
Verses 8 and 13.) 
Although it is the desire of every man to die of old age, 
there are many passions more powerful. As Lord Bacon said— 
“There ia no passion in the mind of man so weak, but it mates and 
masters the fear of death....Revenge triumphs over death; love slights it; 
honor aspires to it; grief flyeth to it; fear pre-occupateth it.” 
But to die of old age is the laudable ambition of all. 
We may assume that death is a normal, though the last, 


* Delivered January 29, 1921. 
124 


CHANGES IN HEALTH AND LONGEVITY 125 


act of life. In Goethe’s words, ‘‘Life is the most exquisite 
invention of Nature, and death is her expert contrivance to 
get plenty of life.”’ 

To die of age is comparatively rare. Disease and accident, 
in times of peace, are the chief causes of death in civilized 
communities; and premature and therefore wasteful death is 


AGE AT WHICH POPULATION IS REDUCED TO ONE-HALF POPULATION AT BIRTH 
(Life-Table Experience) 


Experience Males Females 
of 
England and Wales (1901-10) 58-59 years 62-63 years 
England and Wales (1909-11) 61-62 years 65-66 years 
United States of America 
Experience of (1909-11) 

Entire Population ..... Original Registra- 

tion States 58-59 years 62-63 years 
LE Original Registra- 

tion States 59-60 years 63-64 years 
>» DEO RaSh CBee Original Registra- 

tion States 34-35 years 40-41 years 
Native White .......... Original Registra- 

tion States 60-61 years 64-65 years 
White in Cities ....... Original Registra- 

tion States 55-56 years 60-61 years 
eyuite, rural .......:.. Original Registra- 

tion States 65-66 years 67-68 years 
LOGO) gee ae eee 64-65 years 66-67 years 
Massachusetts ......... 58-59 years 62-63 years 
MUICHIPAN ..........54. 64-65 years 66-67 years 
New Jersey ........... 57-58 years 62-63 years 
Ae A eee 55-56 years 61-62 years 


the rule among us. This is illustrated by the following table, 
showing in various life-table experiences the age at which 
a given number (say 100,000) starting at birth become reduced 
to half their original number (say 50,000). 

(It is convenient here to explain for the benefit of non-technical readers 
that a life-table represents “a generation of individuals passing through 
time.” Theoretically it may be formed by actually watching a large 
group of persons from birth to death, and ascertaining the number of 


126 HARVEY SOCIETY 


survivors and the average future expectation of life at each successive 
birth-day. But such a life-table would be obsolete before it could be 
utilized; and in the life-table figures quoted hereafter, the death-rates 
for each age-period of life during a short series of years are assumed to 
determine the number of survivors to the next age-period, who are then 
subject to the death-rate of the next age-period in the same years, and 
so on.) 

Dr. Farr (35th Ann. Rep. of Reg. General) described the 
age between 45 and 55 as the middle arch of life, as shortly 
after the age of 45 was reached, a million born at the same time 
were reduced to half a million. Now a much larger proportion 
past this middle arch of life. 

In most of the above communities half of the total popu- 
lation born has scarcely disappeared before reaching the 60th 
annual turnstile. 

This is true for a life-table population in which a given 
number of persons are traced through life on a fixed basis of 
experience. In actual life, there is in most communities a 
greater stream of incoming new lives by birth than of departing 
lives; and the loss of life under these circumstances is heaviest 
in the earlier years of life. This is illustrated in the follow- 
ing table giving the proportion of deaths at all ages which 
occurred at different age-periods in 


ENGLAND AND WALES, 1901-10 
PROPORTION OF DEATHS AT ALL AGES (100) OCCURRING 
AT DIFFERENT AGE-PERIODS. 


Age Males Females 
HirstpOeVyearsie commie 35.0 31.0 
Twenty years 5-25 ........ 7.8 8.3 
Twenty years 25-45 ........ 12.6 12.2 
Twenty years 45-65 ........ 20.8) 44.6 19.1) 48.5 
Ages 65 and upwards ..... 23.8) 29.4) 
100.0 100.0 


Thus in actual experience only 44.6 per cent of the male and 
48.5 per cent of the female deaths occur at ages over 45. 


CHANGES IN HEALTH AND LONGEVITY 127 
THE VITAL SUPERIORITY OF THE FEMALE 


It will be noted that a smaller proportion of female than 
of male deaths occur in early life; also that on the average 
females live longer than males; and the following table shows 
that at every age except between 5 and 15, the female is lower 
than the male death-rate at corresponding ages. 


PERCENTAGE EXCESS OF MALE OVER FEMALE DEATH-RATE AT EACH 
AGE-PERIOD DURING TWO DECENNIA.* 


EXPERIENCE OF ENGLAND AND WALES 


Age 1851-60 1901-10 
CL ahe cya) ai ee en aia ee Bree +15 +19 
SERIE eve chavs elena, wie Salcha tt 1 — 3 
BN iether ate ts ish avavele ee iviehe « — 3 — 5 
TOSS oe RS Se a oe —9 Se 1 

SIEM ti aPy (sch ea\s (3c 6 ie'ssalers ous + 4 +19 

Pe ioe sick oiels o.s.c'< $3 peaie's —4 +17 

3D Sadoe Soest COE Dep ero + 3 +22 

25 po) Wan BS eer ae +18 +30 

Te oe Ae eo +14 +28 

Re eves CreiOciche wolste 3,550 9.3 +11 +20 

75 and upwards ........... + 6 +12 


The death-rate at every age in both sexes has declined; 
but males show an increasing excess of mortality as compared 
with females, amounting to a maximum excess of 30% at the 
age-period of 45-55. The excess of female over male mortality 
at ages 5-15 in 1901-10 and at ages 10-15 in seven consecutive 
decennial periods of English experience would form an admir- 
able subject for further study. Excepting at these ages the 
superiority of female over male vitality is evident throughout 
life; a fact which is perhaps too little known. 

In England and Wales, for every 1,000 live births of female 
infants there were 1049 live births of male infants in 1841-50, 

*This and most other tables given in this paper are derived from 


Dr. Stevenson’s contributions to the Reports of the Registrar General 
of England and Wales. 


128 HARVEY SOCIETY 


the proportion slowly falling to 1038 in 1901-10, and rising 
again to 1045 to every 1000 female births in the three 
years 1916-18. 

In the birth registration area of the United States in 1918 
the proportion of male to female live births was 1059 to 1000 
among the white and 1020 to 1000 among the negro population. 

But this excess of male over female is soon removed. The 
superiority of the female in the struggle for survival is shown 
markedly in the first day after live-birth, through every week 
of the first month, and in each trimester of the first year of 


DEATH-RATE PER 1000 BIRTHS AT EACH PERIOD OF INFANCY 


United States-Birth Regis- 


England and Wales. 1918 tration Area. 1918. 
Males Females Males Females 
Under one day ........ 12.6 9.6 17.6 13.1 
1 day and under) 
1 week Bierce: 13.3 10.7 17.0 13.1 
Ord f WEARS seine ceria 6.0 4.9 6.5 5.4 
BEG *WVEEE % 2 viele e velo 5.2 8 ee 4.8 3.9 
Ath “week: 2 Pewee sciee 3.9 he 3.7 3.1 
Total under 1 month .... 41.0 31.8 49.6 38.6 
Icto oemonthis see. +e. 18.9 15.0 Dil use 
3.\to) G months... 2c. 18.1 13.6 17.9 14.5 
6 to-9 months: «.... i025 15.6 12.6 14.5 12.7 
Oitosl2 months222 nee 14.3 13.0 TET ya 
107.9 86.0 110.8 90.6 


extra-uterine life; and is shown in American and English ex- 
perience alike. By the end of the second year of extra-uterine 
life girls number more than boys. That greater facility of 
birth of females owing to a smaller cranium is not the sole 
cause is evidenced by the persistence of the phenomenon of sup- 
erlor vitality. 


DEATH-RATES AT DIFFERENT AGES—INCREASES AND DECREASES 


For the registration area of the United States comparisons are 


CHANGES IN HEALTH AND LONGEVITY 129 


only possible between 1900 and subsequent years. In the follow- 
ing table the American experiences for the single years 1900 and 
1911 are quoted from the Mortality Statistics, 1911 (Bureau 
of Census) page 22. The death-rates for the same years and 
ages are given for England and Wales. 


MALES—DEATH-RATE PER 1000 LIVING AT EACH AGE. 


Year O— 5— 10— 15— 20— 25— 35— 45— 55— 65— 75 
and over 


1900 (England and 
tWales .2.... 61.6 4.2 2.3 3.7 5.1 6.7 11.7 19.9 37.1 74.2 168.3 


( 
(U.S.A. 
(Reg. Area .. 54.2 4.7 29 49 7.0 8.3 10.8 15.8 28.9 59.6 146.1 


1911(England and 
(Wales ...... 46.2 35 2.0 30 3.9 5.0 8.0 14.8 29.7 63.5 150.4 


( 
(U.S.A. 
(Reg. Area .. 39.8 34 2.4 3.7 65.3 6.7 10.4 16.1 30.9 61.6 147.4 


The differences are interesting, but it will be desirable to 
compare the experience of other years before final conclusions 
are drawn. In 1900, at ages 0-5 and at all ages over 35, regis- 
tration America had a more favorable male death-rate than 
England; in 1911 its superiority at higher ages was confined 
to ages over 65. In 1900 the English death-rate at ages 0-5 
was 14 per cent and in 1911 was 16 per cent higher than that 
of America (registration area). Evidently then, in view of the 
higher infant mortality in America, the death-rate at ages over 
1 and under 5 is lower in the States than England, a subject 
worthy of further study. For all ages the standardized death- 
rates of England and Wales was 19.9 per 1000 population in 
1900 and 15.6 in 1911; of the original registration area of the 
U. 8. A. 17.6 in 1900 and 15.3 in 1911; there being a 22% 
improvement in England, and a 13% improvement in the 
registration area. 

9 


130 HARVEY SOCIETY 
THE INCIDENCE OF REDUCED DEATH-RATE AT DIFFERENT AGES 


In the next table the historical trend is shown of the death- 
rates of England and Wales in five decennial periods, the increase 
or decrease of the death-rate for various age groups being 
displayed. The table also shows a similar comparison between 
the experience of 1911 and 1900 for the registration area of the 
United States. 

It will be noted that the American experience displays for 
the later period an increased death-rate in men at all ages over 
45, and in women at ages 55 to 75. 

When the experience of 1871-80 is contrasted with that of 
1861-70, the English experience shows an increased death-rate 
at all ages over 35 for males, and at ages over 55 for females. 
When 1881-90 is contrasted with 1871-80 there is no evidence 
of increased death-rate at any age except in men aged 65-75; 
and the experience of the 20 years 1891 to 1910 show a declining 
death-rate in both sexes at all ages, with the exception of a slight 
increase at ages 55-65 in males and at ages 65-75 in females in 
1891-1900, due probably to the influenza pandemic of 1889-93. 
The evidence is definite that there has been steady advance in 
the age to which increasingly favorable death-rates extend. 

Thus a comparison of the experience of (the death registra- 
tion area of) the United States with that of England and Wales 
shows that the registration area stands historically in respect to 
increase or decrease of death-rate at various stages of life 
approximately where England stood in 1871-80; and it is not very 
hazardous to make the same forecast for it, as I ventured to 
make for England in the year 1893, when the first ‘‘ Brighton 
Life-Table’’ was prepared by me.* ; 


In that publication, I pointed out that— 


“Tt is evident that although in England, owing to the large number 
of lives saved during the early years of life, the number surviving to the 
higher ages has increased, thus securing a great gain to the community, 
this is not incompatible with a stationary or even diminished prospect of 


* (See also P. 316 of the author’s “Elements of Vital Statistics,” 1899) 


CHANGES IN HEALTH AND LONGEVITY 131 


life for each individual over a certain age. In England the death-rate for 
males was higher in 1871-80 for all age-groups above the 25-35 period, 


INCREASE OR DECREASE PER CENT OF THE MORTALITY IN 
EACH SEX AND AGE-GROUP COMPARED WITH THE MorTALITY IN THE SAME 
GROUP IN THE IMMEDIATELY PRECEDING DECENNIUM. 


Death Regis- 


England and Wales tration Area. 
1871-80 1881-90 1891-1900 1901-10 1911 
compared with compared with compared with compared with compared with 
1861-70 1871-80 1881-90 1891-1900 1900 
Males 
inden bi 2), /3)5/. + - — 6.9 —10.0 + 1.8 —20.2 —26.6 
Dae reyeretisireic —18.1 —20.3 —19.4 —18.7 —27.7 
Obie es eens —17.3 —20.4 —17.1 —16.1 —17.2 
LS) ao Boor ee —15.1 —17.8 —12.2 —18.5 —24.5 
Oe rete bss —13.1 —22.1 —11.7 —17.4 —24.3 
PAT) ara eae — 6.0 —16.9 —13.0 —17.6 —19.3 
SOC a erele se + 2.3 —10.2 — 7.2 —20.4 — 3.7 
BO econ avs + 4,2 — 3.5 — 2.2 —14.4 + 1.9 
[Gs 85 caer + 5.2 — 0.5 + 0.7 — 9.0 + 6.9 
(015) ie cena eee + 3.9 + 1.1 — 0.1 — 7.9 + 3.4 
75 and over .... + 2.3 — 39 _— 16 — 4.8 + 0.9 
- Females 
Winder Soe. 22. — 8.4 —11.0 1.6 —20.7 —27.3 
L578 aes eee —20.1 —15.6 —16.9 —17.3 —32.6 
MO: evict: —175 — 16.4 —17.5 —15.6 — 32.3 
GTA eee —17.9 —18.9 —17.1 —21.1 —31.3 
ZO is ct.e5-s —14.6 —18.7 —19.5 —21.6 —29.9 
7AT}) A Oe —11.4 —14.4 —17.5 —22.0 —26.8 
Boats is Ses — 3.6 — 9.0 — 9.4 —21.5 —15.3 
AU eras csc — 0.2 — 3.3 — 2.4 —15.1 — 9.2 
DOM at cists + 2.7 — 0.7 — 0.1 —12.6 + 0.8 
Con ees sis + 3.2 — 1.0 +: 0.5 —11.2 + 2.4 


75 and over ..... + 0.8 — 5.2 — ll — 7.0 — 0.2 


and for females was higher in 1871-80 for all age-groups above the 35-45 
period than in preceding decennial periods.” 


After discussing the influence of increased wages and im- 
proved nutrition in more than counterbalaneing the unfavorable 
influence of city conditions of life, I laid stress on the following 


132 HARVEY SOCIETY 


factor which must, I believe, be credited with a large share of 
the credit for the reduced death-rate at older as well as at younger 
ages which has now been realized. 


“Another consideration requires to be borne in mind. We are at present 
in a transition period. The Public Health Acts of 1871 and 1875 heralded 
immense improvements in sanitation, the fruits of which have not yet been 
fully reaped. There has been, more especially since 1875, steady and in- 
creasing improvements in the conditions under which people live. Men now 
40 years of age were born in the pre-sanitary period; and the first 20 years 
of their life were spent under more unhygienic conditions than those now 
holding good. This fact would go far towards explaining a stationary 
death-rate at the higher ages. It does not, however, explain an increased 
death-rate at those ages.” 

“The explanation of this increased death-rate at the higher ages will 
probably be evident, when at the end of another 20 or 30 years the improved 
conditions of life have endured sufficiently long to enable their full force 
and value to be determined. We must be content in the meantime to have 
stated the more important factors which appear to be at work, leaving the 
complete solution of the problem to a time when the statistical experience 
of our country is more mature.” 


At the end of the time asked for in the above comment, it 
is noteworthy that at every age, even beyond 75 years of age, 
the number dying from a given number at risk has decreased; 
and the improved conditions of modern life, sanitary, social, 
and economic, have resulted in England in a lowered death-rate 
at every recorded age-period. 

It is unfortunate that a similar comparison can be made for 
the registration area of the United States only for 1900 and 1911; 
which, as already stated, displays a difference similar to the 
one displayed when the English death-rates at different ages 
in 1871-80 are compared with corresponding death-rates for 
1861-70.** 


The above statement gives the historical position. It will be noted, 
however, that the standardized total American death-rate in 1911 was 15.3 as 
compared with 15.6 for England and Wales. 

I am able to give the following additional contribution to the historical 
position. In the annual report of the Massachusetts Board of Health for 
1896 is given a comparison of the death-rate according to age for both 
sexes in combination in 1875 and 1895 respectively. 


CHANGES IN HEALTH AND LONGEVITY 133 


Death-rate, Massachusetts, U.S.A. 


0 i Shs Saar PD) | SOs 4G BO | COM | 70 80 
Ae a << 73.9 9.8 °47—7.7 105 11.3 13.0 18.3 348 71.1 1764 
Mes. 5: 64.5 62.32 53 7.1 9.7 12.7 205 39.4 82.4 1847 
It will be noted that the death-rate had increased between 1875 and 
1895 at each age period after 50. A somewhat similar increase has occurred 
between 1900 and 1911. 


CHANGES IN ADULT MORTALITY 


Having given a brief outline of the general lowering of the 
death-rate in both sexes at all ages, with the exception of a slight 
share of women in this improvement, I propose now to confine my 
observations to the historical changes after the age 25, and 
more particularly to events after the 40th milestone of life has 
been passed ; as it is especially concerning this period of life that 
our professional pessimists,—as always in the past,—insist that 
we are ‘‘ going to the dogs.’’ 

It is particularly unfortunate that these historical compari- 
sons, owing to the absence of comparable American data, must 
be limited chiefly to English experience with a relatively stable 
population and long experience of accurate vital statistics. 

For England and Wales as a whole, a consecutive series of 
life-tables enables comparisons to be made for long series of 
years. In the following tables, the facts are shown for males. 

Table A. shows that in each successive life-table the number 
of survivors to the age of 25 out of equal numbers born has 
continuously increased with lapse of time. 

The subsequent course of events for adult life can more accu- 
rately be followed in Table B. It will be seen that with the excep- 
tion of ages 60 and upwards in the decennium 1881-90, the number 
of survivors out of every 1000 reaching the age of 25 years has 
steadily increased until after the Psalmist’s term of life is passed. 

Similarly, out of every 1000 reaching 40 years of age, with the 
exception of ages 55 and upwards, in 1881-90, improvement in 
expectation of life is shown at all ages over 40. 

These tables give no evidence of national deterioration at 


134 HARVEY SOCIETY 


ENGLAND AND WALES LIFE-TABLES—MALES Massachusetts, U.S.A. 


Males 
(‘‘In the following tables, the facts are shown for males’’.) 
AS 
Number of Survivors at Higher Ages, out of 1000 Born. 
Experience of .... 1838-54 1881-90 1901-10 1910-12 1893-97 1909-11 
No: at Birth :<-...: 1000 1000 1000 1000 1000 1000 
No. at Age 25 ..... 624 694 745 779 680 760 
SO te ers 595 669 727 762 651 739 
SOP tas. 564 640 705 742 620 713 
AO seine 532 605 677 WG 588 683 
Aen oie 496 564 642 685 554 646 
BO ene rs 6 456 518 599 643 515 604 
HDi vas sere 409 463 544 590 468 551 
GO. 353 356 398 476 521 411 482 
650 36S a 295 322 393 435 344 395 
Ook t 223 239 299 334 267 296 
POL seers 148 154 198 224 185 197 
B. 
Number of Survivors at Higher Ages, out of 1000 at Age 25. 
Zi ve etete 1000 1000 1000 1000 1000 1000 
BO. ee os 954 964 976 978 958 972 
3D See. 904 922 946 952 912 938 
AO: os.2 852 872 909 920 865 899 
BBD Sci st 794 813 862 879 815 850 
DOF erosive 731 746 804 826 758 795 
DO Mess pars 655 667 730 758 688 725 
GOs eae 570 574 639 669 604 634 
Gy eres sc0 473 464 528 558 506 520 
OL esti 357 344 401 429 393 389 
(Cais ae 237 222 266 288 272 259 
C. 
Number of Survivors at Higher Ages, out of 1000 at Age 40. 
AD tenet 1000 1000 1000 1000 1000 1000 
ar eee 932 932 948 956 942 946 
BODE ere 857 856 885 897 876 884 
a eee 769 765 804 823 796 807 
GOOF car 669 658 703 727 699 706 
Ghee 556 532 580 606 585 578 
CON ceestare 420 395 442 466 454 433 


Oveert ener 278 255 291 312 315 288 


CHANGES IN HEALTH AND LONGEVITY 135 


Age 
GRE 7 


Survivors 
at Each Age 


300 


600 


700 


600 


500 


400 


300 


200 


100 


0 


Fic. I.—LiFE TABLE EXPERIENCE, ENGLAND AND WALES, For Four PEeriops. Number of 
male survivors at each subsequent age out of 1,000 at age 25, in 1838-54, 1881-90, 1901-10 
and 1910-12. 


HARVEY SOCIETY 


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CHANGES IN HEALTH AND LONGEVITY 


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138 HARVEY SOCIETY 


higher ages. They show, on the contrary, increased longevity 
in each succeeding period. 

This is further illustrated in Fig. 1. 

For the United States death registration area* historical 
comparisons are only practicable for 1900 onwards, except for 
Massachusetts, for which Dr. S. W. Abbott, the Secretary of the 
then State Board of Health constructed a life-table based on the 
experience of the years 1893-97,t the data for which are probably 
comparable with those for Massachusetts published in the life- 
table volume of the Federal Census Bureau. In this volume 
is given inter alia a life-table for Massachusetts, based on the 
experience of 1909-11; and in the table these two experiences 
are compared. 

The results when the whole of life is taken into account show 
improved prospects of life in every age period in Massachusetts ; 
so in the main do the figures for equal numbers starting at age 
25; but for equal numbers starting at age 40, there appears to be 
slight vital deterioration from age 65 and upwards. 

Although the materials for historical comparisons in U.S. A. 
are scanty, the series of life-tables issued by the Bureau of 
Census, based on the deaths in the 3 years 1909-11 and the pop- 
ulation of 1910, give valuable material for comparison with the 
data for England and Wales. Dr. Wm. H. Davis, the Chief 
Statistician for Vital Statistics of the Census Bureau, informs 
me that the English and American life-tables are comparable, 
in respect of methods of construction. In the following table 
are compared the number of survivors out of 1000 males at birth, 
at age 25, and in each successive five additional years of age. 
The columns are arranged in order of the number of survivors to 
the highest age, beginning with the experience of greatest vitality. 

It will be noted that the aggregate white males in the rural 
parts, and in the whole of the registration area, and the pop- 

*This area comprised in 1900, 40.5% of the total population of 
the U.S.A. 

+ The 30th Annual Report of the State Board of Health of Massa- 


chusetts for 1898 gives also an earlier life-table for persons in 
Massachusetts dealing with the experience of the year 1855. 


CHANGES IN HEALTH AND LONGEVITY 139 


ulation of the States of Indiana and Michigan showed the largest 
number of survivors to age 25, Michigan coming next.t 

If the experiences from age 25 onwards be compared, rural 
males, the males of Michigan and of Indiana have approximately 
an equal number of survivors to the age 70, while Massachusetts, 
New Jersey, and New York States have relatively few. 

The following table compares the experience of males in 
England and Wales in 1910-12, with that of white males and 
white native-born males in the registration area of the United 
States in 1909-11. 

In Figure 2. the relative experience of urban and rural 
populations and of Massachusetts is shown. 

The picture is not materially changed when the survivorship 
of 1000 men starting at age 40 in each of these states is con- 
trasted. The populations living preponderantly in cities evi- 
dently occupy an inferior position. That the conditions of city 
life explain, largely at least, the marked differences of vitality in 
the different states is suggested by the partial coincidence 
between the degree of urbanization and the paucity of survivors. 
At the census of 1910, 92.9% of the population of Massachusetts 
was urban (i.e. lived in districts with population exceeding 
2500) ; 78.9% in New York; 75.2% in New Jersey, as against 
47.2% in Michigan and 42.5% in Indiana. The proportion of 
foreign born population in 1910 was about 32% in Massachusetts 
and New York State; 29.5% in New Jersey ; 22.1% in Michigan, 
and 9.2% in Indiana. It may be added that for every 100 
foreign born persons in Massachusetts the highest proportion 
is Irish (21.2%), in New York, Russians (20.5%), Italians 
(17.3%), and Germans (16.0%) coming next. 


SUMMARY 


The close similarity between the experience of the male 
population in adult life in England and in the United States 
is striking. It is, further, noteworthy that the inclusion of 


¢ Separate life-tables have been published for Indiana, Massachusetts, 
Michigan, New Jersey and New York. 


140 


HARVEY SOCIETY 


A. 


Number of Survivors at higher ages out of 1000 Born. 


England and 
Ww 


* Original Registration States 


ales 


United States. * 1909-11 


Males All Native- All White 


born White Males 


Males 

1000 1000 
768 771 
744 748 
716 721 
683 688 
648 651 
608 607 
561 556 
501 490 
426 409 
337 315 


1000 at Age 25. 


1910-12 
Noi bina s. c pee 1000 
AGIAGEL2O: etins sete meee 779 
BOR sareacn sateen 762 
SDI are cyte hel roto 742 
AQ) ei eee 717 
ADDY a tee e ie aestalos 658 
DO nosis le ern eee ne 643 
DOM hire Saeks amredere ave 590 
COP ePrice speech hehe 521 
GORA sie se ro ehectere 435 
CON irs, Slecs 334 
B. 
Number of Survivors at higher ages out of 
ALTA GER 2D easier 1000 1000 1000 
OD ire vet oth ois 6 eases 978 969 971 
SRO OA eeeecu etre? 952 932 936 
a er tA 920 889 894. 
AD) fovea nia ise dpeserey ote 879 844 846 
SO! cists Soe eee 826 792 788 
Oe oh vrckeeyatereeieions 758 731 722 
COp oe ate one cue fetrene 669 652 636 
GB oes cee eee 558 555 531 
20 fas oe eee 429 439 409 
(Oe ae Snr 288 308 280 
c: 
Number of Survivors at higher ages out of 1000 at Age 40. 
AteApe T4022 ox. cckees, ce 1000 1000 1000 
AD Wee aie esc stets 956 949 946 
BO teres acto eter 897 890 882 
Faeroe SeO ee ALC 823 821 808 
CO) essa SeSoeur. 727 734 712 
OD is Jo's Siriwtare chats 606 624 595 
BONS oor tansee cee 466 493 458 
347 314 


CHANGES IN HEALTH AND LONGEVITY 141 


800 


700 


600 


500 


400 


300 


100 


0 


Fic. II.—Lire TABLE EXPERIENCE OF THE UNITED STATES (1909-11). Number of male sur- 
vivors at each subsequent age out of 1,000 at age 25 in the aggregate urban and rural white 
populations of the original registration states and in Massachusetts. 


142 HARVEY SOCIETY 


foreign with native whites does not result in a very marked 
change in survivorship at the higher ages. 

Summing up the teaching of the preceding tables we arrive 
at the following conclusions :— 

1. The vital experiences of England and Wales and of the 
death registration area of the United States are very similar, 
and almost equal. 

2. At nearly all ages, including the first year of life, females 
have an intenser inherent power of survival than males; and 
females have profited more than males from the increased vitality 
at all ages in recent years. 

3. English experience shows in successive decennial periods 
a reduction of death-rate which encroaches on the higher ages 
with advance of time. After the end of the decennium 1881-90, 
with a magnificent exception, each age up to the end of life 
has shared in the reduced rate of mortality. 

4. Stated in terms of survivorship, out of every 1000 reach- 
ing 40 years of age, improvement in expectation of life (depending 
on the summation of survivors at all higher ages) is shown 
at all ages over 40, with the exception of ages over 55 in 1881-90. 

5. This temporarily increased death-rate at higher ages, 
which was probably associated with the Influenza Epidemic of 
1889-93, has been followed by a marked decline of death-rate 
at these higher ages. 

6. The satisfactory result is shown in English experience of 
a diminishing death-rate at all ages, though on a much greater 
seale in the younger than in the more advanced years of life. 

7. A comparison of the life-table experience of Massa- 
chusetts at an interval of twelve to fifteen years gives no evidence 
of vital improvement. 

8. The current life-table experience of the white population 
of the United States (registration area) is almost identical with 
that of England; the male population (whites) of both countries 
have an almost equal chance of survival to the age 25; and for 
equal numbers starting at the age of 25 or at the age 40, the 
native born white population of America have a larger pro- 


CHANGES IN HEALTH AND LONGEVITY 143 


portion of survivors to the age 75 than the population 
of England. 
9. The position of the negro is lamentable, assuming that in 
the registration area of the States, the figures are trustworthy.** 
10. For the rural parts of the population the expectation of 
life and the number of survivors to age 75 are much higher 
than in the entire registration area, while in cities and in the three 
States—New Jersey, New York and Massachusetts,—having a 
preponderantly city population,—life is considerably curtailed. 


INCREASE IN TOTAL DEATH-RATE IN U. S. A. AT AGES OVER 49. 


Three facts emerge prominently from the above study of the 
American and English vital statistics: 1st, that in England 
there has for several decades been an almost continuous fall in 
the total death-rate, affecting middle and advanced as well as 
early life; 2nd, that the average position of the white popula- 
tion of the United States (registration area) and that of England 
are approximately equal; although 3rd, it appears that the male 
death-rate at ages over 45 in the United States is still slightly 
increasing beyond what it was 11 years earlier. Why is this? 

An explanation has already been suggested, if it be admitted 
that time is needed for the results of almost inseparable social 
and sanitary improvements to be felt at all ages. Her vital 


** 1000 male negroes are reduced to one-half between their 34th and 
35th birthday, while this does not happen for the white population before the 
59th birthday is reached. 

** T doubt whether this figure can be trusted. Deficient birth registra- 
tion among the negroes may have vitiated to some extent the life-table 
estimates of negro population at ages 0-5, and increased the apparent 
death-rates during this period. This would not, however, influence the 
number of survivors in a life-table population out of 1000 males who reach 
the age 25 as shown in the following table:— 


Age 
Total White Pop.) ..... 25) 30) (ob) 40M 45n 507 55) 60) 16500) vb 
Reg. Area UES \3) eis 1000 971 936 894 846 788 722 636 531 409 280 


Negroes ) 
Reg. Area. Nipecus sas 1000 938 865 787 704 614 516 413 309 213 130 


144 HARVEY SOCIETY 


position is equal to that of England, due possibly to the 
higher wages, better nutrition and less alcoholism, of the mass 
of the American as compared with the mass of the English popu- 
lation. And yet she is still historically in the position as to age 
distribution of death-rates occupied by England in 1871-80, when 
the older portion of the English population had not enjoyed in 
their childhood the social-sanitary betterment which their children 
enjoyed. This being so, we may anticipate an extension of the 
reduced death-rate in the United States at all ages ere long. 

This view as to the reason for the failure of the American 
population at the higher ages to share in the reduced death-rates 
of earlier life, is confirmed by the complex position of this 
country with respect to immigration. As already seen, nearly 
one-third of the population of the States of Massachusetts, New 
York and New Jersey are foreign-born, and of the remaining 
two-thirds about half have foreign parentage, or mixed foreign 
and native parentage. These foreigners are derived in varying 
proportions from Germany, Ireland, Italy, Russia and Austria- 
Hungary, in some of which countries they have in earlier life been 
permanently exposed to circumstances of malnutrition and 
insanitation; and they, furthermore, in their earlier years resi- 
dence in the States have been subjected possibly to excessive strain 
and privation, in circumstances of insanitation. It would be 
surprising if there were not a persistently high or even an 
increased death-rate of persons at higher ages in the registration 
area. This subject has been elucidated statistically by Dr. Louis 
I. Dublin, who has shown that the foreign-born *n New York and 
Pennsylvania experience a higher death-rate than native born 
of native parentage at nearly all older ages, and that this holds 
good also for native born of foreign or mixed parentage.** 


THE REGISTERED INCREASED MORTALITY FROM SPECIAL DISEASES 


Having arrived thus far, we are now able to consider the 
statements frequently made as to special causes of alleged in- 


** The Mortality of Race Stocks in Pennsylvania and New York, by 
L. I. Dublin and G. W. Baker (Amer. Publ. of the Amer. Statist. Assoc. 


March, 1920) 


CHANGES IN HEALTH AND LONGEVITY 145 


65 75 35 as 55 
Aqe 
Fic. If].—Dgaru Rate Per MILLION Mates aT Eacu AGE PERIOD IN 1881-90 AND 
1901-10 from 
A. Pneumonia. B. Bronchitis. 


65 75 


10 


146 HARVEY SOCIETY 


creased mortality at higher ages. The following statement, based 
doubtless on official published figures, may be quoted as typical 
of numerous statements to a similar effect, published in scientific 
journals and in the daily press. 


“The death-rate from degenerative diseases in the U. S. registration 
area has increased 41% in 20 years. By this term is meant the wear-and- 
tear diseases such as cancer, arterio-sclerosis, Bright’s disease, ete., which 
are due to bad personal habits.” 


In examining the question as to whether this increase is 
real or apparent, or only partially real, we need to remember the 
limitations of accuracy of medical certification of death. There 
has been steady improvement in medical certification, but this 
in itself has necessitated caution in accepting historical com- 
parisons of diseases. The rule of safety in making historical com- 
parisons is to confine such comparisons to individual diseases, 
and not combine them into groups, as ‘‘ cireulatory,’’ ‘‘ renal,’’ 
‘* nervous,’’ and so on. The same rule applies, though to a less 
extent, when making contemporaneous comparisons. If I depart 
from this council of wisdom in what follows, it is to illustrate the 
dubiety attaching to the statistics thus displayed. 


PNEUMONIA AND BRONCHITIS 


Even for diseases like pneumonia and bronchitis, there is 
some ambiguity in historical comparisons of statistics. There 
is not only change in medical fashions of certification, but also 
in one period a larger share of pneumonia may be secondary 
to uncertified influenza, or of bronchitis or pneumonia to uncer- 
tified measles, than in another period. In the following curves 
the death-rates from pneumonia and bronchitis, respectively, in 
England and Wales among males at various ages over 25 for the 
two periods 1881-1890 and 1901-10, respectively, are compared. 

The decline in the male death-rate from bronchitis at each 
age-group is noteworthy; as is also the fact that in the decen- 
nium 1901-10 the death-rate from pneumonia increased only 


CHANGES IN HEALTH AND LONGEVITY 147 
at ages 65 and upwards. Notwithstanding the increased long- 
evity of the population, in the year 1918, in England and 


Wales, only 3.8% of the total male deaths was attributed to 
‘old age,’’ or ‘‘senile decay,’’ while in the 25 years, 1848-72 in- 


ok 


LT Nested tt tt 
~ Ua Peritoniti PR ee a 


7 Sis 


Roo Set 
eres 


190F 1902 1903 1906 1905 1906 1907 1908 1908 1910 1911 


Fic. IV.—ILLUSTRATING TRANSFERENCE OF CAUSES OF DEATH. 


clusive, the number under this heading averaged 5.1% of the total 
deaths. Even more striking as illustrating changes in the medical 
certification is the following illustration of American experience, 
borrowed from a paper by Dr. L. I. Dublin on ‘‘ The Registration 
of Vital Statistics and Good Business.”’ 


148 HARVEY SOCIETY 


CARDIAC AND RENAL DISEASES 


These considerations apply with even greater force when his- 
torical comparisons are made of the mortality from eardiae and 
renal diseases, as shown for the English experiences in 1881-90 


Death Rate 
per Million 


4800 


3200 


1600 


0 
25 
Age 
Death Rate 
per Million 
3200 
1600 
oO 
25 
Age 


Fic. V.—DEATH RATE PER MILLION MALES AT EACH AGE PERIOD OVER 25 IN 1881-90 
AND I90I-10 : : 
A.—Valvular disease of the heart, endocarditis angina pectoris. 
B.—Acute and chronic nephritis, Bright’s disease. 


and 1901-10 respectively. After the age 45, an increase is shown 
in the death-rate (stated in terms of the population at the ages 


CHANGES IN HEALTH AND LONGEVITY 149 


o 

3B 

ae is) aa r=) oO z>) 

a fo is) & So =x 
So i=) oO S o =) 
S = ° ° —) acs 


Fic. VI—DraTH RATE PER MILLION MALES AT DIFFERENT AGE PERIODS IN 1881-90 
AND IQOI-10. 
A.—Tuberculosis (all forms). 
B.—Cancer. 


under risk) for each group of diseases, the maximum increase 
being at ages 65-75 and at 75 and upwards. To what extent 
this increase is real, and to what extent it arises from more 


150 HARVEY SOCIETY 


accurate medical diagnosis and certification of the cause of death, 
cannot be stated with a high degree of probability; but it must 
be borne in mind that this increase is associated with a reduction 
in the death-rate from all causes in the aggregate at these very 
ages. The only absolutely certain facts are that on the average 
in English experience we live longer than in the past; but those 
who do not die literally of old age are certified in a larger 
proportion than in the past to have died of circulatory and 
renal diseases. 


TUBERCULOSIS 


The curves of English experience in 1881-90 and in 1901-10 
for tuberculosis shows the decline in the death-rate from this 
supremely important disease; also the gradual postponement of 
the age of maximum death-toll from it. We are more immediately 
concerned in this paper with mortality after middle life, and the 
curves bring out the too little remembered fact that tuberculosis 
remains one of the chief causes of death right up to old age. 


CANCER 


It would require a separate lecture to discuss the question of 
increase of cancer. The balance of evidence appears now to 
support the view that cancer of certain organs has increased, 
although Professor Willcox, bringing up to date a paper by Mr. 
George King, F.I.A., and myself****, has recently come to the 
conclusion tentatively reached by us in 1893. 

In this earlier paper, the national returns from each division 
of the United Kingdom were subjected to accurate analysis, and 
statistics were given based on the death-rate of Frankfort-on-the 
Rhine for 1860-89, showing the incidence of cancer according to 
site. The conclusion reached was that the apparent increase of 
cancer is confined to ‘‘inaccessible’’ cancer of difficult diagnosis ; 
and Professor W. F. Willcox has continued his comparison of can- 
cer death-rates in Frankfort down to 1913, with the result of con- 
firming the earlier observations. The subject has been rediscussed 


****“On the Alleged Increase of Cancer (Proc. Roy. I. Soc., Vol. 54. 1893) 
Diarrheal Diseases 


CHANGES IN HEALTH AND LONGEVITY 151 


in much detail by Dr. T. H. C. Stevenson in the annual report of 
the English Registrar General for 1917, in the light of English 
eancer data giving localization of the lesion ; and the conclusion he 
reaches is that in England ‘‘amongst males mortality from 
accessible cancer has increased more rapidly than from inacces- 
sible, whereas amongst females the position is reversed, the 
result for both sexes jointly being a moderate excess of increase 
from inaccessible cancer.’’ 

In other words, the English figures do not support the 
conclusion drawn from the Frankfort figures, which at the time 
they were examined were the only figures available. Whether 
cancer mortality is increasing or not, the practical point is 
that from middle life onwards it is one of the chief causes of 
premature mortality. 

So far we have seen that a remarkable increase has occurred 
in the registered death-rate at ages over 45 from certain diseases ; 
and that this is associated with a declining death-date from all 
causes in the aggregate at these ages. The absence of a corre- 
sponding decline in the total death-rate at these higher ages 
in the registration area of the United States is better explained 
by immigration of a diverse population, than by the assumption 
that causes of degeneration are operating in the native born 
population of the United States to an extent beyond that in 
England. Of course, this does not imply that the conditions 
causing ‘‘ degenerative diseases’? do not require appropriate 
action in both countries. The English Registrar General, in his 
Decennial Supplement for 1901-10 gives valuable tables of the 
death-rate at various ages from 32 of the chief causes of death. 
From these tables the diagrams already given comparing the 
experience of 1881-90 and of 1901-10 for 
Pneumonia 
Bronchitis 
Tuberculosis 
Cancer 
Cardiac Diseases 
Renal 
have been taken. 


152 HARVEY SOCIETY 


In the twenty years between the two periods the chief causes 
of death which showed decrease and increase, respectively, were 
as follows :— 


CAUSES OF DEATH 


Group 1. Grovp II. 
DECREASING INCREASING 
Smallpox Influenza 
Measles Diphtheria 
Scarlet Fever Diarrheal Diseases 
Whooping Cough Pneumonia 
Croup Cancer 
Enteric Fever Diabetes Mellitus 
Syphilis Valvular Diseases of Heart 
Tuberculosis Endocarditis 
Rheumatic Fever and Rheumatism Nephritis and Bright’s Disease 
of the Heart Suicide 
Meningitis 
Epilepsy 
Laryngitis 
Bronchitis 
Pleurisy 
Violence 


In supplement of the evidence already stated, the following 
diagram may be studied. In A the age distribution is shown of 
the male death-rate from all the diseases in Group I, above, in 
1881-90 and 1901-10, respectively. In B are displayed the corre- 
sponding facts for Group II; while in C is shown the age- 
distribution of the total male death-rate from all other causes 
in the two decennia. 

We thus see, as has already been displayed by the life-table 
method, that the balance is on the side of gain of life. For 
England we must decide between two possibilities. Either 
increased mortality from certain diseases in midde and advanced 
life has been more than counterbalanced by decreased mortality 
from other diseases; or there has been merely transference of 
entries owing to gradually increasing accuracy of certification 
of deaths; or these two factors are represented in the results to 
an uncertain extent. 


CHANGES IN HEALTH AND LONGEVITY 153 


For the registration area of the United States the situation is 
not so clear. As in England, there has been great increase in 
the registered mortality from certain diseases during middle and 


Death Rats 


Death Rate 
per Millen 


ne 


a 


fic. VII.— DEATH RATE PER MILLION MALES AT DIFFERENT AGE PERIODS IN 1881-90 
AND I9QOI-I0. 
= —Group of diseases with decreasing death rate. 
B.—Group of diseases with increasing death rate. 
C.—All other causes of death. 


late life. Thus, Dr. Frederick L. Hoffman in a paper on ‘‘ The 
Mortality from Degenerative Diseases,’’ while deprecating hasty 
conclusions from imperfect data, gives tables from which the 
following extracts are taken :— 


ey 30000 


69000 


154 HARVEY SOCIETY 


PERCENTAGE INCREASE OR DECREASE IN THE DEATH-RATE FROM ALL 
CAUSES AND FROM EACH OF THE FOLLOWING DISEASES 
BETWEEN 1900 anp 1915. 


At Ages 
30-40 40-50 50-60 60-70 70-80 
Apoplexy and Cerebral) 


Softening ) .... 4+29.4 +11.1 418.8 +33.3 +39.7 
Heart and Arterial ) 
Diseases ) .... +63 +19.8 +300 +563 +81.7 
Kidney Diseases ) .... #210 + 18 +22.2 +430 +641 
All Causes ) .... —226 —85 +09 +58 + 42 


The total death-rate from all causes at ages over 45 has also 
increased among males in the registration area, though to a rela- 
tively small extent. Furthermore, the prospects of survival to 
old age in this area are on the average equal to those of the 
English population ; and it is likely that the increased death-rate 
from all causes and from these ‘‘ degenerative diseases’’ is due to 
the introduction of foreign populations, who have lived in youth, 
and possibly after arrival in this country, an arduous life of over- 
strain under circumstances of lower civilization with excess of 
infective diseases. 

It would be foolish, in view of the above broad facts, for the 
average population, to commit oneself to a pessimistic view as to 
middle and late middle life in the future either for the English 
or the American white population. A more favorable view is, 
however, not incompatible with the existence of circumstances 
favoring, or even producing, premature decay in special groups. 
But these circumstances do not exist to an increasing extent, or are 
more than counterbalanced for the mass of our populations, who 
chiefly determine the trend of our national statistics; and it is 
all the more satisfactory—especially from a public health stand- 
point—that this should be so, in view of the increasing trend 
towards city life. 


POSSIBILITIES OF DIMINISHING DISEASES 
AT AGES 40 To 70 


There is ample evidence to show that, apparently irrespective 
of modes of life, longevity is the rule in certain families; while 


CHANGES IN HEALTH AND LONGEVITY 155 


in others, equally apart from perceptible differences in mode of 
life, the arteries fail prematurely. It would appear that there 
is no condition in which the influence of heredity is more marked 
than in the capacity to attain old age. 

Apart from this unequally distributed inherent capacity for 
old age, we must, if asked to state in a single formula the most 
serious impediment to the attainment of old age, agree that 


INJURY DUE TO INFECTIONS IS THE CHIEF CAUSE OF MORTALITY 


Next to infections, as a cause of premature death, comes malig- 
nant disease, the most pitiless of enemies, depriving us by cruel 
steps of those whose ripe judgment and mature knowledge make 
them almost irreplaceable. It is between the ages of 40 and 60 
that men begin to repay the community for the varied expendi- 
ture hitherto incurred on them. Prior to this the balance is often 
on the wrong side; and it is at these ages that cancer chiefly 
claims its victims. 

In men in England at ages 45-55, one death out of 10.5 total 
deaths from all causes; at ages 55-65, one death out of 8.1; at ages 
65-75, one death out of 9.6; and at ages over 75, one death out of 
19.3, total deaths were due, in 1901-10, to this cause. And it still 
remains true that, although in every civilized country earnest in- 
vestigators are searching for a line of action which may be hopeful, 
if not certainly successful, at present we can only point to the 
importance of avoiding protracted local irritations, and to the 
essential value of early diagnosis and treatment of the disease, as 
competent to prevent death in a certain proportion of cases. 

We must confess our almost equally great inability in respect 
of catarrhal infections, whether ordinary catarrhs, or their more 
serious congeners, bronchitis and pneumonia. Apart from 
avenues of hope in respect of pneumococcic infections, there is 
little prospect of early conquest over these diseases. 

Pandemic influenza, with streptococcie secondary infection, 
has recently proved to be a more serious cause of death than a 
world war; and no action for its abatement, on a large scale, has 
been practicable. 

Tuberculosis, although capable of being reduced to a shadow 


156 HARVEY SOCIETY 


of its present. importance—were we prepared to invest the neces- 
sary money and energy in continuous and complete action 
against it—still stalks the earth, and cuts off a large share of our 
population, especially at ages when they are only beginning to 
repay their communal indebtedness. Tuberculosis is also, much 
more than is recognized, a common cause of death at ages over 50, 
either as a chronic disease, often masquerading as senile bron- 
chitis, or as an acute complication of other diseases. 

As tuberculosis becomes relatively less serious, then cancer 
more than takes its place as a cause of premature mortality. 

Diseases of the heart and blood vessels form a complex group, 
and have diverse causation. Of the evil influence of excessive 
muscular work, of over-feeding, alcoholism, or excessive smok- 
ing, or other unhygenie personal habits in securing prematurely 
senile arteries and heart, I will assume that there is no doubt; 
but it is practically certain that such factors are of relatively 
small importance as compared with the havoe played by the 
multiple infections to which we are subjected. The chief enemies 
which prevent our arteries and heart from fulfilling their duties 
to a robust old age are the specific infections of rheumatic fever, 
of syphilis, the pneumococci, and various streptococci from 
focal or other infections, and still oftener secondary to an attack 
of an acute specific infectious disease. 

We are now thoroughly advised of the magnitude of the mis- 
chief done by syphilis. Cerebral hemorrhage before the age of 
40 or 45 may be assumed nearly always to owe its origin to this 
disease; and we know that more than one-tenth of the inmates 
admitted to our lunatic asylums are there owing to syphilis, and 
die a premature death because of this infection. Will the com- 
munity have the courage and wisdom to adopt the medical, police, 
social and moral measures required to reduce it to insignificance ? 

It must be confessed that but little more appears to be known 
concerning rheumatic fever than when in the Milroy Lectures 
for 1895 * I showed by elaborate mortality and sickness statistics 
derived from the general mortality experience of different Euro- 
pean countries, from general notification experience of Seandi- 


* Lancet, May 9th and 16th, 1895. 


CHANGES IN HEALTH AND LONGEVITY 157 


navian countries, and from the experience of large general 
hospitals in England and other countries, that rheumatic 
fever is an epidemic disease, of which widespread epidemics 
occur at intervals of a few years, though in the intervals 
it is never entirely absent from most communities. I 
drew attention to pandemics of rheumatic fever, particularly 
those of 1868, of 1874-75, and of 1884. I also showed that in 
England the epidemic prevalence of rheumatic fever in the 
period for which records are obtainable has always occurred in 
years of exceptional scarcity of rainfall. 

The causation of renal diseases or of arterio-sclerosis, apart 
from the influence of acute infectious diseases, is still obscure. 
We can, however, assert with a high degree of probability that if 
rheumatic fever could be avoided, if syphilis could be eliminated, 
and if the acute and chronic infectious diseases of childhood and 
youth and early manhood could be reduced to a shadow of their 
present dimensions, there would result an immense leap forward 
in the standard of health of the general community, and in the 
number of persons attaining a stalwart and healthy old age. 

The chief and most promising line of attack on the disabling 
diseases of middle life, and even of higher ages, consists in the 
adoption of all known preventive and curative medical measures 
in childhood and in youth, adolescence and early manhood. It is 
chiefly in these years that the bill is incurred which has to be 
paid two, three or four decades later. This does not imply, of 
course, that efforts made to anticipate and retard the onset of 
illness in older persons are fruitless. They are very desirable. 

We have in fact a quadruple line of action open to us in 
securing a healthy life of physiologically normal duration :— 

1. To pursue the present lines of public health activities with 
complete efficiency, and thus reduce the prevalence of the 
infectious diseases (chronic and acute), which, though now 
controllable, are not controlled. 

2. To undertake every additional line of public and private 
control of disease in the first twenty-five years of life, which our 
more recent knowledge of preventive medicine shows to 
be practicable. 


158 HARVEY SOCIETY 


3. To adopt the same measures so far as they are applicable 
to ages over 25. 

4. To follow every line of investigation which may enable 
us to secure further control over disease. 

There can be no doubt that, although every line of action 
indicated above must be followed to ensure success, the greatest 
and earliest results will be occurred by a great increase of 
activities under the first two of these headings. 


WITH INCREASE OF AVERAGE LENGTH OF LIFE HAS THERE BEEN 
IMPROVED HEALTH? 


The facts already stated prove not only that out of a given 
number born a larger number than formerly survive to the more 
useful years of life and to old age; but that out of equal numbers 
taken at age 25, or even at age 40, the prospects of survivorship 
to old age have improved. Any doubt on this point, for the white 
population of the United States, results probably from the vast 
introduction of a foreign population belonging in large measure 
to a lower order of sanitary and social organization. 

But these facts are not incompatible with the possibility that 
increased survival means a large amount of invalidism and 
inferior health in the population. Are we in the fullest sense 
living longer, or are we merely longer in dying? This problem 
cannot be discussed adequately in the present paper. I may 
be permitted to quote the following remarks written by me in 
1893. At that time the death-rate had increased at the higher 
ages, as it has recently done in the United States. But the 
general comments are relevant still.* 

(1.) “A favorite explanation of the diminished expectation of life in. 
adult years is that, owing to the saving of life in the earlier years of life— 
a saving which has been especially in zymotic diseases and phthisis and other 
tubercular diseases—there has been a larger number of weakly survivors, 
who would under the former regime have been carried off by these diseases. 
In other words, the operation of the law of the survival of the fittest has 


been impeded, with results unfavorable to the health and vigor of adult 
life. This argument assumes that weakly children are more prone to attack 


* The Brighton Life-Table, 1893, or Elements of Vital Statistics, p. 316. 


CHANGES IN HEALTH AND LONGEVITY 159 


by infectious diseases than robust children, an assumption which experience 
does not confirm. These diseases appear to attack the majority of children, 
weakly or robust, who are exposed to their infection. It might be reason- 
ably expected, therefore, that with a decrease in the total deaths from 
infectious diseases, there would have been at least a corresponding decrease 
in the number of those who are left maimed by an attack of one of these 
diseases to survive to adult life. I personally think that the weeding out 
of weakly lives, caused by the greater mortality among weakly children 
suffering from an infectious disease, is almost entirely counterbalanced by 
the greater number of children made weakly in former times by non-fatal 
attacks of an infectious disease. 

The case for deterioration of the race by survival of patients who would 
formerly have died in early life from phthisis and other tubercular diseases, 
appears to be a stronger one. It is probable that a larger proportion of 
phthisical patients are cured than formerly. It is probable also that many 
more children with a strong tendency to phthisis, or even suffering from 
its early symptoms are prevented by the improved medical treatment and 
the improved social conditions of recent years, from developing the disease. 
These now may survive to adult life and become the parents of children with 
a strong tubercular tendency. 

Such a fact need not, however, cause any serious apprehension for two 
reasons. In the first place, hereditary tendencies to phthisis only act under 
favorable predisposing conditions, such as damp and overcrowded houses, 
sedentary occupation in a cramped position, etc.; and in presence of the 
active exciting agent, the specific bacillus to which phthisis and other 
tubercular diseases are due. The exciting cause of tuberculosis is the 
introduction ab extra of the specific infection by inhalation or by means 
of food. 

In the second place, assuming that more phthisical patients survive 
than formerly, is it not equally true that fewer persons become phthisical 
than formerly? With a diminution of the active cases of phthisis, the 
number of centres for phthisical sputum, the chief cause of subsequent 
infection, must have diminished to a corresponding extent. Of the fact that 
the predisposing causes of phthisis-damp and overcrowded houses, ill- 
ventilated workshops, etc.—are steadily diminishing, there is evidence on 
every hand. It is, therefore, reasonable to suppose that much at least of 
the deteriorating effect of the survival of tubercular persons is counter 
balanced by the large number of persons who are prevented by improved 
sanitary and social conditions from becoming tubercular. 

It is premature at present to attempt by statistical means to determine 
how far the counteracting influences which are at work, balance each other, 
or failing a balance, on which side is the preponderating effect. 

(2.) The increased stress of modern life is supposed by many to explain 
the increased death-rate among adults. It is doubtful if such increased 


160 HARVEY SOCIETY 


strain exists in the community as a whole. Each adult as he becomes year 
by year more deeply involved in the battle of life, comes to the conclusion 
that the general strain of life in the community is increasing, forgetting 
that the same causes operated as life advanced in previous generations. 
There is reason for thinking with Dr. Pye-Smith that much of the evil 
ascribed to “over-pressure” is really due to over-feeding and drinking. 

Assuming, however, that over-pressure exists in certain stations of 
life, e. g., among city merchants, medical men, ete., it cannot be said to 
exist generally among professional men. Clergymen, lawyers and civil- 
servants are as classes long-lived. 

Even assuming that over-pressure exists throughout the whole of the 
professional and mercantile classes, these do not form the mass of the 
community. The majority of the population of England amd Wales belong 
to the wage-earning classes, and the conditions of these classes will therefore 
necessarily have the greatest influence on the total result. 


Those conditions, as we know, have greatly improved. 

I see no reason for altering the view stated in the preceding 
extract, except that I should now attach less importance to here- 
ditary predisposition in tuberculosis, and should state my 
conclusions with less hesitation. Under the circumstances of 
modern civilization the assumption that natural selection can act 
as under savage conditions is completely unwarranted. Civilized 
life, leading to progressive improvement of environment and of 
personal habits, submerges any possible influence of natural 
selection in removing those unfit for survival, substituting for it 
a process of steady uplifting in fitness of the general population. 

This is well illustrated in the following curves, which show 
that infants who have escaped the assumed selective influence 
of a high infant mortality in infancy continue to survive all 
through life in larger numbers, than infants among whom exces- 
sive infant mortality has prevailed. 

The recent recruiting figures have been adduced as evidence 
of widespread physical deterioration, and they doubtless show 
that both in this country and in the United Kingdom a large 
proportion of recruits suffered from physical defect or disease, 
rendering them unfit for military service. I have no wish to 
minimize the importance of these figures. That they indicate 


CHANGES IN HEALTH AND LONGEVITY 161 


any deterioration in physique in the population, historically, is 
not proved and is highly improbable. 

In 1844 over half the recruits in Leeds were rejected ; and in 
Birmingham and the surrounding towns in 1852 only one-third 
of the men who enlisted were approved. We have always thought 
we were a decadent race, and so have other nations before us. 


Mortality pe 
Mean Population ortality 
1891-1900, 1,000 Birtha, 
England and Wales ... «++ 30,643,479 ae 157 
Selected Healthy Districts ... 4,477,485 ate 109 


@ 3S. 0 B 20 25 30 3§ 40 45 30 33 @ G5 FO FS BO 4S. 
aB Ss 


the pumber of surviv 


ore 
at cach 5 yearly intervm 
abore. 


[J] England and Wales - - 
#011 | Selected HealthyDistricts ---—-—- 


Pic. VIII.—Showing the number of survivors at each successive year of life out of 1,000 
_ infants born in England and Wales and in selected healthy districts in 1881-90. 
This table is to be read as shown in the following example:—At age 20 the number of sur- 
vivots was 812 in healthy districts, 726 in the country as a whole; at age 60 was 573 in 
healthy districts, 441 in the country as a whole; and so on. 


The ancient Greeks thought themselves to be degenerate, and the 
Spartans adopted the ill-considered action of exposing weakly 
infants to avoid this result. Sophocles is quoted by Dean Inge 
as stating that the best fate of man is ‘‘ not to be born, or being 
born, to die.’’ Shakespeare refers to this ‘‘ waning age,’’ and has 


other similar passages. In 1721 Bishop Berkeley wrote an 
11 


162 HARVEY SOCIETY 


‘« Essay towards preventing the ruin of Great Britain ’’; and you 
will remember Wordsworth’s sonnet in which the following 
passage appears :— 

** Milton, thou should’st be living with us at this hour 


England hath need of thee; 
She is a fen of stagnant waters” 


He adds, however :— 
“Tt is not to be thought of that the flood of British freedom...... 


That this most fatal stream in bogs and sands 
Should perish; and to evil and to good 
Be lost forever.” 


Every Tory squire still believes that England is going to the 
dogs; but I prefer the sanguine view expressed by Tennyson as 
embodying the real outlook of both England and America :— 


“This fine old world of ours is but a child, 
Yet in the go-cart.” 


KIDNEY FUNCTION* 


DR. A. N. RICHARDS 


Professor of Pharmacology, University of Pennsylvania 


HE subject assigned to me, Kidney Function, is far too 
broad for discussion within the permissible limits of one 
lecture. I therefore propose to restrict what I have to say to 
the subject: 
Glomerular Function and the Modes of its Regulation. 

What I have to present is based upon work which has been 
proceeding with interruptions in the Laboratory of Pharmacology 
of the University of Pennsylvania for a number of years past; 
this work has been jointly carried on by Dr. O. H. Plant and 
myself during the years 1915 to 1920, and by Dr. Carl F. Schmidt 
and myself from September of last year until now. Their col- 
laboration has been invaluable.** 

1. Evidence that the Glomerulus of the Kidney is the Chief 
Structure concerned in the Renal Elimination of Fluid from 
the Blood. 

Until the classic work of the English anatomist, William 
Bowman, published in 1842, there was no convincing evidence 
that connection existed between the Malpighian bodies and the 
uriniferous tubules. By extraordinary skill in dissection, Bow- 
man proved that the capsule of the Malpighian body is the ex- 
panded extension of the membrane of the tubule. His first 
identification of the complete unit of structure by which urine is 
formed must therefore be regarded as the beginning of modern 
study of renal function. 

Appended to Bowman’s very complete description of the 
vascular arrangements of the kidney is a theory of the parts 
played by tubule and glomerulus in the formation of urine. He 
laid emphasis upon the structural similarity of the epithelium of 

* Delivered February 26, 1921. 


** The results of this work will shortly be published in the American 
Journal of Physiology. 


163 


164 HARVEY SOCIETY 


the tubules and that of secreting glands, and drew the inference 
that the tubules eliminate from the blood ‘‘the peculiar principles 
found in the urine.’’ He laid equal emphasis upon the dissim- 
ilarity of structure of tubules and capsule and stated his con- 
ception of the significance of this dissimilarity in these words, 
which, though frequently quoted, may well be repeated (1): 


“Thus the Malpighian bodies are as unlike as the tubes passing from 
them are like the membrane, which, in other glands, secerns its several 
characteristic products from the blood. To these bodies, therefore, some 
other and distinct function is with the highest probability to be attributed. 
The peculiar arrangement of the vessels in the Malpighian tufts is clearly 
designed to produce a retardation in the flow of blood through them. It 
would indeed be difficult to conceive a disposition of parts more calculated 
to favor the escape of water from the blood than that of the Malpighian 
body. A large artery breaks up in a very direct manner into a number 
of very minute branches, each of which suddenly opens into an assemblage 
of vessels of far greater aggregate capacity than itself, and from which 
there is but one narrow exit. Hence must arise a very abrupt retardation 
in the velocity of the current of blood. The vessels in which this delay 
occurs are uncovered by any structure. They lie bare in a cell from which 
there is but one outlet, the orifice of the tube. This orifice is encircled 
by cilia in active motion directing a current towards the tube. These ex- 
quisite organs must not only serve to carry forward the fluid already in 
the cell, and in which the vascular tuft is bathed, but must tend to remove 
pressure from the free surface of the vessels, and so to encourage the escape 
of their more fluid contents. Why is so wonderful an apparatus placed at 
the extremity of each uriniferous tubule if not to furnish water to aid in 
the separation and solution of the urinous products from the epithelium 
of the tube?” 


This is the first suggestion, founded it is true, upon tele- 
ological argument from structure, that the glomerulus is the chief 
site of fluid elimination in the kidney. This suggestion devel- 
oped into universal belief. The experiment which established its 
truth was not made until 1878 when Nussbaum (2) performed the 
operation in frogs of ligation of the renal arteries. This excluded 
the glomeruli from the circulation but, owing to the double blood 
supply of the frog’s kidney, did not abolish circulation in the 
vessels of the tubules. The result of this ligation was cessation 
of urine elimination. 

This observation, confirmed by others (3), nearly approaches 


KIDNEY FUNCTION 165 


to direct proof of the assumption made by the older anatomists. 
Since it is completely in harmony with considerations of struc- 
ture, since it is supported by a mass of less direct evidence ob- 
tained in other ways and since there is no opposing evidence so far 
as I am aware, we may regard this question, so fundamental to all 
further study of kidney function, as satisfactorily settled. 

II. The Nature of the Process by which Fluid is Separated 
from the Blood in the Glomerulus. 

In Bowman’s statement of his hypothesis that the glomerulus 
separates water from the blood, no clear idea is given of the 
nature of the process. Unaware of the epithelium which covers 
the glomerular tuft, he regarded the capillaries as projecting 
naked into the capsule, and he speaks of the cilia at the orifice of 
the tubule as presumably having power of diminishing pressure 
on the capsular side of the capillary tuft and so facillating 
escape of fluid from the blood. It seems to me that his words 
vaguely indicate the escape of fluid because of pressure within 
the capillary vessels. 

There is no such vagueness, however, in Carl Ludwig’s 
statement made in 1844, of his conception of the process (4). 
Using the anatomical facts demonstrated by Bowman and con- 
firmed by himself, and applying principles of hydraulics, he 
stated that a significant pressure must be exerted by the blood 
within the glomerular capillaries upon their walls and that this 
pressure must result in the filtration of a certain amount of fluid 
through them. He assumed that the membrane through which 
the fluid passed was normally impermeable to proteins, fats, and 
to salts which might be combined with these, and hence that the 
urine as formed in the glomerulus is a protein-free filtrate con- 
taining blood ecrystalloids in the proportion in which they exist 
free in the blood. 

I have no wish to enter in great detail into a discussion of 
the evidence for and against the filtration theory: it has been 
adequately reviewed many times and forms part of current physi- 
ological teaching. Since, in the development of what is to follow, 
an appreciation of the chief elements of strength and of weakness 
in the filtration theory is necessary, I make no apology for briefly 


166 HARVEY SOCIETY 


presenting the most important facts. The question whether the 
glomerulus filters fluid or secretes fluid is more than academie. 
A well based conviction that the understandable process of filtra- 
tion is the chief factor of glomerular activity permits clearly 
defined views concerning the nature of alterations in glomerular 
function which occur in health and disease. It carries with it 
as an inevitable corollary a conviction of reabsorption of both 
water and dissolved substances from the lumen of the tubule; 
for no other process could account for the difference in composi- 
tion between a blood filtrate and the urine as it leaves the kidney. 
Absence of such conviction on the other hand necessitates refuge 
in the conception of ‘‘secretion,’’ a word implying ignorance 
or uncertainty of processes involved and ill-defined point of 
attack on the further questions of alterations in renal function. 

There are three groups of experiments which, I think, form 
the chief support of the filtration theory. 

First, experiments which demonstrate the parallelism between 
urine elimination and renal blood pressure. These include the 
experiments in Ludwig’s laboratory by Goll, (5), showing that 
changes in general arterial blood pressure, induced by vagus 
stimulation, hemorrhage, injection of blood, or ligation of large 
arterial trunks caused changes in a similar sense in urine flow; 
and those by Hermann (6) in which diminution in urine was 
found to follow partial obstruction of the renal artery. They 
include also numerous experiments which developed from Claude 
Bernard’s discovery of vasomotor nerves — experiments in which 
the nerve supply of the kidney was either divided or stimulated 
and resulting increase or decrease in urine found to be attribut- 
able to dilation or constriction of the vessels in the kidney (7). 
It was recognized by Ludwig and his colleagues that such changes 
in the renal circulation as were studied in these experiments, in- 
volved alterations not only in renal blood pressure but in velocity 
and volume of renal blood flow as well. Reasons were adduced 
(Hermann) for belief that the effective variable in these experi- 
ments was that of pressure. The force of the experiments and the 
influence of Ludwig was such that his conception of glomerular 


KIDNEY FUNCTION 167 


filtration and tubular reabsorption became the generally ac- 
cepted view (8). 

The second group of experiments to which I refer is based 
upon this principle of physics; that in order to separate a dis- 
solved substance from its solvent by filtration through a mem- 
brane, permeable by the solvent but not by the dissolved substance, 
filtration pressure must be greater than the osmotic pressure 
of the dissolved substance. Tammann of Rostock in 1896 showed 
that the osmotic pressure of all the substances dissolved in the 
blood plasma was nearly 8 atmospheres (5840 mm. Hg) (9): 
that the osmotic pressure of the organic solids of blood plasma 
amounted to 840 mm. Hg. (He regarded the osmotic pressure 
of proteins as negligible.) Since no pressures of this order of 
magnitude are to be found in the animal circulation he concluded 
that the only substances of plasma which could physically be 
held back in the glomerulus are the proteins; hence the fluid 
separated in the glomerulus must be the water of the blood con- 
taining all dissolved substances except proteins. 

Starling, in the same year (10), discovered that the osmotic 
pressure of plasma proteins amounted to 30-40 mm. Hg. He 
showed that a force of this magnitude exerted by substances re- 
tained within the blood vessels was sufficient to explain in part 
the absorption of fluid from tissue spaces into the blood vessels. 
In 1899 he extended this reasoning to the explanation of glom- 
erular function (11). By improved method he redetermined 
the osmotic pressure of plasma protein and obtained the figure 
25-30 mm. Hg. If the osmotic pressure of plasma protein is the 
force which blood pressure must overcome in order to filter fluid 
from the blood in the glomerulus, then it should be found that 
the lowest arterial blood pressure compatible with urine elimi- 
nation is slightly above this. His own experiments and those 
of many others showed that urine ceased to be eliminated when 
arterial pressure fell below 40 mm. Hg. Further, if glomerular 
function is filtration, then the difference between arterial blood 
pressure and the maximum pressure in the ureter against which 


168 HARVEY SOCIETY 


urine can be eliminated should be almost that of the osmotic 
pressure of the proteins. He found this difference, during pro- 
fuse diuresis in the dog, to be 32-43 mm. Hg. These results, con- 
firmed and extended by Knowlton (12), are so completely in 
accord with the demands of the filtration theory that they furnish 
the strongest support for it. 

The third group of experiments in this connection are those 
of Bareroft and Straub (13), made in 1910. They applied to 
the kidney the methods so fruitfully developed by Barcroft for 
estimating the rate of metabolism of organs. Saline diuresis— 
i. e., diuresis following the injection of sodium chloride solutions 
—was found to be unaccompanied by increase in utilization of 
oxygen or formation of carbon dioxide. Knowlton and Silver- 
man later showed that this was true for diuresis following injec- 
tion of pituitrin (14). The conclusion was drawn that physical 
factors rather than ‘‘vital’’ or ‘‘secretory’’ are concerned in this 
increase in kidney function, the inference being that filtration 
is increased. 

These are the facts which to my mind most nearly constitute 
‘‘proof’’ of the filtration idea: they are reinforced by considera- 
tions of the structure of the glomerulus and by observations in 
other directions; that the more rapidly urine is eliminated, the 
more nearly it comes to resemble a filtrate from the blood, that 
the glomerular fluid is alkaline as tested by intravital indicators, 
that the osmotic pressure and chloride content of the cortex more 
closely resemble that of the blood than does that of the medulla. 
This collection of facts led Bayliss to write in 1915 ‘‘the evidence 
for this (glomerular filtration) is overwhelming’’ (15): and 
Cushny, in his development of the ‘‘modern’’ theory of urine 
formation, to accept glomerular filtration as a fundamental 
truth (16). 

It is easy to develop conviction of the truth of filtration by 
study of the work to which I have alluded. It is not so easy 
to hold it after consideration of some of the questions which have 
been put to the filtration theory and have not found satisfac- 
tory answer. 

Heidenhain in 1874 began the publication of his work on the 


KIDNEY FUNCTION 169 


kidney from which developed the so-called Bowman-Heidenhain 
theory. As is well known he injected indigo carmine into the 
circulation and failed to find traces of it in the capsule or any 
staining of glomerular structures by it. Since it was to be found 
in the lumen of the tubule and since the tubular epithelium was 
stained by it he was forced to conclude that it had been secreted 
by the tubules and had not been filtered by the glomerulus (17). 
This observation led him to further results which obliged him 
to deny the filtration-reabsorption theory completely and to at- 
tribute urine formation to secretory processes in the epithelium 
of glomerulus as well as of tubule; i. e., to processes not explain- 
able by known physical or chemical laws. 

Most of Heidenhain’s contentions have since been successfully 
met by adherents of the filtration idea; Cushny’s monograph con- 
tains an admirable exposition of this subject. One objection, 
however, seems to me to have been least satisfactorily answered 
and it happens that this is the one to which Heidenhain himself 
attached the most weight. It concerns the effects of compression 
of the renal vein upon urine elimination. The following is a 
translation of his own words (18). 


But if mechanical filtration does really occur, then elimination of 
water must always increase with the pressure. An old experiment shows 
that this is not so. For if the pressure in the glomeruli is increased by 
partial or complete occlusion of the renal vein, an immediate diminution 
in urine occurs. 

This fact contradicts the pressure hypothesis in the most abrupt 
(schoffstem) manner. 

If it is considered that increase in aortic pressure, if only a few mm., 
often causes a considerable increase in urine, and that after partial or com- 
plete occlusion of the renal vein a considerable rise of pressure within the 
glomerular vessels must occur, then it is apparent that here is a phenom- 
enon completely unexplainable by the filtration hypothesis. 


Ludwig was aware of this objection and had met it by demon- 
strating that complete obstruction of the renal vein in the living 
animal caused such swelling of the veins within the kidney 
that the tubules were compressed and their lumina obliterated 
(19). Obviously no urine could issue from the kidney under 
these circumstances. It appears that Heidenhain accepted Lud- 


170 HARVEY SOCIETY 


wig’s demonstration of the effects of complete occlusion (20), 
but he did not regard it explanatory of the events which follow 
partial closure of the vein. Slight obstruction, of a degree 
sufficient to lessen, but not to suppress, urine flow could not 
cause such lessening by engorgement of veins with resulting 
closure of tubules. The fact that urine continued to flow, though 
at a lower rate, indicated that the tubules were patent. Paneth’s 
later experiments (21), showing the possibility of diuresis by 
sodium nitrate during constriction of the renal vein, confirmed 
this conclusion. For this reason Heidenhain regarded the failure 
of slight compression of the renal vein to increase urine flow as 
the strongest argument against the filtration hypothesis and it 
was this that led him to the belief that the velocity of blood 
flow through the glomerulus, rather than the pressure of blood 
within it, was the determining factor in the first formation of 
urine in the kidney. 

In answer to this objection it was pointed out by Tammann 
(9) that if the fluid is filtered from the blood in the glomerulus, 
any stagnation of flow in the glomerulus, as by venous obstruc- 
tion, would lead to rapid increase in osmotic resistance to filtra- 
tion. It has not been shown that this factor can be so effective 
during partial occlusion of the vein as to more than compensate 
for the increased glomerular pressure. It has been suggested 
by De Souza (22) that blocking of the renal vein causes reflex 
constriction of renal artery, but no evidence of this has been 
presented, so far as I am aware. Consideration of these matters 
leads me to think that the argument against filtration based upon 
the effects of obstruction of the renal vein has not been ade- 
quately answered. 

Another series of obstacles in the way of unreserved accept- 
ance of the filtration hypothesis has arisen from the comparison 
of urine elimination with vascular conditions in the kidney as 
shown by oncometer records of kidney volume; and these diffi- 
culties have increased with the later development of improved 
methods of estimation of flow of blood through the kidney. 

The oncometer, first applied to study of renal physiology by 
Roy and Cohnheim in 1883, registers changes in the total volume 


KIDNEY FUNCTION 171 


of the kidney : these changes are commonly referred to alterations 
in the state of the renal blood vessels. In 1901 Gottlieb and 
Magnus (23) made an admirable series of observations on blood 
pressure, kidney volume and urine flow during diuresis. Follow- 
ing the injection of single doses of diuretics, remarkable paral- 
lelism between urine elimination and vascular dilatation as 
shown by the oncometer was observed: but when repeated dosage 
was given this parallelism failed. Diuresis was observed to in- 
crease in some instances at a time when renal vessels, as shown 
by the oncometer, were constricting ; in others it diminished while 
renal vessels were similarly shown to be dilating. 

These objections were materially supported by the late Pro- 
fessor Brodie of Toronto. He extended the observations of 
Magnus and Gottlieb by including in his experiments direct 
estimations of blood flow through the kidney. In his lecture 
before the Harvey Society in 1910 (24) and in his Croonian 
lecture of 1911 (25), he stated that following the injection of 
diuretics, in five experiments, he had observed the following 
coincident phenomena :—Increased kidney volume (indicative of 
dilatation of vessels) ; diminished blood flow (indicative of con- 
striction of. vessels) ; increased urine elimination. 

Both Magnus and Brodie apparently accepted the common 
implication of vascular changes; viz: that dilatation of renal 
vessels means rise of intraglomerular pressure, and constriction 
of renal vessels means decrease in intraglomerular pressure, and 
hence their observations became so self-contradictory when viewed 
in the light of the filtration hypothesis that they were forced 
to abandon it. 

In the considerations thus far advanced I have hoped to show 
that in spite of the array of strength back of the belief that 
urine is first formed in the glomerulus by a process of filtration, 
sound observations exist, made by most competent observers, 
which have forced them to deny it. Concern over these difficul- 
ties, and the necessity of a conviction concerning them, led to 
a series of experiments by my colleagues and myself which have, 
we think, a direct bearing on their solution. 

In Hermann’s (second) paper (6) on kidney function pub- 


172 HARVEY SOCIETY 


lished in 1862 it is stated that ‘‘the effect of pressure changes 
as compared with other factors which modify urine excretion 
ean only be brought out clearly when one has control over the 
blood entering the vascular system and can regulate it at will.’’ 
I cite this to show that the desire for some sort of artificial ex- 
perimental control over circulatory conditions in the kidney in 
order to reduce the number of variables in an experiment, is 
very old. Hermann devised a clamp by which the calibre of the 
renal artery could be narrowed, hoping to identify the effects 
of lowered renal blood pressure by this means: somewhat similar 
experiments have more recently been made by others. <A defect 
in such experiments, recognized by their authors and emphasized 
by Heidenhain, is that such a device simultaneously alters both 
blood pressure and blood flow in the renal circulation and there 
is no direct means of distinguishing effects due to one of these 
to the exclusion of the other. 

During the years 1912-14, C. K. Drinker and I designed and 
constructed an apparatus for the perfusion of isolated surviving 
organs, capable of pumping a pulsating stream of fluid in a 
manner similar, as pulse records showed, to that of the heart. (26). 
Its volume output was controllable within fairly wide limits. 
With it we perfused the dog’s kidney and were able to show that 
the fluid which issued from the ureter was urine and not a 
transudate. In 1914-15 Dr. O. H. Plant and I elaborated a method 
for perfusing the rabbit’s kidney in situ with this apparatus 
(27). Our method possessed these advantages and possibilities: 

(1) The perfusion fluid was the undiluted blood of the 
animal whose kidney was perfused plus blood taken fresh from 
another animal of the same species. Hirudin was used to 
prevent clotting. 

(2) The artificial circulation through the perfused kidney 
was inaugurated without any interruption in blood flow through 
the organ, and in some instances, urine flow continued without 
interruption during the change from normal to the artifi- 
cial circulation. 

(3) While the output of the perfusion apparatus could be 


KIDNEY FUNCTION 173 


varied at will, for any particular adjustment the output was 
constant, regardless of the resistance offered by the vessels through 
which it drove the blood. It was thus possible to alter pressure 
by various means within the kidney vessels without simultaneous 
alterations in volume flow, or velocity of blood in them. It is in 
this respect that our experiments differed essentially from those 
of earlier workers. (28). 

The means which we used to alter pressure in the circulation 
of the perfused kidney were these: stimulation of the splanchnic 
nerve; injection of adrenalin; partial occlusion of the renal vein. 

Since all of these agencies raised pressure in the renal cir- 
culation and since the conditions of our experiment were such 
that they could not materially change the blood flow, we seem 
justified in attributing such results as were obtained to changes 
in renal blood pressure. 

Each of the three agencies tested increased urine formation 
in a number of experiments practically without exception. 

It will be noted that among these agencies employed is venous 
obstruction, which, in the intact animal always causes diminution 
of urine, a fact regarded by Heidenhain as the strongest argument 
against filtration. In our experiment, in which it increased urine, 
there was no stagnation of blood in the glomerular capillaries 
which might neutralize the effects of increased glomerular pres- 
sure as a filtering force. The experiment seems to me to remove 
the force of Heidenhain’s objection and to confirm the suggestion 
that in the intact animal partial occlusion of the renal vein so 
lessens the rapidity of renewal of blood in contact with the 
glomerular endothelium that the effect of increased filtering 
force is nullified. 


III. Regulation of Glomerular Pressure. 


The experiments just described have served us in three ways: 
they yield evidence that rise of pressure alone in the renal cir- 
culation can cause increase in urine; they point to a solution of 
Heidenhain’s difficulty which is consistent with the filtration the- 
ory ; and they provide a point of departure for an analysis of the 


174 HARVEY SOCIETY 


effects of increased renal pressure. In this last connection, 
the action of adrenalin has been most useful. 

If the vascular reaction of a perfused kidney to minute 
doses of adrenalin is compared with the same reaction of another 
structure, similarly perfused—e. g., the leg—a striking difference 
appears. Any dosage of adrenalin which causes constriction of 
the vessels of the leg also causes diminution in volume of the leg 
as shown by the oncometer. When a perfused kidney is similarly 
tested, it is found that large dosage of adrenalin causes a similar 
effect, 1. e., constriction of vessels as shown by rise of perfusion 
pressure and shrinkage of volume of the kidney; but smaller 
doses, which still cause some degree of constriction of vessels as 
shown by the perfusion pressure cause either no change in or 
distinct swelling of kidney volume. 

In this experiment with the kidney we have an apparent 
paradox of coincident constriction of vessels as shown by rise of 
perfusion pressure and dilatation of vessels as shown by swelling 
of the kidney. 

The only reasonable explanation of this paradox which has 
occurred to us is this:—between the afferent and efferent vessels 
of the glomerulus is interpolated the distensible capillary area of 
the glomerular tuft. The walls of the afferent and efferent vessels 
both contain smooth muscle; both are supplied with nerve fibrils 
(presumably sympathetic) ending in contact with the muscle 
cells (29). If, under the conditions of our experiment, the ef- 
ferent vessel were constricted, a passive rise of pressure must 
occur in the glomerular capillaries proximal to it and the disten- 
sion of these, thus brought about, might cause swelling of the 
kidney. In support of this view we recall the generalization 
which Elliott’s work has established, viz: that the action of adren- 
alin is equivalent to stimulation of sympathetic innervation: and 
we have an observation of our own, made with the frog’s kidney 
which shows unmistakably that adrenalin has the power of con- 
strieting blood vessels peripheral to the glomerulus. 

In the minds of many physiologists a certain stigma appears 
to attach to perfusion experiments with isolated organs, when the 


KIDNEY FUNCTION 175 


attempt is made to apply results so obtained to the interpretation 
of events within the intact animal body. If it were possible to 
demonstrate constriction of the efferent vessel by adrenalin in 
the intact animal with associated diuresis the force and usefulness 
of the experiments just cited would be increased. Reason for 
thinking that this might be possible seemed to exist. The efferent 
vessel of the glomerulus is a narrower tube than the afferent 
vessel. A constrictor influence, acting alike on both, would there- 
fore produce a greater increase in frictional resistance to blood 
flow in the smaller (efferent) vessel: for this reason it seemed 
probable that very minute amounts of constrictor substances 
might, by more effective constriction of the efferent vessel, produce 
simultaneously three effects in the intact animal: diminution in 
blood flow through the kidney by constriction of efferent vessel ; 
increase in urine by increased glomerular pressure; swelling of 
the kidney by distension of the glomerular capillaries. The event 
showed that this combination could be demonstrated following 
minute, but clearly constrictor, doses of adrenalin and pituitrin. 

These experiments seem to me to yield evidence not only that 
the glomerular process is filtration but also that intraglomerular 
pressure—filtration pressure—is regulated by the relative degree 
of constriction or dilatation of the afferent and efferent vessels. 
This latter belief is intimated in a statement by Ludwig in 1856. 

Since the afferent and efferent vessels of the glomerulus, as well as the 
roots of the renal vein, contain muscle within their walls, the possibility 
exists that the blood stream in the kidney changes according to the contrac- 


tions of these muscles, even though the movements of the heart and the 
general circulation in the organism remain unchanged (30). 


In connection with the action of constrictor substances, like 
adrenalin and pituitrin, it becomes apparent how it is possible 
for the same substances in different dosage to produce opposite 
effects. Minute amounts causing more effective constriction of 
the smaller efferent vessel may increase urine by increasing intra- 
glomerular pressure: larger amounts by constricting both afferent 
and efferent vessels may diminish urine by decreasing ingress to 
the glomerulus and so lessening both intraglomerular pressure 


176 HARVEY SOCIETY 


and velocity of flow. The literature shows that small dosage of 
adrenalin may cause diuresis. Nothing is easier to determine 
than that larger doses cause partial or complete suppression of 
urine. Similar, apparently contradictory, evidence concerning 
pituitrin can be found. 

Permit me now to revert to Brodie’s statement of a group 
of occurrences which he regarded as completely inconsistent with 
the filtration theory :—diminished blood fiow through the kidney, 
increase of kidney volume, increase in urine. This group of oc- 
currences, as we think our experiments indicate, is precisely that 
which would be expected as a result of preferential slight con- 
striction of the efferent vessel, and instead of being inconsistent 
with the filtration theory is demanded by it. 

From this reasoning it would seem as though any substance 
which is constrictor to renal vessels should, in suitable high dilu- 
tion, show evidence of diuretic power, unless it lowers general 
blood pressure or diminishes permeability of the glomerular 
membranes. This supposition is now being tested. 

I am inclined also to suggest another generalization, based 
upon this evidence that intraglomerular pressure may be altered 
by more effective action of a substance upon the efferent than 
upon the afferent vessel. It concerns the action of arterial dilator 
substances in general. If it be agreed that glomerular urine is 
a protein-free filtrate from blood, then it follows that any sub- 
stance, in solution in the blood, which causes dilatation of renal 
arterioles and which in part passes out of the blood with the 
glomerular filtrate must from these facts be potentially diuretic: 
for its effective concentration will be greater in the blood in the 
afferent vessel than in the blood in the efferent vessel; and its 
dilator action will be greater on the afferent than on the efferent 
vessel, and for this reason alone intraglomerular pressure 
must rise. 

Tt should be noted that by effective concentration I mean 
concentration in relation to the colloids of the blood. 

Without having the direct evidence to support this idea, I 
venture to present it, in the belief that it is applicable to the 
glomerular behavior of a large number of substances—water, urea, 


KIDNEY FUNCTION 177 


the caffeine series, salts, etc., all of which are vasodilator and all of 
which, we believe, leave the blood stream as it passes through 
the glomerulus. 

If we regard the renal arterioles as very sensitive both to 
constrictor and dilator substances, as they most certainly are, 
and if we admit the possibility of such preferential action as I, 
have indicated on either efferent or afferent vessel, we must see 
in this a very delicate mechanism whereby intraglomerular pres- 
sure and hence the first formation of urine is regulated in accord- 
ance with the chemical composition of the blood. 


IV. Description of Glomerular Circulation. 


In this description of experiments, both of our own and of 
others which concern the nature of glomerular function and its 
mode of regulation, an implication has been permitted which now 
appears to me to require correction. Its correction does not, 
I think, materially alter the force of the conclusions which have 
just been drawn, but it adds an element in the conception of 
glomerular regulation which may be of greater importance. 

The kidney contains a great number of urine-forming units. 
The number of glomeruli in the cat’s kidney has been estimated 
at 16,000: in the kidney of a dog weighing 11 kilos, 150,000: in 
the human kidney, 2,000,000 (31). For each glomerulus there 
is a tubule. It seems to me that it has been tacitly assumed in 
the great bulk of writing on kidney function that the circulation 
through all of these units is at least roughly uniform, that they 
take equal part in the sum of activities which made up the total 
function of the whole organ. I have found one explicit state- 
ment of another conception. In Hermann’s first work (1859) on 
kidney function, he noted that the two kidneys may eliminate 
different amounts of urine, and he stated that it was simplest to 
assume that all parts of the kidney do not act to the same degree 
all of the time, that one part of the excreting surface may rest 
or be active, while another part is in reserve (382). 

We have observations which indicate that this is a true 
conception. 

In the development of the idea that glomerular pressure may 

12 


178 HARVEY SOCIETY 


be regulated by the degree of constriction of its efferent, as 
compared with its afferent, vessel it became highly desirable that 
we get evidence as direct as possible concerning changes in size 
of the glomerulus during the action of adrenalin under controlled 
conditions of blood flow. In 1919 Krogh of Copenhagen published 
his extremely important paper on the behavior of capillaries in 
muscle (33). He used methods of direct microscopic observation 
of muscles illuminated either by transmitted or reflected light. 
It occurred to us that the use of the same method might enable 
us to see the glomeruli of the kidney in operation, provided we 
could find a kidney sufficiently translucent to permit a certain 
penetration of light rays. In September of last year Dr. 
Schmidt and I found that the frog’s kidney fulfills this demand. 
When we focussed the light of an are lamp or a 1000 watt mazda 
lamp upon the ventral surface of an exposed frog’s kidney in 
situ, the low power of the.microscope showed in the interstices 
of the radicles of the renal veins nests of capillaries which to our 
view and that of competent microscopists could be nothing else 
than glomerular tufts. It soon became possible to distinguish 
the outline of the capsule, in many cases the entrance of the affer- 
ent vessel, and in not a few instances the exit of the efferent 
vessel as well. Because not all of these structures had the same 
appearance and to prevent egregious error we spent some time 
in attempts to identify a certain group of glomeruli in the living 
kidney, to follow this group through processes of fixation and 
embedding in order to prepare a stained section which should 
contain the structures examined in the living kidney. With the 
aid of Dr. B. Lucke this was successfully done. This identifica- 
tion has given a sense of security concerning previous and sub- 
sequent observations which we might not otherwise have had. 
When the lateral border of the ventral surface of the frog’s 
kidney is observed in this way, the large renal veins and their 
tributaries are most prominent. Arterial branchings and the 
divisions of the renal portal vein, being deeper in the kidney are 
less obvious. Details of the tubules are commonly indistinct. 


KIDNEY FUNCTION 179 


In the interstices of the veins are seen the glomerular tufts. 
They vary in size from 80 to 250 microns in diameter. Some 
show a great multiplicity of tortuous narrow channels, each of 
a diameter sufficient to permit passage of one red cell. The 
capillary wall is not easily seen. Blood flow through these chan- 
nels is oftentimes bewilderingly rapid. In other instances the 
appearance is of another type; instead of a multiplicity of chan- 
nels, only one or two capillary loops are visible, these have wider 
diameter and show sluggish flow of more densely packed cor- 
puscles. In the more slowly flowing blood streams pulsations are 
apparent; in the more rapidly flowing stream they may not be. 
Between these two extremes intermediate variations occur, 

Concerning the problem which was the impetus for beginning 
these observations—i. e., the question whether the glomeruli could 
be seen to swell as a result of the constrictor action of minute 
amounts of adrenalin upon the efferent vessel—the answer is 
still indeterminate. A series of measurements by Dr. Schmidt 
of glomerular diameters before, during and after the injection of 
doses of adrenalin of the order of 0.1 ce. of 1:1,000,000 showed 
swelling, and in so far were confirmatory of our conclusions drawn 
from the mammalian experiments. But since a distinct improve- 
ment in the general circulation resulted from this injection the 
increased glomerular size may have been due to this. Before a 
final answer can be obtained, the experiment must be performed 
on the kidney, perfused with blood at a constant rate. This ex- 
periment has not yet been made. Other features of the glomer- 
ular circulation seemed to demand more immediate study. 

In our earliest experiments the variability of our preparations 
was striking. In some preparations as many as eight glomeruli 
could be counted in a field of 2 mm. diameter; in others only 
three or four in the whole kidney in so far as it was accessible 
to inspection. Our frogs were pithed and if two or three drops 
of blood were lost in this operation the number of glomeruli to 
be found in the kidney was small. If, however, such a frog were 
immersed in a saline bath or if his abdominal cavity were filled 


180 HARVEY SOCIETY 


with isotonic salt solution, the number of visibly active glom- 
eruli increased. 

Acting on the suggestion which this fact afforded, we have 
made a series of counts of the glomeruli which show active cir- 
culation under varied conditions. 

Bits of silk thread were laid transversely across the surface 
of the kidney at approximately equal distances of about 2 mm. 
(the diameter of our low-power field.) From five to eight fields 
were thus separated for ease in counting. A bit of cover slip 
was lightly laid over these, both to prevent displacement of 
threads and to avoid surface glare. 

I shall cite figures to show alterations in number of glomeruli 
in which blood was flowing, before, during, and after the intro- 
duction of various substances to be mentioned. 

1. Isotonic salt solution. As has been mentioned, salt solu- 
tion is absorbed from the open abdominal cavity of the frog and 
as a result circulation improves if it has been lessened from 
hemorrhage. These figures illustrate: 

Soon after preparation five fields showed 5 active, 8 inactive, 
total 13 glomeruli. 

Thirty minutes after salt solution had been introduced into 
the belly the same fields showed 28 active, 0 inactive, total 
28 glomeruli. 

2. Injection of blood.—0.5 ec. of whole blood was taken from 
the aorta of one frog and immediately injected into anterior 
abdominal vein of a frog whose glomeruli had been counted. Be- 
fore injection, active glomeruli 10, inactive 27, total 37. 

5 minutes after injection, active glomeruli 39, inactive 9, 
total 48. 

3. Injection of isotonic salt solution—0.5 ec. of 0.6%. Be- 
fore—41 active, 9 inactive, total 50. 10 minutes later, 54 active, 
8 inactive, total 62. 20 minutes later, 44 active, 6 inactive, 
total 50. 

4. Then urea, 0.1 ec. 20%. After—65 active, 2 inactive, 


total 67. 
5. Caffeine—7 fields counted. Before injection 81 active, 


KIDNEY FUNCTION 181 


11 inactive, total 92. 0.1 ec. 2% caffeine. 5 minutes later, 104 
active, 0 inactive, total 104. 

6. Glucose: 0.1 ec. 10% glucose: Before injection, 31 act- 
ive, 12 inactive, total 43. Followed by progressive increase in 
number of active till 35 minutes after, 62 active, 3 inactive, 
total 65. 

7. Hypertonic Sodium Sulphate. (5%) 0.1 ec. Before, 6 
active, 0 inactive, total 6. After 13 minutes—51 active, 0 in- 
active, total 51. 

8. Adrenalin: constrictor dose: 0.1 ee. 1:100,000: 3 fields. 
Before injection 49 active, immediately after 12 active, seven 
minutes later, 48 active. 

9. Pituitrin: constrictor dose: 0.1 ee. 1:10 dilution of Pitu- 
itrin ‘‘S’’. Before—l4 active, 5 inactive, total 19. After, 0 
active, 16 inactive, total 16. Later 5 active, 12 inactive, total 17. 

These and many similar observations have led to the conclu- 
sion that even under the most favorable of operative conditions, 
i. e., with the least loss of blood, all the glomeruli of the kidney 
of the frog do not receive blood simultaneously. Conditions 
which depress the circulation such as blood loss or destruction 
of the cord, or agencies which constrict blood vessels in the kidney, 
such as constrictor doses of adrenalin or pituitrin lessen the 
number of glomeruli which receive blood. Plethora, absorption 
or injection of isotonic salt solution, hypertonie NaCl, hypertonic 
sodium sulphate, urea, glucose, and caffeine—all are capable of 
impressively increasing the number of glomeruli which receive 
blood at one time. 

Not only is the number of glomeruli showing active circula- 
tion altered by the agencies which I have mentioned, but also 
the number of capillary loops within a single glomerulus which 
take part in the capillary blood flow. Tarlier in this section I 
referred to glomeruli of two rather widely different aspects in 
so far as blood flow through them is concerned: one in which 
narrow, rapidly flowing currents of blood indicate a complex net 
work of tortuous channels; others in which one or two loops only 
are visibly filled with blood and in these blood usually flows more 


182 HARVEY SOCIETY 


slowly and in a wider stream. The dilator agencies, urea, caf- 
feine, etc., mentioned above have the power of transforming a 
glomerulus of the latter type into one of the former. 

Adrenalin, on the other hand, in constrictor dosage, trans- 
forms a glomerulus showing a multiplicity of channels with 
rapid flow into one with fewer patent capillary loops and 
slow flow. 

This indicates that just as all glomeruli in a kidney do not 
receive blood at once, so too in a single glomerulus, not all the 
capillary loops need be patent at one time. Dilator (diuretic) 
agencies increase the number of capillaries in the glomerulus 
through which blood is flowing; constrictor substances and de- 
pression of the general circulation lessen the number. 

Another characteristic of glomerular blood flow in the frog’s 
kidney is that it is not always continuous, but may be intermit- 
tent. Intermittence of glomerular flow is more apt to occur in 
a kidney showing active rapid circulation than in one in which 
blood flow is more sluggish. It was first observed by us in frogs 
after improvement of the circulation following absorption of salt 
solution; it has, however, been observed in frogs subjected to no 
other preparation than that required for looking at the kidney. 
The intermittence of blood flow may be of different types: in 
some instances there may be diminution in all and cessation in 
many at the same time, as though resulting from an influence out- 
side of the kidney, as for example by changes in the general 
circulation or as a result of nervous stimuli to the blood vessels. 
This type is easily understandable. 

What we think of, however, as true intermittence is less easy 
to comprehend: two adjacent glomeruli may be situated within 
a few microns of each other: blood flow in one may stop com- 
pletely, to be resumed after an interval, without interruption 
or even perceptible alteration in flow in the other. This phe- 
nomenon may be multiplied so that in a favorable field one sees 
a lively series of irregular interruptions in flow through the 
various glomeruli visible. 


KIDNEY FUNCTION 183 


The interruptions bear no relation to heart beat. The inter- 
mittence of one glomerulus was timed with a stopwatech— 


15 seconds on: 12 seconds off 27 seconds on: 11 seconds off. 


In another: 


103 seconds on: 10 seconds off: 90 seconds on: 45 seconds off. 


In another preparation, 5 glomeruli were watched at once: 


Nos. 3, 4 and 5 stopped at the same time: Nos. 1 and 2 
kept on actively. After three minutes No. 4 begins: Nos. 3 
and 5 are blank. 


We have tried to get a graphic representation of this phe- 
nomenon. <A keyboard with five keys was connected each with 
a signal magnet arranged to write on a drum. Five glomeruli 
in a field were chosen and a key assigned to each. Discontinu- 
ance of flow was registered by pressing the key and keeping 
down till flow resumed. The recorder also noted on the drum 
obvious variations in rapidity of flow which could not be desig- 
nated as complete cessation or resumption. Charts were then 
made of these records. 

Study of these charts forced the conclusion that while at 
times there are interruptions common to all, in the main the 
circulatory activity of one is independent of others: and the 
inference is drawn that a local regulatory mechanism must exist 
analogous to that shown by Krogh to exist in muscles. 

Preliminary attempts to gain deeper insight into the circum- 
stances of this phenomenon have been made. Not very much can 
safely be stated at present. We are sure that the phenomenon of 
intermittence persists after complete destruction of the whole 
central nervous system—brain and cord. There is evidence that 
intermittence of the glomerular circulation is commonly associ- 
ated with simultaneous and synchronous intermittence of the 
afferent vessel. In this connection it is very striking that when 
flow stops abruptly in a single active glomerulus corpuscles do 
not remain stagnant in its capillaries: they may remain for an 
instant then they fade out of view and the whole glomerulus 
may become invisible. This must mean that the capillaries of the 
glomerulus possess power of independent contraction, capable of 


184 HARVEY SOCIETY 


emptying their lumina after blood has ceased to flow. This 
statement must be held as applicable to the afferent and efferent 
vessel, since they as well as the glomeruli are emptied when blood 
flow stops. Dr. Schmidt has made one observation which we 
hope to repeat: in one instance eapillary flow in the glomerulus 
ceased abruptly, and blood cells disappeared from it; but the 
afferent vessel remained full of blood, the corpuscles oscillating 
back and forth at the entrance of the glomerulus until presently 
the glomerular capillaries opened and flow through the whole 
structure resumed. 

This emptying of the capillaries after cessation of flow—in- 
dicating, as we believe, independence of contractibility of their 
walls—is much less marked or may be absent in the dilated 
sluggishly flowing capillaries of some of the glomeruli to which 
reference has been made. These are apt to remain engorged 
with cells when flow ceases. We take this to mean that there are 
normal differences in tonus and normal variations in tonus. 

We do not yet know what the nature of the influence which 
regulates this tonus is. 

Making the assumption that these observations are applicable 
to the mammalian kidney, they give me a conception of glom- 
erular circulation different from that which I had previously 
held. Instead of a uniform circulation of blood through all the 
glomeruli, varying with general and renal blood pressure, we 
conceive of a circulation, restricted under conditions of moderate 
blood flow to only a fraction of the glomeruli; and instead of equal 
circulation through all of the capillaries of a single glomerulus 
we conceive of the possibility of restriction of flow through a frac- 
tion of the available pathway. This restriction in number of 
functioning glomeruli and in patent capillary loops may be 
brought about by general influences (circulatory and nervous) 
brought to bear from outside the kidney and unequally effective 
in different units of the kidney through anatomical differences, 
such as length of vessel; in addition we think of the restriction 
as due to a local, peripheral control of contractile power, not 
only of afferent and efferent vessels but of the intervening capil- 
laries as well. The phenomenon of intermittence permits us to 


KIDNEY FUNCTION 185 


think of alternating rest and activity of glomerular structures 
and prevention of damage such as would conceivably result from 
prolonged interruption of blood flow. 

The phrases ‘‘dilatation of kidney vessels’’ and ‘‘ constriction 
of kidney vessels’’ come to mean not only the increase and de- 
erease in volume and rate of a stream already flowing but also 
the increase and decrease in actual number of functioning glom- 
eruli and of open glomerular capillaries. The possibilities in the 
direction of increase or restriction of filtering surface become 
more impressive. 

On this basis it is not difficult to understand how relatively 
enormous changes can take place in glomerular blood flow without 
correspondingly great changes in the size of the kidney as reg- 
istered by the oncometer. For obviously the capsule does not 
collapse when flow through the tuft ceases. It is easy to under- 
stand and to accept such puzzling experiments as those of 
Loewi—in which the ability of blood flow to increase under in- 
fluence of caffeine in a kidney imbedded in plaster of paris 
was demonstrated. 

It becomes easier to understand how a kidney might eliminate 
from blood of the same composition and in equal spaces of time 
urines of widely different composition: for a urine issuing as 
the result of highly active blood flow and high glomerular pres- 
sure in a smaller number of glomeruli must be different from 
that which issues as the result of slower blood flow and lower 
glomerular pressure from a larger number of glomeruli. The 
resorptive powers of the tubules would be effective to differ- 
ent degrees. 

The difficulty of injecting the glomeruli uniformly even in 
fresh kidneys is comprehensible; as is also the lack of uniformity 
among the glomeruli in the action of circulating toxic substances. 

A lead may be given concerning the causation of albuminuria 
under conditions not far removed from the physiological: it is 
a very old observation that complete arterial interruption of the 
circulation in the kidney for a short time is followed by album- 
inuria. If intermittence of glomerular flow is a normal phen- 
omenon, it would appear that albuminuria might occur if, for any 


186 HARVEY SOCIETY 


reason, the duration of the normal intermittent cessation of 
flow increased. 

If you will permit me I will give the briefest resumé of the 
chief points which we have attempted to present :— 

1. New evidence has been secured that increment of blood 
pressure, uncomplicated by increment in velocity or volume of 
blood flow in the kidney increases urine formation. This is re- 
garded as added support of the filtration hypothesis. 

2. Evidence has been secured indicating that some of the 
most weighty objections to the filtration hypothesis ean be reason- 
ably explained in a manner consistent with it. 

3. Indications have been shown that nervous stimuli and 
chemical substances may exert different degrees of effective in- 
fluence upon the afferent and efferent vessels of the glomerulus, 
and that this may be a factor in that automatic regulatory con- 
trol of glomerular filtration which is responsible in part for 
the maintenance of constancy of blood composition. 

4. And finally a new description of the mode of circulation 
through the glomerular vessels has been presented which, when 
verified and extended, we hope will be of service in the study 
of the normal and pathological physiology of the kidney. 


REFERENCES 


1 Phil. Trans. Roy. Soc., 1842, pp. 74 and 75. 

? Arch. f. d. ges. Physiol., xvi, p. 139, 1878; xvii, p. 580, 1878. 

* Adami: Journ. of Physiol., vi, p. 382, 1885; Beddard: Ibid., xxviii, p. 20, 
1902; Cullis: Ibid., 34, p. 250, 1906; Bainbridge, Collins and Menzies: 
Proc. Roy. Soc., B., 86, 355, 1913. 

“Wagner’s Handworterbuch der Physiologie, ii, p. 637, 1844 

“Goll: Zeitschr. f. rat. Med., iv, p. 78, 1854. 

*Hermann: Sitzungsber. d. kais. Akad. d. Wiss. Wien, xlv, ii, p. 317, 1862. 

7 Bernard: Lecons sur les proprietes physiologiques des liquides de l’organ- 
sme, ii, 1859, p. 169; Eckhard: Beitr. z. Anat. u. Physiol., iv, p. 155, 
1869: Ustimowitsch: Ber. u. d. Verh. d. k. Sachs. Gesell. d. Wiss. z. 
Leipsig (Math. phys. Cl.), xxii, p., 1870: Griitzmer: Arch. f. d. 
ges. Physiol., xi, p. 370, 1875. 

* Cf. Heidenhain: Hermann’s Handbuch der Physiologie, vi. p. 318. 

®°Tammann: Zeitschr. f. physikal. Chem., xx, p. 180, 1896. 

* Starling: Journ. of Physiol., xix, p. 312, 1896. 

4 Starling: Ibid., xxiv, p. 317, 1899. 


KIDNEY FUNCTION 187 


* Knowlton, Ibid. xliii, p. 219, 1911-12; 47, p. 1, 1918. 

* Barcroft and Straub: Ibid., xli, p. 145, 1910-11. 

* Knowlton and Silverman: Am. Journ. of Physiol., xlvii,, p. 1, 1918. 

* Bayliss: Principles of General Physiology, First Ed., 1915, p. 355. 

* Cushny: The Secretion of Urine, 1917. 

™ Heidenhain: Arch. f. mik, Anat., x. p. 1, 1874. 

* Heidenhain: Hermann’s Handbuch, v, i, pp. 324, 325, 1883. 

“Ludwig: Sitzungsber. d. k. Akad. d. Wiss. zu Wien. Nov. 1883. 

* Heidenhain: Hermann’s Handbuch, v.i, p. 317: Cf. also Paneth: pp. 
550, 551. 

= Paneth: Arch. f. d. ges. Physiol., xxxix, p. 515, 1886. 

* De Souza. Journ. of Physiol., xxvi, p. 139, 1900-01. 

* Gottlieb and Magnus: Arch. f. exp. Path. u. Pharm., xlvi, 223, 1901. 

* Brodie: Harvey Lectures, 5th Series, 1909-10, p. 81. 

* Brodie: Proc. Roy. Soc., B., Ixxxvii, p. 571, 1913-14. 

* Richards and Drinker: Journ. Pharm. and Exper. Ther. vii, p. 467, 1915. 

7 Richards and Plant: Ibid., p. 485. 

* Richards and Plant: Am. Journ. of Physiol., xlii, 592, 1917. 

” Smirnow: Anat. Anzeiger, xix, p. 347, 1901. 

* Ludwig: Lehrbuch der Physiologie des Menschen, 1856, ii, p. 257. 

* Cited from Cushny. The Secretion of Urine, p. 5. 

“Hermann: Sitzungsberichte d. k. Akad. d. Wiss. zu Wien, Math— 
Naturwiss. Cl., xxxvi, p. 349, 1859. 

* Krogh: Journ, of Physiol., lii, p. 457, 1919. 


TYPHUS AND RICKETTSIA* 
DR. S. B. WOLBACH 


Associate Professor of Pathology and Bacteriology, Harvard University 


\ AY TASK this evening is a double one, to give you an outline 

of recently acquired knowledge of typhus as a disease and 

to place before you the present status of a group of micro-or- 

ganisms, as yet poorly defined and insufficiently studied—the 

‘*Rickettsia’’ in which we find the most generally accepted cause 
of the disease under consideration. 

The original work included in this lecture was done jointly 
with Professor John L. Todd of Montreal and Doctor F. W. Pal- 
frey of Boston, and represents in part the results obtained by 
the Typhus Research Committee of the League of Red Cross 
Societies to Poland.* The origin of this Commission was the 
idea of Doctor R. P. Strong, at that time Medical Director of the 
League of Red Cross Societies. 

Up to the time of our departure we had access to very few 
of the papers published in Germany during the war. Abstracts 
in English and French periodicals indicated that much excellent 
work had been done upon the pathology of typhus and the organ- 
isms associated with the transmission of the disease by lice— 
the latter pointing strongly to the probability of Rickettsia 
being the cause of typhus. 

Although our work in Poland was planned wholly inde- 
pendently by Doctor Todd and myself along lines which were 
the direct outcome of previous work with other diseases, we find, 
now that it is finished, that it proves to be in the main, a eare- 
fully conducted control of the work of many widely sepa- 
rated investigators. 

Nicolle, Comte and Conseil, in 1909, were the first to transmit 

* Delivered March 12, 1921. 


* Other members of the Commission were A. Bacot, M. C. Melver, 
James Denton, Henry Pinkerton, F. A. Hardy. 


188 


TYPHUS AND RICKETTSIA 189 


typhus to animals. They not only succeeded in infecting monk- 
eys, but were able to transmit the disease from monkey to 
monkey by means of louse feeding experiments. Later in the 
same year Anderson and Goldberger confirmed the susceptibility 
of the monkey to Mexican typhus, and in 1910 that brilliant 
worker, Ricketts, and his associate, Wilder, confirmed both the 
susceptibility of the monkey to Mexican typhus and the possi- 
bility of transmission by the louse. Ricketts and Wilder also 
described in the blood of patients and in lice minute bacillus- 
like micro-organisms, which we now eall Rickettsia. Other con- 
firmatory work on the transmission to monkeys was done by 
Gavino and Girard in Mexico. 

The transmission of typhus to guinea-pigs by Nicolle, Conseil 
and Conor in 1911 was a great step forward. It presents another 
example of the value of repeated and painstaking trials in the 
face of initial negatively interpreted results. Nicolle and his 
associates showed also that the virus could be indefinitely main- 
tained in guinea-pigs and that they were on the whole 
more susceptible than the lower monkeys available for labora- 
tory purposes. 

Hegler and von Prowazek, in 1913, saw bodies in polymorpho- 
nuclear leucocytes of typhus patients which they believed were 
micro-organisms, and in one instance, in smears of a louse, small 
paired coccus-like micro-organisms described by them so meagerly 
as to leave one in doubt as to the value of their observations. 

Sergent, Foley and Vialette, in 1914, in a much more exten- 
sive study of lice from typhus cases, reported minute ‘‘cocco- 
bacilli’’ not found in thousands of control lice taken from normal 
persons. They also, in 1914, infected three human volunteers 
with typhus by means of lice, one by louse feeding, one by sub- 
cutaneous injection of louse emulsion and one by scarification 
with crushed eggs of infected lice. 

Da Rocha-Lima, an associate of Prowazek, in later work upon 
typhus in 1916 described in detail the minute micro-organisms 
in typhus lice, and laid emphasis upon their intra-cellular situa- 
tion in the epithelium of the louse’s alimentary tract. He noted 
their occurrence in enormous numbers. Both he and Prowazek 


190 HARVEY SOCIETY 


became infected with typhus, presumably from dissecting lice, 
and von Prowazek died. Ricketts’ fatal infection also, according 
to his Mexican friends, was through his experimental lice. 

The name Rickettsia prowazeki was given by da Rocha-Lima 
to those minute micro-organisms in honor of these two unfortu- 
nate investigators, and from then on we find in the literature 
evidence for and against the etiological significance of Rickettsia 
in typhus, a similar problem in regard to trench fever and 
Rickettsia, and the recording of Rickettsia in lice from normal 
persons and in other insects than lice. 

In 1914 Frenkel called attention to a specific lesion of the 
blood vessels of the skin in typhus; and a number of other German 
pathologists during the war made pathological studies confirming 
and extending Frenkel’s findings, notably Aschoff, von Chiari, 
Jaffé, Kurt Nicoll, Ceelen and Spielmeyer. Ceelen, in 1916, 
noted lesions associated with blood vessels in the central nervous 
system in man analogous to the lesions in the skin. Von Prowazek, 
in the same year, described identical brain lesions in monkeys, 
and Ceelen, in 1917, the same lesions in the brains of guinea-pigs. 

My own work on Rocky Mountain spotted fever between 1916 
and 1919 had convinced me, just as Ricketts was convinced by 
his work, that this disease and typhus had many features in 
common. The inability to cultivate the rickettsia-lke micro- 
organisms of Rocky Mountain spotted fever, necessitated a series 
of experiments which proved the specificity of the micro-organism 
which I named Dermacentroxenus rickettsi. With the agree- 
ment of Professor Todd, our work upon typhus was outlined 
upon the spotted fever work. Our program was not completely 
carried out owing to unavoidable delays in getting down to 
work and to the greater difficulties of working with lice as com- 
pared with ticks—chiefly in regard to their feeding habits. 

Similarities between Rickettsia and Dermacentroxenus and 
between the pathological reactions of the two diseases in man and 
animals deserve some attention on this occasion. 

In view of the large variety of micro-organisms cultivated 
from typhus and the non-conclusive evidence to be expected from 
immunological experiments, we placed greatest value in prelim- 
inary steps upon other procedures than cultivation experiments. 


TYPHUS AND RICKETTSIA 191 


Our work was formulated to answer the following questions: 

1. What micro-organisms are acquired by lice nurtured 
upon typhus patients? 

2. Can any micro-organism be shown to be specific for lice 
nurtured upon typhus patients? 

3. Can it be shown by animal experiments that any micro- 
organism is inseparable from, and therefore probably identical 
with the virus of typhus? 

4. What is the distinctive pathology of typhus? 

5. What micro-organisms can be demonstrated in the lesions 
of typhus? 

The louse work required not only ‘‘clean’’ lice but lice con- 
trolled from time to time in regard to their freedom from 
micro-organisms. 

It was also necessary to ascertain the types of micro-organisms 
present in lice collected from presumably healthy individuals in 
the region from which our patients were obtained, and in the 
pursuit of this material through the infection of Mr. Bacot we 
obtained valuable information about the etiology of Trench fever. 

Before proceeding to the final question of etiology and nature 
of typhus, a brief review of the subject of Rickettsia is desirable, 

The rickettsias of greatest interest are those found in lice in 
connection with typhus and trench fever and in lice presumably 
free from any disease virus. They have also been found in 
other ‘‘insects’’ which I shall take up later. 

A satisfactory definition of Rickettsia is at present not pos- 
sible, so I shall endeavor to mention the properties in common 
of the thirteen or fourteen micro-organisms so far described 
under this name. 

Morphology :—Bacterium-like on the whole. They are smaller 
than bacteria and occur characteristically in pairs. Large forms, 
bacillary and filamentous, have been described in connection 
with two carefully studied rickettsias and it seems probable that 
a simple cycle or sequence in morphological development is a 
characteristic of the pathogenic forms. 

Staining Reactions :—Difficulty of staining with the common 
staining solutions used for bacteria is a striking feature, as well 
as the failure to retain the stain by Gram’s method. The only 


192 HARVEY SOCIETY 


satisfactory staining methods are the modifications of Romanow- 
sky’s method and the most satisfactory is Giemsa’s solution. 

Motility :—All are non-motile (but in view of a possible devel- 
opment cycle, a motile stage may yet be shown to exist). 

Cultivation:—So far all have resisted cultivation with the 
exception of the rickettsia from the sheep ‘‘louse’’ which grows 
on a relatively simple glucose blood agar medium. 

Resistance to Physical and Chemical Agents:—Not enough 
work has been done to generalize. The viruses of typhus and 
Rocky Mountain spotted fever are extremely susceptible to heat, 
drying and chemical agents. On the other hand, the virus of 
trench fever resists 80° C. of dry heat for twenty minutes and 
drying for many months. 

Host Specificity :—All rickettsias have an insect host which in 
the case of the pathogenic ones are the vectors. All are highly 
specific for their insect host while the pathogenic ones may infeet 
widely separated mammals. 

Hereditary Transmission:—In every instance where careful 
study has been made it has been found—with the exception of 
the rickettsia of typhus—that the organisms pass down through 
successive generations, in the eggs. Rocha-Lima has offered 
some evidence that this is also true of Rickettsia prowazekt, and 
Sergent, Foley and Vialette, 1914 (quoted by Nuttall, Parasitol- 
ogy, Vol. 10) accidentally communicated typhus to a monkey and 
a man with the offspring of lice which were supposed to be in- 
fected only with relapsing fever. 

Classification:—Is of course impossible, and it is probable that 
we have already included under Rickettsia a number of very 
different micro-organisms. The rickettsia of the sheep ‘‘louse’’ 
has little to distinguish it from bacterium, while I believe the 
rickettsia of typhus has a number of peculiarities which neces- 
sitates its separation at present. The rickettsia-like cause of 
Rocky Mountain spotted fever which I prefer for the present 
to consider under a distinctive name, while resembling in many 
ways Rickettsia prowazeki, is very unlike the morphologically 
simple rickettsia of trench fever. 

The following table indicates the wide distribution of 
‘‘Rickettsia’’? in ‘‘insects’’ and one important generalization 


193 


TYPHUS AND RICKETTSIA 
which I believe to be warranted in view of their great specificity 


for their insect hosts and hereditary transmission is that they 
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under ‘‘Rickettsia’’ can only be tentative with the meagre data 
13 


must be kept in mind that the grouping of these micro-organisms 
so far determined. 


with occasional representatives pathogenic for mammals. 


194 HARVEY SOCIETY 


The following data concerning the Rickettsia in the preceding 
table are available. 

Rickettsia mélophagia:—This micro-organism was discovered 
by Noller in 1917 while studying flagellates of the sheep louse 
or tick. He succeeded in cultivating it upon a glucose blood 
agar medium. Jungmann in 1918 confirmed Noller’s work, in- 
eluding the cultivation, and determined that the infection of the 
insect host is hereditary. Rickettsia melophagi is not path- 
ogenic, it occurs characteristically upon the cuticular surface 
of the epithelium of the sheep louse’s stomach, but may invade 
the cells and in morphology it corresponds to the small 
or coccoid forms of R. pediculi and R. prowazeki; it is 
not pleomorphic. 

The unnamed Rickettsia from the dust louse, Psocus, Sikora, 
1918, 1920, is of course not associated with any mammalian 
host. It is transmitted hereditarily, lives wholly extracellularly 
in stomach of its host, and is non-pathogenic. Sikora was unable 
to infect Pediculus with this Rickettsia. 

Rickettsia pediculi, Rickettsia quintana and Rickettsia wol- 
hynica are morphologically identical and in all probability are 
identical (Wolbach and Todd, 1920), (Bacot, 1921). They are 
on the whole easier to stain than Rickettsia prowazeki, and are 
much more uniform in morphology. They are slightly plumper 
and more definitely oval than Rickettsia prowazeki. They occur 
characteristically extracellularly in the louse’s stomach and ad- 
here to the cuticular border of the stomach epithelium in a 
striking manner. Sikora and others maintain that exceptionally 
Rickettsia pediculi invades the epithelial cells of the louse’s 
stomach, but we cannot confirm this statement. It is trans- 
mitted hereditarily in the louse. The virus of trench fever (and 
therefore Rickettsia pediculi, if we are correct in our conclusions) 
resists a dry heat of 80° C. for twenty minutes and ordinary 
desication in sunlight for long periods (four months) in contrast 
to the viruses of typhus and Rocky Mountain spotted fever. 

Rickettsia prowazeki:—Is strikingly pleomorphic, multiplies 
exclusively within cells in the louse and is very susceptible to 


TYPHUS AND RICKETTSIA 195 


drying and heat. Da Rocha-Lima has produced some evidence 
that in the louse it is transmitted hereditarily. 

Rickettsia rocha-lima? Weigl in Warsaw in 1920 showed us 
preparations of lice containing intracellular pleomorphic Rickett- 
sia indistinguishable by us from Rickettsia prowazeki. Accord- 
ing to Weigl this is a non-pathogenic rickettsia infecting man 
and was acquired by lice fed upon himself and upon members 
of Denekin’s army. We are not convinced that Weigl was 
dealing with a rickettsia other than Rickettsia prowazekt. 

Rickettsia lectularius, Arkwright, Atkin and Bacot, 1921, is 
an extremely interesting micro-organism, morphologically very 
similar to Rickettsia prowazeki in pleomorphism and staining. 
It is non-pathogenic and is apparently widely distributed in 
bed-bugs in England and Europe. It multiplies exclusively 
intracellularly in various organs of the bed-bug and is trans- 
mitted hereditarily. Arkwright, Atkin and Bacot describe a 
morphological cycle or sequence of forms, similar to that of 
Rickettsia prowazeki and Dermacentroxenus rickettst. 

The unnamed Rickettsia from culex pipiens discovered by 
Noller and referred to by Sikora, 1920, occur extracellularly in 
the mosquito. No further data are furnished. 

Rickettsia ctenocephali, Sikora, 1918, is a non-pathogenic 
micro-organism exhibiting large and small forms, but not as 
pleomorphic as Rickettsia prowazeki and Rickettsia lectu- 
larius. It occurs in the coelum of the cat flea and is trans- 
mitted hereditarily. 

The unnamed Rickettsia from the mouse flea was briefly 
mentioned by Sikora in 1918. It occurs intracellularly in the 
Malphigian tubules. 

The unnamed Rickettsia from the bird mite is another intra- 
cellular representative discovered by Noller and mentioned by 
Sikora, 1920. 

The Rickettsia in the Kedani mite is highly questionable. 
Sikora, 1920, mentions it as a recently discovered cause of 
Tsutsugamushi disease, information of which came by word 
of mouth. 


196 HARVEY SOCIETY 


Dermacentrozenus rickettsi, the cause of Rocky Mountain 
spotted fever, has been included among Rickettsia by a number 
of authors and I have therefore included it in the above table. 

A comparison with Rickettsia prowazeki while showing a 
number of common features, brings to light many differences in 
morphology and in behavior in the insect vector. Dermacen- 
troxenus is less bacterium-like than any of the Rickettsias and 
in multiplicative form always shows red and blue stain- 
ing materials. It does not appear in thread-like or filamentous 
forms as does Rickettsia prowazekt. 

In the louse Rickettsia prowazeki continues to multiply in- 
definitely in the stomach epithelium, eventually causing the 
death of the louse through suspension of digestion. Dermacen- 
troxenus, however, after a stage of active multiplication, largely 
intranuclear, floods all the tissues of the tick and then diminishes 
in number, leaving behind in certain tissues, including the 
salivary gland, forms which are different from the multiplicative 
forms and which I regard as in a resistant stage. 

For the present I prefer to keep separate Dermacentroxenus 
—a parasite in Arachnida—from the Rickettsia which are para- 
sites in Insecta. 

Cross immunity experiments now in progress show that 
guinea-pigs which have recovered from typhus respond differ- 
ently from normal guinea-pigs to inoculation with Rocky Moun- 
tain spotted fever. While all the typhus immune guinea-pigs 
developed spotted fever, they all showed a lengthened incubation 
period, and lower temperatures. The mortality was also strik- 
ingly reduced by about 50 per cent. 

The Rickettsia that concern us most are those in lice. Early 
control work by Brumpt and Strong, apparently based wholly 
upon the examination of smear preparations, showed the presence 
of rickettsia in lice from presumably disease-free persons in 
France. Da Rocha-Lima, in 1916, showed that there were two 
types of rickettsia in lice, one extra-cellular, which multiplied 
wholly outside of the epithelial cells of the gut in the lumen and 
upon or in the cuticular border of the cells, and one associated 
with typhus which multiplied exclusively within the epithelial 


TYPHUS AND RICKETTSIA 197 


cells of the louse’s gut. The former he named Rickettsia pediculi 
and he believed it to be a non-pathogenic micro-organism confined 
to the louse. The latter is Rickettsia prowazeki. In no control 
work has it been shown that intracellular rickettsia occur in lice 
from a certainly typhus free-population, although both Rocha- 
Lima and Tepfer state that very rarely Rickettsia pediculi may 
invade the cells. Todd and I, in view of the heavy typhus 
infestation of the countries in which this work was done, regard 
these observations as open to strong doubt. On the other hand, 
since the association of Rickettsia with trench fever has been 
given etiological significance by Toepfer, 1916, Munk and da 
Rocha-Lima, 1917, Arkwright and Bacot, 1919, Byam, 1919, and 
since the rickettsia observed by these authors are of the extra- 
cellular proliferating type and indistinguishable from Rickettsia 
pediculi of da Rocha-Lima, the question of deciding the specificity 
of Rickettsia for trench fever is a most difficult one. The query 
is:—are Rickettsia quintana (wolhynica) and Rickettsia pediculr 
identical? If so, is this Rickettsia the cause of trench fever? 

Our control work with lice in Warsaw demonstrated the 
common occurrence of exclusively extra-cellular rickettsia in 
lice collected at a public bath-house. Mr. Bacot, of our commis- 
sion, who collected and worked with these lice between March 
31 and April 5th, developed on April 17th a sharp febrile attack 
and subsequently underwent a course of illness corresponding 
objectively and subjectively with trench fever. He was carefully 
studied by our own physician, Doctor Palfrey, and by Doctor 
Kruger of the American Red Cross. Mr. Bacot, during this 
period, was feeding upon his person a stock of lice brought from 
England, which were known to be free from rickettsia for a 
period of over two years before our work and which were care- 
fully controlled by us just prior to Mr. Bacot’s illness. 

On April 27th Rickettsia began to appear in Mr Bacot’s stock 
lice. They shortly appeared in enormous numbers and study of 
the lice by serial sections showed that they were always extra- 
cellular. Now follows what we regard as the most important 
observation of all—that Mr. Bacot (Brit. Med. Jour., 1921, Jan. 
29, p. 156) continued to infect clean stock lice fed upon his person 


198 HARVEY SOCIETY 


with Rickettsia long after his recovery, as late as September, 
four months after the attack and three months after the disap- 
pearance of all symptoms. We have here strong presumptive 
evidence that Mr. Bacot acquired his infection from the Warsaw 
lice and that the Rickettsia transmitted by him to his own stock 
of lice were identical with those in the Warsaw lice. We believe 
that these experiences constitute strong evidence for the identity 
of Rickettsia pediculi and Rickettsia quintana (or wolhynica) as 
well as for the eiological relationship of Rickettsia to trench 
fever. They predicate of course that the mass of population in 
Central Europe is immune to trench fever, and tolerant of 
Rickettsia pediculi infection. 

For the present time then we must assume that there is but 
one type of extra-cellular rickettsia in human lice,Rickettsia 
pediculi (Rickettsia quintana, Rickettsia wolhynica). 

Certain observations which are not reconcilable with the ac- 
ceptance of Rickettsia as the cause of trench fever have been 
made by Brumpt and Strong. The former not only found 
Rickettsia in lice from presumably healthy prisoners of war, 
but failed to experience any ill effects from nurturing these lice 
upon himself. Strong also fed Rickettsia containing lice col- 
lected from healthy individuals upon other healthy individuals 
without observing any ill effects. 

According to Strong’s experiments, the virus of trench fever 
is not transmitted by infective lice to their ova, while according 
to a number of observers, including Bacot, Rickettsia pediculi 
are found in the ova; a discrepancy which would indicate that the 
virus of trench fever and Rickettsia are separable. The positive 
filtration experiments of Strong with trench fever virus may 
also be regarded as evidence contrary to acceptance of Rickettsia 
as the cause of trench fever. 

Our own work with Rickettsia from typhus cases was done 
with lice brought by Doctor Todd from Canada and by myself 
from Boston, and fed during the duration of the research upon 
ourselves. They were repeatedly examined before, during and 
at the conclusion of the research and remained free from infection 
of any sort. Some of them were fed for short periods on other 


TYPHUS AND RICKETTSIA 199 


members of the commission so that we know that they harbored 
no virus as well as no demonstrable micro-organisms. 

What did these lice acquire in the way of micro-organisms 
while feeding upon typhus eases? The answer is Rickettsia 
prowazeki! We fed our lice in boxes and each box was usually 
placed on several cases. From twenty to forty lice were used in 
each box and fifty-two boxes out of sixty-five were successfully 
put through outlined programs. Lice in twenty-five of these 
boxes became infected, but when we finally recognized the condi- 
tions favorable for infection of the lice, 1. e., temperature between 
feedings; stage of the disease and duration of the experiment, 
we were able to secure infection of lice with Rickettsia in each of 
the last thirteen consecutive feeding experiments. The intra- 
cellular location of the Rickettsia was demonstrated in lice from 
every box by serial sections, and the pleomorphism which has 
distinguished Rickettsia prowazeki from Rickettsia pedicult in 
our experience was constant in the smear preparations. 

We found, however, that the lice did not become uniformly 
infected in positive boxes, and that frequently a high proportion 
remained uninfected with Rickettsia and the question arose ;— 
is it possible to have the virus present without demonstrable 
micro-organisms This we attempted to answer by guinea-pig 
inoculations with the alimentary tracts of lice taken at random 
from lots which had been given ample opportunity to become 
infected. The injections were always made intra-peritoneally 
and at the time of dissection of each louse a preparation was made 
for microscopical search for Rickettsia. All remaining lice from 
the same lots were examined by smear preparations and by serial 
sections in order to determine the percentage which contained 
Rickettsia. The results of the guinea-pig inoculations were 
judged by a characteristic temperature reaction following a 
suitable incubation period, and were in nearly every instance 
controlled at the conclusion of the experiment, either by the in- 
jection of blood from an early typhus case or in the case of 
positive temperature reactions, by histological examination of the 
brain and by inoculation of other fresh guinea-pigs. The human 
blood used in testing the immunity of the guinea-pigs at the 


200 HARVEY SOCIETY 


conclusion of the experiments was proved to be infective for fresh 
normal guinea-pigs. 

By these experiments we proved that of a number of lice fed 
in the same box, some would become infected with the virus of 
typhus, others not, and therefore, that uniform infection with 
Rickettsia was not a requirement in a chain of evidence. Al- 
though our experiments were fewer in number than we should 
have done had more guinea-pigs been available, the results, based 
upon forty-two guinea-pigs inoculated with gut emulsions of lice 
from ten boxes brought to light other important facts. 

Of the forty guinea-pigs thirteen developed typhus. All of 
these thirteen guinea-pigs were inoculated with lice from four 
boxes, some members of which from each were infected with 
Rickettsia. Of twenty guinea-pigs inoculated with lice from 
the other six rickettsia free boxes none developed typhus, though 
two died within a few days of pneumonia. Rickettsia were 
found in the smear preparations of nine lice used to infect the 
thirteen guinea-pigs, so in but four instances did we fail to 
find Rickettsia in the preparations from lice that did convey 
typhus. Since we have proved by the study of serial sections 
of lice that but one cell of the stomach epithelium may be infected 
with Rickettsia at the conclusion of a feeding experiment upon 
typhus patients, it is obvious that the examination of a small 
portion of the emulsion used for injection is not an adequate test 
for the presence of Rickettsia in infective lice. In no instance 
did lice containing Rickettsia fail to infect guinea-pigs. On the 
other hand, in seven lice from infected boxes which failed to con- 
vey typhus to guinea-pigs, no Rickettsia were found. We are 
inclined toward the conclusion—from the above experiments 
that the virus of typhus in the louse is inseparable from Rickettsia. 

In six of the fifty-two boxes we found a few lice doubly in- 
fected, with Rickettsia prowazeki and Rickettsia pediculit. These 
six boxes were all fed at the same period—-about the middle of 
our research—and the source of infection with Rickettsia pedicult 
was with considerable certainty traced to three of several patients 
on whom these boxes were fed. The occasional occurrence of 
Rickettsia pediculi was anticipated by us because of our experi- 


TYPHUS AND RICKETTSIA 201 


ence with the Polish lice from which Mr. Bacot became infected. 

The study of Rickettsia prowazekii is not completed, but I shall 
give an account of what information we have. The Rickettsia 
of typhus literature is a small bacterium-like micro-organism, 
ovoid or elliptical in shape, usually occurring in pairs. Short 
and long rods with polar bodies and coccoid bodies in chains have 
been described. The ovoid coccoid form in pairs is usually 
regarded as the type form. The two elements composing the 
pairs stain deeply with Giemsa’s stain, taking a red coloration 
while the material between the two stains pale bluish. Where 
the organism occurs singly there is often a zone of pale blue 
material surrounding or tapering from the deeply staining red 
ovoid body. The minute paired forms, while composed usually 
of ovoid elements, are often composed of two pyriform elements 
joined at their narrow extremities lying in a straight line or 
forming an obtuse angle. These pyriform elements stain blue 
and contain in their distal extremities red stained, round, ovoid 
or ellipsoidal bodies. They seem to be a variation or possibly 
a divisional stage of the blue staining rod form with polar bodies 
described below. 

The minute cocoid and paired coccoid forms were invariably 
present in greater or less numbers in all our preparations from 
Rickettsia infected lice. 

Measurements by us from negatives of photomicrographs 
made accurately at 2000 diameters and read under low magnifica- 
tion with a micrometre ocular calibrated so as to make ten 
divisions of the scale equal one millimetre, give the following 
dimensions. The smallest single elements range from 0.25y by 
0.4u to 0.3» by 0.454. The paired forms range from 0.25y by 
0.7 to 0.32 by 1.lp. (The above method of measuring micro- 
organisms is probably accurate to 0.05z). 

These measurements correspond closely to those of da Rocha- 
Lima who gives 0.3, by 0.4p for single elements and 0.34 by 0.9p 
for the paired forms. 

In all smears, in addition to the small forms described above, 
we have noted the presence of small numbers of slightly larger, 
more deeply staining and more uniformly shaped paired coccoid 


202 HARVEY SOCIETY 


bodies, somewhat lanceolate in shape and devoid of bluish stain- 
ing intermediate substance. These forms can be recognized in 
sections of lice and are the forms most easily demonstrable in 
human tissues. 

In the systematic examination of one hundred and eighteen 
smears containing Rickettsia prowazekii, the rod-like forms men- 
tioned by da Rocha-Lima with deeply stained polar granules, 
were seen frequently in large numbers and almost invariably 
in small numbers. They are proportionately most numerous in 
sparsely infected lice and stain best when embedded in fragments 
of cytoplasm. The polar granules stain deep red, the body of 
the rod is light clear blue, their dimensions range from 0.25p to 
0.354 in width to Ip to 2.54 in length. Other palely staining 
rods, much swollen in the central portion and capped at each end 
with a biscuit-shaped red staining body, occur in the presence 
of the bacillary forms and probably represent degeneration or 
involution forms. A third form, which has been described previ- 
ously only by Otto and Dietrich, has been seen often in smears 
by us, and is associated with early infection of the louse or of 
individual cells in the louse. This is a filamentous form and its 
association with early infection of cells is based upon the study 
of sections of infected lice. 

For a considerable period in our work we avoided decision 
upon delicate filamentous forms which appeared only in lice fed 
upon typhus patients and never in the control lice. Constant 
association of these forms with the minute forms in the same 
lice or in other lice from the same boxes and the failure to find 
them in smears from any louse which, though fed upon typhus 
eases, did not produce typhus when injected into a guinea-pig, 
compelled us to accept them as a form of Rickettsia prowazekt. 

These filamentous or thread-like forms in smear preparations 
are usually curved, sometimes sharply flexed in one or several 
places. In width they range from 0.3p to 0.4u and in length 
are often extraordinary, 10y to 40u or 50p. The threads stain 
blue and the outlines seem unbroken though varying slightly 
in width in the same filament. Within the blue stained filaments 
are red stained bodies in pairs and chains corresponding in 


TYPHUS AND RICKETTSIA 203 


dimensions to the free lying Rickettsia bodies. Some of the 
thread forms stain homogenously—pale blue. Within a single 
filament the arrangement of the red stained bodies suggest the 
division of the whole into any one of the previously described 
forms, coccoid bodies singly or in pairs and the thick or slender 
bi-polar bacillary or rod forms. In occasional preparations we 
ean identify portions of crushed epithelial cells from the louse 
gut filled with enormous numbers of filamentous, rod and coccoid 
forms with apparent stages in the formation of the two latter 
forms from the former. 

The early occurrence of these filamentous forms is borne out 
by finding them in sections of lice lying curled within non-swollen 
cells of the mid-gut at a time when very few cells are infected 
with the coccoid Rickettsia. Similar bacillary and threadlike 
or filamentous forms have been described by Arkwright, Atkins 
and Bacot as a part of the developmental cycle of a Rickettsia- 
like (Rickettsia lectularius) parasite of the bed-bug. These 
authors suggest that the small Rickettsia (leetularius) bodies 
develop through the bacillary stage into filaments while others 
continue to multiply by simple fission. The filamentous forms 
finally break up into the minute Rickettsia bodies. An intra- 
cellular development of minute forms also leads to the formation 
of larger lanceolate paired forms from which bacillary and fila- 
mentous forms develop. 

The demonstration of Rickettsia in man and experimental 
animals is much more difficult than in lice. We have not been 
able to find them free in the blood plasma as described by 
Ricketts, nor are we prepared to accept von Prowazek’s conclu- 
sion that granules seen by him in leucocytes are Rickettsia; they 
may be micro-organisms, but we cannot prove that they are differ- 
ent from granules seen in leucocytes from non-typhus cases. 

Before going further into this problem in our chain of evi- 
dence it is advisable to consider in some detail the pathology 
of typhus. 

Ricketts, as others before him, classed typhus with plague 
as a hemorrhagic septicemia. The German investigators during 
the war described the essential lesions of the disease in connection 


204 HARVEY SOCIETY 


with blood vessels, and I now venture to describe the disease as 
one of the blood vessels of the skin, musculature and central 
nervous system. It is a disease affecting primarily one tissue, 
the vascular endothelium, and is attended by marked prolifera- 
tive reactions of this tissue. 

It was part of our program to learn all we could about 
the disease process in typhus, because in tissue reactions we 
find evidence for classification or the grouping of diseases and 
from them may sometimes predict the probable nature of the 
exciting agent. Our knowledge of histo-pathology is now suffi- 
ciently complete to warrant the formulation of a few criteria 
for prediction. I was almost tempted to say laws—but I shall 
say invariable histological sequences. 

In the infectious diseases a proliferative response means I 
believe the presence of the exciting agent within the affected 
cells; I need in this connection only to mention tuberculosis, 
leprosy, syphilis, the Leishmania infections, and finally Rocky 
Mountain spotted fever. 

The lesions in typhus take origin in blood vessels, and while 
cell degenerations occur which lead to thrombus formation and 
hemorrhages, the initial reaction is in large degree proliferative. 
Within the lumina of blood vessels the evidence is complete in 
regard to the role of the endothelium, but there is also a marked 
proliferation of cells in the perivascular zones on the part of 
cells whose origin may be disputed. We believe them to be 
cells of endothelial origin, but we can avoid dispute by calling 
them macrophages. In the perivascular collections of cells there 
are of course many cells of other types, polymorphonuclear 
leucocytes and cells of the lymphocyte series. 

The total volume of surface affected in typhus is very great, 
including as it does the vessels of the whole surface of the body, 
and the voluntary muscles. In the viscera minor involvement of 
capillaries and vessels of pre-capillary size are found in the heart, 
rarely in the lungs, in the kidneys and in the male genitalia. Le- 
sions of the genitalia, however, in marked contrast to Rocky 
Mountain spotted fever, are not constant or striking. The cent- 
ral nervous system, again in complete contrast to Rocky Mountain 


TYPHUS AND RICKETTSIA 205 


spotted fever, is the seat of extraordinary lesions. The lesions, 
while always associated with small blood vessels—capillaries and 
pre-capillaries—extend into the substance of the nerve tissue. 
They constitute one of the most interesting features in the path- 
ology of typhus. They involve all portions of the central nervous 
system, but are most numerous in the medulla, mid-brain, pons 
and basal ganglia of the cerebrum. These nervous lesions, when 
fully developed, may reach the size of miliary tubercles, and are 
composed of endothelial and neuroglia cells, among which fibrils 
do not appear until late. It is the most striking of the prolifera- 
tive reactions to the virus of typhus and it is not in any way to 
be considered merely as a perivascular reaction, because it is a 
true invasive lesion of the brain tissue. It has taken very careful 
study to arrive at the somewhat tentative conclusions that this 
proliferative reaction on the part of the neuroglia is always 
preceded by a lesion of a blood vessel. Much help has been ob- 
tained from brains of animals, as every stage in the development 
could be studied, and here again we have ascertained that the 
first response in the brain, as elsewhere, is a reaction of the 
vascular endothelium, evidenced by swelling, mitotic division, 
and thrombosis. We are of the opinion, which we cannot yet 
fully support by objective evidence, that the virus of typhus is 
taken up or enters the neuroglia cells, and is responsible for 
the continuation of the process. This is further borne out by the 
fact that occasionally guinea-pigs which recover from the acute 
disease sometimes after a considerable period of normal tempera- 
ture, succumb to the nervous lesions, dying with symptoms very 
much like those of rabies. The test of this opinion will be fur- 
nished when we have demonstrated the presence or absence of 
the virus in the nervous tissue after a period of normal tempera- 
ture. It seems also probable that the peculiar and characteristic 
perivascular lesions in the skin and elsewhere are brought about 
by the migration of endothelial cells carrying the parasite into 
the perivascular zone. Weare fairly certain that we have demon- 
strated Rickettsia in such regions. 

The pathology of typhus is so distinctive that a diagnosis 
may be made by histology, directly from excised skin of patients 


206 HARVEY SOCIETY 


or by the examination of the brains of inoculated guinea-pigs. 
In the experimental study of typhus we are firm in demanding 
histological control of experimental animals, whenever the pres- 
ence of typhus is a requisite for drawing conclusions. 

In typhus, as in Rocky Mountain spotted fever, we are pre- 
sented with a puzzle in the escape of many vascular organs. We 
failed to find lesions specific of typhus in the thyroid, pancreas, 
adrenal glands, gastro-intestinal tract and liver. In the pitu- 
itary the glandular portion escapes lesions, while the nervous 
portion in a very high percentage of cases shows specific lesions. 
I only mention this as one of the unexplained features of 
the disease. 

The pathology of typhus explains quite satisfactorily the 
symptomatology. It is not a septicemia, but we have only to 
consider the tremendous area represented in the capillary and 
pre-capillary circulation of the skin and muscles to account for 
the severe toxic manifestations, while every phase of the rash 
may be shown to correspond with the type of damage done to 
blood vessels. The very peculiar extensive surface necrosis of 
the body, unlike the decubitus of other diseases, we have shown to 
be due to centripetal extension of thrombi, beginning in the 
skin. The symmetrical, so-ealled ‘‘gangrene’’ of extremities may 
possibly be due to involvement of nerves, and occasionally we 
have found lesions of blood vessels within nerve trunks. The 
nervous symptoms which are so prominent in typhus, excitability, 
delirium, coma, meningismus, trismus,, and cerea flexibilitas, are 
in all probability associated with the lesions of the central 
nervous system. Certainly of the cases studied by us clinically 
those which have shown the severest nervous symptoms have 
shown the most extensive pathology of the central nervous system. 
The motor symptoms are consistently to be co-ordinated with 
involvement of the cerebral cortex, and.we are inclined to believe 
that the extensive involvement of the fourth ventricle, which 
is occasionally accompanied by capillary hemorrhages, may ac- 
count for the vaso-motor collapse, which was occasionally seen 
in our series. 

The last important link in our chain of evidence was the dem- 


TYPHUS AND RICKETTSIA 207 


onstration of Rickettsia-bodies in human and animal lesions. This 
has been accomplished by means of the same technique employed 
in the study of Rocky Mountain spotted fever, with more diffi- 
culty, however, because of the smaller size and weaker affinity 
for stains. In typhus tissues two forms of Rickettsia-bodies can 
be found, a larger, more deeply staining paired form, usually 
lanceolate, and surrounded by a clear zone, and a smaller paired 
form, usually occurring in masses. Such findings have been 
constant in practically every post mortem obtained before the 
thirteenth day of the disease, in a fresh condition, a total of 
twenty-five. They have been found with regularity in skin ex- 
eised from fifteen living patients. Actual proof that these 
bodies seen within endothelial cells are identical with those 
observed in the intestinal epithelium of lice is beyond our means 
at present. All we can say is that we are dealing with forms 
unquestionably parasitic in nature and consistent in morphology 
with Rickettsia. 

This carries me through the main purposes of our work as 
permitted by the amount of time at my disposal. We have the 
constant association of a parasite in lice fed upon typhus eases, 
in lice known to be free from micro-organisms and carefully 
controlled, béfore, during and at the conclusion of the experiment. 
We have made experiments which prove that the presence of this 
parasite, Rickettsia prowazeki, is necessary for infectivity of the 
louse for guinea-pigs, and finally, we have demonstrated in tissues 
in the lesions of typhus a parasite morphologically consistent or 
identical with Rickéttsia prowazeki. 


BIBLIOGRAPHY. 


* Anderson and Goldberger. On the Infectivity of Tabardillo or Mexican 
Typhus for Monkeys and Studies on its Mode of Transmission. 
Public Health Reports, Washington, 1910, XXV, No. 7, p. 177. 

? Arkwright, Atkin and Bacot. An Hereditary Rickettsia-like parasite of 
the Bed-bug (Cimex lectularis). Cambridge, England, 1921, Parasit- 
ology, Vol. XIII, No. 1, p. 27. 

* Aschoff. Ueber Anatomische Befunde bei Fleckfieber. Berlin, 1915. Med. 
Klinik, XI, No. 29, p. 798. 

*Bacot. On the Probable Identity of Rickettsia Pediculi with Rickettsia 
Quintana. British Med. Jour., 1921, Jan. 29, No. 3135, p. 156. 


208 HARVEY SOCIETY 


*Brumpt. Au sujet d’un parasite (Rickettsia prowazeki) des Poux de 

homme consideré a tort comme l’agent causal du Typhus exanthé- 

matique. Bull de la Soc. de Path. Exotique. Paris, 1918, Vol. XI, 
No. 3, p. 249. e : 

*Byam. Trench Fever. Oxford University Press, London, 1920. 

*Ceelen. Die pathologische Anatomie des Fleckfieber. Ergeb. d. Allg. 
path. und Path. Anat. des Menschen und der Tiere. Lubarsch u. 
Ostertag., Weisbaden, 1919, XIX, No. 1, p. 307. 

‘von Chiari. Die Veranderungen der Bindehaut des Auges bei Fleckfieber. 
1917, Wien. Klin. Wehnschr., XXX, No. 47, p. 1479. 

* Frenkel. Ueber Fleckfieber und Roseold. 1914, Miinch. med. Wehnschr., 
LXI, No. 2, p. 57. = 

”Gavino and Gerard. Nota Preliminar Sobre El Tifo Experimental en 
los Monos inferiores. Mexico City, 1910. Publicaciones del Instit. 

- Bact. Nacional., No. 1, May 20. 

“ Gavino and Gerard. Nota Preliminar Sobre Ciertos Cuerpos Encontrados 
en la Sangre de los Individuos Atacados de Tifo. Mexico City, 1910. 
Pub. del. Instit. Bact. Nacional, No. 2, May 20. 

%Gavino and Gerard. Segundo Nota Sobre el Tifo Txantematico en Los 
Monos inferiores. Mexico City, 1910. Pub. del. Instit. Bact. Nacional, 
June 20. 

**Gavino and Gerard. Estudio Experimental sobre el Tifo Exantematico. 
Mexico City, 1911. Publicaciones del Instituto Bact. Nacional, No. 7, 
Nov. 12th. 

“Hegler and von Prowazek. Untersuchungen ueber Fleckfieber. Berlin. 
Klin. Wehnschr., 1913, L, No. 44, p. 2035. 

“% Jaffé. Zur Pathologichen anatomie des Fleckfibers. Berlin. 1918. Med. 
Klinik, XIV, No. 9, p. 210. 

© Jaffé. Mikroskopische Untersuchungen mit besonderer Berucksichtigung 
der Frage der Diagnosestellung. ibid., No, 22, p. 540. 

* Jaffé. | Mikroskopische Untersuchungen mit besonderer Berucksichti- 
gung ganz frischer und gang alter Falle. ibid., No. 23, p. 564. 

* Jaffé. Zur Pathogenese des Fleckfieber-knétschens. ibid., No. 49, p. 1209. 

Munk and da Rocha-Lima. I. Klinik und Aetiologie des sogen ‘“Wol- 
hynischen Fiebers.” II. Ergebnis des ietiologischen Untersuchungen 
und deren Beziehungen zur Fleckfieberforschung. 1917. Miinch. med. 
Wehnschr., LXIV, Nos. 42 and 44, p. 1357 and 1422. 

* Nicoll. Pathologischen anatomische studien bei Fleckfieber. Beitr. z. 
Patholog. Anatomie u. z. allg. Path., Jena, 1919, LV, Hft. 1, p. 120. 
“Nicolle, Comte and Conseil. Transmission expérimental du typhus 

exanthématique par le pou du corps. 
C.R. Acad. des Sciences, Paris, 1909, September, CXLIX, p. 468. 
* Nicolle, Conseil and Conor. Recherches Expérimentales sur le Typhus 


1500 diameters. 


i. 


ia prowazek 


icketts 


ith Ri 


fected w 


in 


gut of louse i 


ion 


Fic. I.—Smear preparat 


Fic. II.—Early typhus lesion in a human artery of the skin. 


Fic. J11I.—Rickettsia prowazeki in endothelial cells of a capillary of the skin. Mexican 
Typhus. Human case. 


Fic. IV.—Cell distended with Rickettsia, from the stomach epithelium of an experimen- 
tally infected louse. The size of the Rickettsia is slightly exaggerated in relation to the 
magnification of the cell. 


TYPHUS AND RICKETTSIA 209 


Exanthématique. Annalés de l’Inst. Pasteur, Paris, 1912, XXVI, April, 
No. 4, p. 250. May, No. 5, p. 333. 

*Noller. Blut und Insekten-flagellaten zuchtung auf Platen. Archiv. f. 
Schiffs. u. Tropenhyg., Leipzig, 1917, XXI, No. 4 u. 5, p. 53. 

“Nuttall. The Part played by Pediculus Humanus in the Causation of 
Disease. Cambridge, England, 1917—1918, Parasitology, Vol. X, No. 
1, p. 43. 

** Ricketts and Wilder. The typhus fever of Mexico (Tabardillo). Jour. 
Am, Med. Assoc., Chicago, 1910, LIV, p. 463. 

* Ricketts and Wilder. The Transmission of the typhus fever of Mexico 
(Tabardillo) by means of the Louse (Pediculus Vestimenti). Jour 
Am. Med. Assoc., Chicago, 1910, LIV, p. 1304. 

** Ricketts and Wilder. The Etiology of the Typhus Fever (Tabardillo) of 
Mexico City. Jour. Am. Med. Assoc., Chicago, 1910, LIV, p. 1373. 
*da Rocha-Lima. Beobacthungen bei Flecktyphus laiisen. Leipzig, 1916. 

Arch. f. Schiffs—u. Tropenhyg. XX, No. 2, p. 17. 

*Sergent, Foley and Vialette. Sur des Formes Microbiennes Abondantes 
dans le corps de Poux Infectes par le Typhus Exanthématique et 
toujours absentes dans les Poux témoins, non typhiques. Paris, Mem. 
de la Soc. Biol., 1914, Vol. LX XVII, No. 2, p. 101. 

* Sikora. Beitrage zur Kenntnis der Rickettsien. Arch. f. Schiffs. u. 
Tropenhyg., Leipzig, 1918, XXII, Dec., p. 442. 

“Sikora. Beobachtungen an Rickettsien, besondern zur Unterscheidung der 
R. prowazeki von R. pediculi. Arch. f. Schiffs, u. Tropen-Hyg. Leipzig, 
1920, Vol. XXIV, p. 347. 

“ Spielmeyer.- Die Zentralen Veranderungen beim Fleckfieber und ihre 
Bedeutung fur die Histopathologie der Hirnrinde. Berlin,1919. Zeitschr. 
f. de Gesamte Neurol. und Psych. Orig., XLVII, No. 1, p. 1. 

*Strong. The Significance of Rickettsia in Relation to Disease. Con- 
tributions to Medical and Biological Research, Dedicated to Sir William 
Osler. 1919, Paul Heber, New York, Vol. II, p. 1205. 

“Toepfer. Zur Ursache und Uebertragung des Wolhynischen Fiebers. 
Miinch-Med. Wchnschr., 1916, LXIII, No. 42, p. 1495. 

* Wolbach. Studies on Rocky Mountain Spotted Fever. Boston, 1919. 
Jour. Med. Research, XLI, No. 1. p. 1. 

* Wolbach and Todd. A Note on the Etiology and Pathology of Typhus 
in Mexico. Ann. Inst. Pasteur, Paris, 1920, Vol. XXXIV, No 3, p. 153. 


14 


CHEMICAL DYNAMICS OF MUSCLE* 


DR. F. GOWLAND HOPKINS 


Professor of Biochemistry, University of Cambridge. 


HE task of the biochemist has scarcely begun when he has 
merely determined the nature of the substances which occur 
in living tissues. He must, if he will justify his calling, endeavor 
to define the part played by each one of these substances in those 
dynamic events which underlie the manifestation of life. He 
used, indeed, to be assured that this task was impossible because 
by the mere intrusion of his methods such events are annihilated. 
No student of biology dare, of course for the moment forget 
the peculiar instability of the materials with which he works. 
But the recent striking progress of Biochemistry has shown that 
the supposed predicament can, given sufficient ingenuity, 
be avoided. 

In this lecture an account will be given of certain endeavors 
made to relate material changes with energy exchanges in the 
case of a tissue which offers certain special advantages for study. 
In a striated muscle we have an organ of which the normal fune- 
tion is at any time easily displayed and remains as a sufficient 
eriterion of life. If, even when out of the body, a muscle on 
stimulation responds with a normal contraction we should strain 
our philosophy by denying that it is ‘‘ alive.’’ So long as it thus 
responds, even if it be with diminishing vigor, there is still 
something left for study of the arrangements which constitute 
the living condition. In the case of amphibian muscle which, as 
in other departments of physiology, has been much employed in 
the researches I am to describe, we have the additional advantage 
of dealing with a tissue which, given the right conditions—and 
of these an efficient oxygen supply is among the most important— 
yields the above criterion of life for days, and, at low tempera- 
tures, even for weeks after it has been removed from the body 
and deprived of a circulation. Hence in this connection, as in 


* Delivered April 2, 1921. 
210 


CHEMICAL DYNAMICS OF MUSCLE 211 


others, its great convenience. Almost every fact that I am to 
mention, however, has been shown to apply to mammalian as 
well as to amphibian muscle. 

Of the researches to be reviewed some have been long familiar ; 
others are quite recent, and one or two have not yet been pub- 
lished. I would like you to understand, however, that you will 
be asked to follow one line of progress in particular, and the 
development of a consequent and particular point of view. 
Without neglecting any fundamental facts, which in my opin- 
ion militate against that point of view, I will take a straight 
path towards it, avoiding all collaterals, however interesting 
and important. 

It is in connection with the functions of oxygen in living 
processes that the study of striated muscle displays its greatest 
interest. Till recently it had taught us most of what little we 
know about oxidation in animal tisues; at the moment it seems 
to be revealing quite unexpected aspects of these fundamental 
processes. Even since Lavoisier and Laplace made the great 
contribution to knowledge which more than any other has served 
to emphasize the unity of nature biologists have been trying to 
decide how precisely materials burn in the body. Needless to 
say no history of these efforts can be attempted here: but I will 
ask you to recall the development of one particular idea and 
to realize how potent has been its influence upon biological 
thought. I mean the conception that oxygen does not function 
in a living tissue immediately upon its arrival, but is first built 
up into an unstable complex which, only subsequently, when the 
tissue receives a stimulus, yields free energy by a sudden break- 
down. This conception has led to, and is inseparably associated 
with, all those views which visualize life, as having its essential 
seat in living giant molecules, subject to continuous breakdown 
and reconstruction. Such views, held vaguely, or, as in the 
biogen hypothesis of Verworn and the side chain theory of 
Ehrlich, made highly objective, have greatly dominated thought. 

It was in connection with muscle when in 1867 Hermann 
put forth his inogen hypothesis that in an elementary form they 


212 HARVEY SOCIETY 


arose. In my belief a fair consideration of the facts now known 
about the muscle is sufficient to prove them wrong.. 

You will of course remember that in Hermann’s view the 
contraction of muscle follows upon the sudden, almost explosive, 
breakdown of a complex substance leading to the appearance 
of lactic acid and carbon dioxide. This unstable stuff is the 
inogen, the source of energy. At first, influenced by his belief 
that the processes of Rigor Mortis were in essence similar to 
those of a Contraction, Hermann taught that the protein myosin, 
which separates in a gelatinous form during rigor, was part of 
the inogen. It is sufficient, however, to remember that the es- 
sence of Hermann’s teaching was that the production of carbon 
dioxide in muscle depends not upon the direct and contemporary 
oxidation of relatively simple compounds, but upon the trans- 
ference of oxygen, previously combined in a complex molecule 
from less stable to more stable relations. Thus arose that con- 
ception of intramolecular oxygen which has given form to many 
biological speculations. Up to near the end of the last century 
the evidence seemed to justify it fully enough. Spallanzani, 
who seldom was in error, had shown even a century earlier, 
that living tissues could long survive and continue to yield ear- 
bonie acid without any supply of oxygen except such as had 
been previously available. Spallanzani’s statements were in 
later years fully confirmed by others and Hermann made the 
evidence rather more definite in the case which especially interests 
us by showing that no trace of oxygen could be pumped out of 
a muscle which nevertheless could actively contract without an 
external oxygen supply, and at the same time produce carbon 
dioxide. Hermann’s consequent views related in particular to 
the case of muscle, but as you will know Pfltiger later on—(with 
vague speculations as to the respective nature of dead and 
living protein )—taught that all tissue respiration is based upon 
the activity of intramolecular oxygen. 

Such views were almost unchallenged for thirty years and 
since I am now to speak of work done in Cambridge, England, it 
is of interest to point out that, in a certain form at least, they 
satisfied the critical mind of him who founded this Cambridge 


CHEMICAL DYNAMICS OF MUSCLE 213 


school, as any who read the last edition of his famous text book 
will discover. This edition had not long left the press, however, 
when one of the last of the brilliant group of workers directly 
inspired by Michel Foster, began some work which was to change 
the whole outlook. 

In 1898 W. M. Fletcher! published an account of an observa- 
tion which like many other observations of great importance was 
in a sense of asimple nature. The technique which made it reli- 
able was not simple, however, and the value of the observation 
arose from its quantitive nature. Properly estimated it will, 
in my opinion, be found to have wholly removed the foundation 
of a belief which, as we have seen, had long dominated animal 
physiology. Excised surviving muscle gives out, it is true, a 
steady stream of carbon dioxide. It is clear, however, and it is 
assumed, implicitly if not explicitly, in all that has been attri- 
buted to Hermann’s inogen that if this CO, arises from this 
hypothetical unstable source of energy, the amount should in- 
erease when the muscle passes from rest to activity. The break- 
down of the inogen, which is ex hypothesi, the source of energy 
must surely be increased when the liberation of energy is in- 
creased. Therefore, since the inogen is also the source of the 
CO,, a muscle, though wholly deprived of oxygen, must give 
out more CO, when it contracts than when it is resting. Fletcher 
showed that it did not. 

The fact is fundamental. So long as a muscle remains in 
any sense normal, prolonged stimulation under anerobic condi- 
tions, fails to produce any effect upon its small but steady output 
of CO,. Very different, as Fletcher further showed, is the case 
where a contemporary supply of oxygen is available. The output 
of CO, during rest is then greater and this output is at once 
increased when work is done. This difference between the chem- 
ical response to stimulation under anewrobic and erobic condi- 
tions, respectively, is again fundamental. There is no evidence 
for the breakdown of a previously constructed inogen, but there 
is, on the other hand, clear evidence that Contraction is associ- 
ated with an increase in contemporary oxidations. 

But what of that relatively small but steady evolution of 


214 HARVEY SOCIETY 


CO, which does, after all, occur anerobically, whether the muscle 
be active or at rest? It may be stated at once that it is not a 
product of metabolism at all. It is not physiological. When, 
indeed, we attempt later to picture the cycle of normal events 
we may frankly forget it. It is merely carbon dioxide liberated 
from alkaline carbonates in the muscle as a result of the steadily 
increasing acidity which, as we are to see, is characteristic of the 
anerobie conditions. To the best of my belief it was H. M. Ver- 
non? who first suggested the possibility of such an origin: Hill 
afterwards referred to it, and later Fletcher*® settled the matter 
by experiment. 

Fletcher’s early work provided further facts of significance. 
He fully confirmed the historical statements of Humboldt and 
later observations of Joteyko by showing that exposure of pure 
oxygen greatly delayed the onset of fatigue and of rigor mortis 
in excised muscle, but he went further and showed that a muscle 
which has lost the greater part of its irritability and is near to 
stiffening may be restored if exposed to pure oxygen.* From the 
facts which he made available Fletcher drew a conclusion which 
foreshadows an essential part of the story I hope to unfold. ‘‘It 
is suggested’’ he wrote in 1902, ‘‘that the hastening or rigor 
mortis and fatigue in a muscle from which oxygen is withheld 
is due to increased accumulation, under circumstances of deficient 
oxidation of the metabolic products within the muscle which are 
the potential precursors of carbonic acid ;’’ while in the presence 
of oxygen ‘‘the dissociation processes alike of resting and active 
muscle, advancing slowly in the former, rapidly in the latter, 
result in the formation of free CO,.”’ 

Since from the days of Berzelias lactic acid had been known 
as a constituent of muscle, and many observers, led by Dubois 
Raymond, had associated its production with activity and rigor, 
Fletcher was of course alive to the probability that this acid is 
among those precursors of CO, which accumulates anerobiecally ; 
but he avoided at this time any dogmatic statement on the 
matter. The state of the literature as it then stood fully justi- 
fied such caution. 

Not long before, for instance, the statement had been made by 


CHEMICAL DYNAMICS OF MUSCLE 215 


more than one observer that as a matter of fact there is no more 
lactic acid in a muscle in full rigor than in one perfectly fresh. 
Older views,—which had themselves never been supported by 
really quantitative work—were traversed, and the significance 
of lactic acid in muscle had become entirely obscure. 

A quantitative study was clearly necessary for further pro- 
gress and in 1907 it was my privilege to join forces with Fletcher 
in an attack upon the problem.’ Although the results of our 
somewhat laborious research have failed to affect the teaching of 
some text books, we have the satisfaction of knowing that they 
have been the acknowledged point of departure for recent im- 
portant studies. 

We found that the confusion in the literature as to the quan- 
titative relations of lactic acid in muscle were wholly due to 
faulty technique in dealing with the tissue itself. When the 
muscle is disintegrated as a preliminary to extraction for analyti- 
eal purposes, the existing equilibrium is entirely upset. Interact- 
ing factors are brought into abnormal relations and the processes 
of change are greatly accelerated. A fresh muscle had been sup- 
posed to contain as much lactic acid as one in rigor simply be- 
cause the acid had been produced in the former by the treatment 
which had preceded estimation. The biochemist had not suffic- 
iently remembered the instability of his material. Fletcher and I, 
however, found it quite easy by means of a simple method, not 
only to avoid starting the changes which led to the formation 
of lactic acid but to arrest them at any point during their pro- 
gress and thus to establish their time relations. 

We were able to show that the accumulation of lactic acid in 
muscle occurs only in the conditions of anerobiosis. With a 
proper oxygen supply it fails to accumulate at all; though this 
is not to say that it fails to be produced. Its formation anerob- 
ically in a quiescent muscle shows no irregular relations: it is 
not, for instance, delayed until rigor appears, or is near. The 
accumulation starts from zero or from the minimal quantity pre- 
sent in fresh muscle and continues at a linear rate, equal amounts 
being produced in successive units of time. The reaction respon- 
sible for its appearance has a normal chemical temperature 


216 HARVEY SOCIETY 


ceefficient, at least between such temperatures as 10° to 20°C. 
At higher temperatures the effects of changes in the tissue struc- 
ture become of influence and the process is accelerated so that 
at 40°C there is a very rapid rise to that ‘‘acid maximum’’ which 
Ranke described long ago. At still higher temperatures, and 
especially near 100°C, the process, like other biological processes, 
is arrested. 

Stimulation increases the rate of production, as would be 
expected. We have indeed every reason to believe, and I shall 
later give recent evidence to support the belief, that in muscle 
the chemical processes of activity differ quantitatively only, and 
in no way qualitatively, from those that proceed during qui- 
escence. If a muscle be tetanized to complete fatigue Fletcher 
and I found that the lactic acid produced always stopped short 
of that maximum which is found in Rigor Mortis or produced 
rapidly at 40°C. In the fatigue of tetanus the amount is about 
half that of Rigor (say 0.2 per cent as against 0.4) 

Roughly to be classed as chemical stimuli, are the effects of 
certain volatile organic substances, such as chloroform, toluol, 
etc. When a muscle is exposed to the vapour of these a maxi- 
mum yield of lactic acid is soon reached and a form of rigor 
is established; possibly because as solvents of lipoids these 
substances alter the permeability of membranes within the 
muscle structure. 

The next point established by Fletcher and myself is of 
fundamental importance. If a muscle which, by exposure to 
anerobie conditions, has accumulated lactic acid, be placed in 
oxygen the acid is removed. The occurrence of this removal 
under the influence of oxygen is significant in all that follows. 
It has been fully confirmed by the later work of Parnas 
and Meyerhof. 

The experimental findings so far discussed have removed all 
basis from the theory of intramolecular oxygen, and have shown 
that an excised muscle is quite able to obtain free energy from 
its stores of potential energy without the aid of oxygen. On the 
other hand while anerobic existence, passive or active, inevit- 
ably involves an accumulation of lactic acid in the muscle, sub- 


CHEMICAL DYNAMICS OF MUSCLE 217 


sequent exposure to oxygen effects its removal. If, however, 
oxygen be available from the first it must be remembered that the 
acid does not accumulate at all. 

There are therefore at this stage of the enquiry perhaps two 
possibilities to consider. The muscle when forced to dispense 
with oxygen may be supposed to derive its energy from potential 
stores by chemical steps differing entirely from those which occur 
under physiological conditions. If so, lactic acid may be an ab- 
normal product playing no part in normal events. On this view 
the anwrobic events are merely vicarious. But another possi- 
bility is that the normal cycle of events consists always of two 
phases separated in time: the first anerobie during which lactic 
acid is formed; the second erobie during which it is removed. 
Now the conception of a respiratory sequence in which anero- 
bie events precede and prepare the way for final oxidations has 
long been familiar to the minds of plant physiologists. Pfeffer 
for instance long ago spoke of the former as processes of intra- 
molecular respiration, and looked upon them as necessary ante- 
cedents to subsequent oxidations. It is such a view that I propose 
to develop in connection with muscle, and I shall now proceed 
to give you further evidence in its favor. But the facts won 
in the study of muscle indicate that the influence of oxygen has 
in the case of animal tissues more complicated relations than those 
usually postulated for the case of plant tissues: relations which 
seem to me to have extraordinary interest. 

At the close of our work upon lactic acid Fletcher and I 
were convinced that the influence of oxygen upon the activities 
of muscle is exerted after, rather than before, or during, the 
actual act of contraction and we were supported in this view 
by an observation previously made by Danilewski® who found 
that heat is given out by a contracting muscle after the actual 
contraction is over. The ordinary methods of chemical analysis 
however, seemed hardly capable of affording a final proof of this 
sequence. Clear evidence concerning the time relations of events 
could be best got from the study of a single contraction, a task 
impossible for the chemist. 

At this stage, however, the Cambridge School of Physiology 


218 HARVEY SOCIETY 


gained an unusual advantage by recruiting, in the person of 
A. V. Hill; one who is at once an accomplished mathematician 
and a skilful experimentalist. Hill’s qualifications have enabled 
him to advance very greatly the thermodynamics of muscle and 
to supply highly essential links in the chain of evidence which 
has led to the standpoint I am to advocate. 

His studies have been made partly on the lines of micro- 
calorimetry, but also, and more particularly, by the use of thermo- 
electric methods which he has greatly refined. A fundamental 
observation made early in Hill’s researches puts upon a firm ex- 
perimental basis the conclusion of Danilewski already quoted; 
namely, that the heat given out by an active muscle long outlasts 
the contraction itself.* But Hill’s further time analysis of the 
thermal phenomena is so important to my thesis that it should 
be very fully grasped, at least in its essentials. The essentials 
are these. Directly associated with a contraction is a rapid evo- 
lution of heat, which occurs both under anerobie and erobic 
conditions, and is, moreover, alike in its time relations and 
other characters, wholly unaffected by the presence or absence 
of oxygen. 

Oxygen, however, has a noteworthy effect upon the sequel. 
In its absence the heat evolution just mentioned is quickly over, 
and is the only thermic change associated with the act of contrac- 
tion. In its presence there is a further evolution of heat, subse- 
quent to, and long outlasting, the act. These facts are clearly 
of great significance. The process which comes first must be 
anerobic; that which comes second ean scarcely fail to involve 
an oxidation. We have here a proof of the suspected sequence 
of events, and data which strongly suggest that at the moment of 
contraction, even under conditions made normal by the available 
supply of oxygen, something is produced anerobically upon 
which oxygen subsequently acts. The chemical facts already 
discussed leave but little doubt that this substance is lactic acid, 
and evidence will be immediately given to show that the forma- 
tion of the acid is as a matter of fact intimately associated with 
the process which gives rise to the early anerobic heat production. 
Later on we shall see that there are abundant reasons for associat- 


CHEMICAL DYNAMICS OF MUSCLE 219 


ing the second oxidative heat production with the occurrence of 
its removal. 

Already we may speak, at least provisionally, of two phases 
in the muscular act, separated in time: an anerobic phase of 
activity, or Fatigue Phase; and an exrobic phase, or Recovery 
Phase. It is convenient to make this distinction now. Further 
justification for it is inherent in all that follows. 

The recovery phase must not be confused with the relaxation 
of the muscle, which like the contraction proper, is primarily 
independent of oxygen and is included in the first phase. I 
shall deal first with this phase of activity. 

Early in his studies Hill demonstrated a fact which yields 
an important point in the evidence. Between the mechanical 
tension which appears in the muscle and the production of heat 
there is always a direct proportionality. Alike in the steady 
anrrobie metabolism of the quiescent muscle, or during stimu- 
lation, or in various forms of rigor mortis however rapidly in- 
duced, the appearance of a given quantity of acid is associated 
with the evolution of a proportional quantity of heat. A spec- 
ially accurate quantitative proof of this was given by the work 
of R. A. Peters* at Cambridge. Using admirable technique, he 
showed that while the indirect stimulation of muscle to fatigue 
involved the evolution of 0.9 calories per gram of tissue, the 
subsequent induction in the same muscles of rigor by chloroform 
added 0.89 cals. per gram. When rigor was directly induced 
in fresh muscle the heat production amounted almost exactly to 
the sum of the above, and double the heat of fatigue, namely 
1.70 cals. Now Fletcher and I had shown, as already mentioned, 
that in rigor the average production of lactic acid is about double 
the production in fatigue, and this Peters confirmed. Each gram 
of acid when it appears in muscle is accompanied by the appear- 
ance of about 450 calories and the constancy of this ratio under 
such different conditions shows that acid and heat owe their 
origin to one and the same process. Equally important in the 
development of the views I am putting before you is the indica- 
tion supplied by such results that the events which give rise to 
lactic acid formation during normal activity are in no sense of 


220 HARVEY SOCIETY 


a different order from those which are responsible for the ap- 
pearance of the acid during the anzrobic metabolism of rest, 
or in rigor however produced or accelerated. 

These results have been in all essentials amply confirmed by 
the very recent work of Meyerhof,’ to which in other connections 
I shall have to make frequent reference. 

His experiments have an advantage over the earlier ones in 
that the estimations of heat and lactic acid were made upon the 
same set of muscles, and the comparison was direct. At the 
same time it must be remembered that only micro-methods could 
be used for such a purpose. Meyerhof found, as the result of 
change in conditions such as the temperature at which the muscles 
are stimulated, certain variations in the heat evolved per unit 
of lactic acid produced but proved that the relation was es- 
sentially of the same order as that assumed by Hill and Peters. 
With regard to the effect of temperature, Hill has very recently 
shown that in the response to a single shock the relation is the 
same at all temperatures. In prolonged stimulation it varies. 
For average conditions we shall be close to the mark of we take, 
with Meyerhof, 400 small calories as the heat production which 
is normally associated with formation of 1 gram of lactic acid. 

Lactic acid is related in a similar quantitative way with 
mechanical changes in the muscle. To get clear on this point 
we must realize certain properties of the muscle as a machine 
which have been brought fully to light by the investigations of 
Hill. Earlier experiments had shown that the actual work per- 
formed by a contracting muscle bears very variable and appar- 
ently accidental relations to the heat evolved. The case is differ- 
ent, however, if we deal with the primary mechanical event which 
follows immediately upon stimulation and precedes any perform- 
ance of work. This is a sudden increase of tension in the fibres 
which can be accurately measured. It means that the elasticity 
of the fibres has suddenly changed, and its occurrence implies 
a sudden conversion of chemical potential energy into mechan- 
ical potential energy. The subsequent developments in the muscle 
depend upon the circumstances in which it is placed. If it be 
free to contract, then part of the energy of the new tensile stress 


CHEMICAL DYNAMICS OF MUSCLE 221 


will appear as work and part, of course, as heat. If the muscle 
after stimulation cannot contract the whole appears as heat. 
Hill has established the important fact that the heat evolution 
is then always proportional to the amount of tension previously 
established in the muscle. Much, I may say here, that what is 
quantitative in our present knowledge is due to Hill’s recognition 
of the importance of studying the dynamies of the isometric con- 
traction. Such studies have yielded proof of the relation 
just mentioned. 

Since the mechanical potential energy established in the iso- 
metric muscle by stimulation degrades into a proportionate 
amount of heat, and this heat has been shown to be propor- 
tionate under all circumstances to the lactic acid produced, it 
follows that the original mechanical potential is proportionate 
to acid production. This Meyerhof has directly shown by estim- 
ating the integrative effects of a series of isometric contractions 
carried on to the point of fatigue. He found that the total 
mechanical effect is in general proportionate to the total acid 
formed, the absolute value of each varying with such factors as 
the nutrition condition of the animals used. 

The relations just discussed compel the belief that acid pro- 
duction, the development of tension, and the heat which ultim- 
ately leaves the muscle, are all essentially due to one event, and 
that a chemical change following immediately upon excitation. 
Here clearly we reach a standpoint, based upon quantitative data, 
of the utmost importance for the understanding of the dynamies 
of muscle. 

Our next desire will naturally be to discover the nature of 
the primary chemical reaction concerned. We need then first to 
know what is the precursor of the lactic acid. All the prob- 
abilities would point. to carbohydrate as the ultimate, if not the 
immediate, source of the acid; but the experimental evidence 
supposed to bear on the matter seemed for a long time hope- 
lessly confused. It is not necessary to enter into the history of 
controversy on the point. Much of it has been due to the 
fact that the data upon which arguments have been based were 
yielded by unsatisfactory methods and so were contradictory 


222 HARVEY SOCIETY 


and without quantitative value. Recent work and especially 
that of Parnas and Meyerhof shows at least that whenever 
lactic acid appears in muscle an equivalent quantity of carbo- 
hydrate disappears. These observers used micro-methods for 
their estimation, though their methods were carefully controlled. 
In my laboratory we have recently repeated work upon this point 
using similar methods upon larger quantities of material. We 
have been impressed by the exactness with which the amount of 
lactic formed under any circumstances corresponds with the 
earbohydrate disappearing. 

Seeking detail as to the exact. nature of the precursor we may 
pass at once to the results of the patient investigation of the 
Frankfort School. Doubtless, having in view the classical dis- 
covery of Harden and Young, who showed that in the chemical 
breakdown of sugar by yeast juice the synthetic formation of a 
phosphoric ester of hexose is an invariable event, and also being 
aware of certain data in the literature which suggested that dur- 
ing the activity of muscle inorganic phosphates may be increased 
at the expense of phosphates organically bound, Embden and 
his colleagues, Laquer and others, set themselves to look for 
hexose phosphate in muscle. 

The final outcome of a patient and laborious investigation was 
the proof that this hexose phosphate does undoubtedly exist in 
muscle and shares in the processes of change.'° Moreover, 
mucle-extracts and other tissue-extracts, while quite incapable 
of converting free sugar into lactic acid, break down the hexose 
phosphate in such a way as to yield simultaneously both lactic 
and prosphoriec acids. The view may be taken, and if true, it is 
one of great interest, that. the association with phosphorie acid 
in some way makes easier that intramolecular shift which is in- 
volved in the production of lactic acid from dextrose. We can 
hardly doubt therefore that between the glycogen and the lactic 
acid of muscular metabolism this combination of sugar with 
phosphoric acid isan intermediary. It is probably the immediate 
precursor of the latter and is in any case a precursor at some 
stage in the processes of production. Its properties justify the 
title ‘lactacidogen’” which Embden has applied to it. 


CHEMICAL DYNAMICS OF MUSCLE 223 


In their more general aspects the occurrences of the active 
phase of a muscle act may be pictured as follows: As the result 
of stimulation, sugar, originally derived from the glycogen stores, 
but situated in some position of advantage in the muscle structure 
and almost certainly combined there with phosphoric acid, suffers 
a sudden breakdown yielding lactic acid. As a result of this 
chemical event, preceded, it may be, by a translocation of some 
pre-existing lactic acid, the muscle elements suffer a marked 
change in respect of their elastic properties, and this leads to 
a development of mechanical tension within them proportionate 
in amount to the acid produced. This tension may then be con- 
verted into work ; but in such conditions as those which exist when 
a muscle contracts isometrically, it is wholly degraded into heat. 
This heat, though by no means to be thought of as identical with 
the heat of the initial chemical reaction, is always proportionate 
to the extent of that reaction, and so also to the lactie acid 
produced. So long as the events of the next phase—the recovery 
phase—are for any reason in abeyance the acid accumulates in 
the muscle. These events, in which the influence of oxygen is 
dominant, must be now considered. 

The recovery period is most easily pictured when conditions 
sharply demarcate it in time, as when a muscle properly supplied 
with oxygen is engaged in a series of single contractions. It 
then intervenes between relaxation and the following contraction. 
But the evidence shows that the chemical processes involved in it, 
so long as oxygen is fully available, continuously play their part 
in the chemical equilibrium of muscle, whether quiescent or active. 

The facts already discussed have shown that the main event 
during recovery is the disappearance of lactic acid. But the 
precise mechanism of its removal is a matter vital to our under- 
standing of the dynamics of muscle. If for instance we endeavor 
to take the simplest view of the situation and, in analogy with 
what has been taught concerning plant respiration, conceive that 
the sequence of events is merely that of acid production during 
activity, followed by complete combustion of the acid, during 
recovery, we meet at once an inherent difficulty which has pre- 


224 HARVEY SOCIETY 


vented many in the past from recognizing in lactic acid a normal 
product of activity. 

The demands of a working mechanism such as muscle are 
somewhat different from those of more quiescent plant tissues. 
It calls not only for a supply of available free energy but for 
the delivery of this at the right moment. 

Now in the breakdown of carbohydrate to yield lactic acid a 
very small fraction, perhaps one-fortieth, of the chemical po- 
tential of the former is made available as free energy. The rest 
would be set free during the subsequent combustion, but as the 
act of contraction has ex hypothesi preceded this, the natural 
conclusion would be that the mechanical activity receives no 
support from oxidations, which then would provide heat alone. 

Under such circumstances the consumption of material neces- 
sary to yield a given amount of work would be out of all pro- 
portion greater than what is known to occur in the normal in- 
tact animal. 

If then the splitting of carbohydrate into lactic acid as a 
source of energy for the contraction be no abnormal process, 
vastly uneconomical, to which the muscle is merely driven by 
deprivation of oxygen; if the sequence of events we are pictur- 
ing be real; then, in some way, energy must somehow be made 
available for activity during what we have ealled the Recovery 
Phase. Recent research has made it clear that there is a real 
post-contractile return of material and energy to the system of 
the muscle. The facts are of great interest and would seem to 
bear not alone upon the dynamics of muscle but no less perhaps 
upon the nature of the relations between oxygen and living pro- 
cesses in general. 

During our work upon lactic acid, Fletcher and I obtained 
an experimental result which seemed to us significant. We sub- 
mitted muscles to processes of alternating fatigue and recovery, 
repeated many times. As during each period of recovery lactic 
acid left the muscles, it is clear that the treatment referred to, 
if it involve complete oxidation, must ultimately have made a 
heavy drain upon the sources of the acid. Organs so treated 
might be expected to show signs of consequent deficiency in these. 


CHEMICAL DYNAMICS OF MUSCLE 225 


Yet when they were warmed to 40°C as to obtain from them 
Ranke’s ‘‘heat maximum”’ it was found that they yielded just 
as much lactic acid as perfectly fresh unfatigued muscles. 
Though we tried not to dogmatise upon the matter, we thought 
that here was some justification for believing that the acid was, 
during the recovery periods, not burnt away, but perhaps rebuilt; 
not, of course, with the oxygen into an iwnogen, but into whatever 
substance had first yielded the acid anerobically. It was after- 
wards shown however, by Lacquer, that a simpler explanation for 
the facts is available. The production of lactic acid of muscle 
is a self regulated reaction stopping short when a certain maxi- 
mum is reached. If therefore the original supply of precursor 
is relatively large we need not expect that its partial exhaustion 
will appreciably reduce the final maximum. There are certain 
considerations to suggest that the experimental result described 
is not entirely to be explained in this way; but I need not dwell 
upon them because there is now other and more direct evidence 
to show that the processes of recovery reverse the processes 
of fatigue. 

Quite early in his researches Hill measured the heat given 
out in the period which follows a single muscular contraction, 
and found that this so called Heat of Recovery to be quantita- 
tively of the same order as the Heat of Contraction. To this 
result he applied the following argument: The lactic acid pro- 
duced in contraction disappears during recovery and since the 
heat associated with the formation is known to be about 400 
cals. per gram, while the heat or recovery is about the same, only 
some 400 cals. can be evolved during the removal of l gram. But 
the total heat of combustion of 1 gram of lactic acid is something 
like 3,700 cals. It is impossible, therefore, that more than a 
fraction of the acid which is removed during recovery can be 
actually burnt. Most of it must be removed in some other way; 
as Hill thought, by reconstruction into a substance of higher 
potential energy. 

But, before the argument can be completed, more precise and 
direct information is wanted as to how much material is actually 
oxidized in the recovery phase. This is not necessarily measured 

15 


226 HARVEY SOCIETY 


by the heat given out. It can be determined, however, by meas- 
uring the amount of oxygen consumed, especially if at the same 
time we get to know the respiratory quotient. Such a determina- 
tion was first made by Parnas" in the course of work begun at 
Cambridge. Parnas found, first of all, that the oxygen consump- 
tion of an excised muscle, resting, but previously fatigued and 
therefore loaded with lactic acid, was definitely greater than that 
of a fresh resting muscle containing at most a minute quantity 
of acid. His results seemed to show that this excess in the oxy- 
gen consumed corresponded with some exactness to the combustion 
requirements of the amount of lactic acid known to have disap- 
peared from the fatigued muscle by the end of the experiment. 
But he found also, and here he demonstrated a point of great 
importance, that the heat actually evolved was considerably less 
than what this combustion would produce; the former being in- 
deed only half the latter. Parnas drew from his results the con- 
clusion that while the lactic acid was not resynthetised, but wholly 
burnt, the energy of its combustion was not all lost to the muscle. 
On the contrary, a moiety of this energy is by some unknown 
means employed in restoring potential to the contractile system. 
You will not deny that this return of energy to the physical 
mechanism under the influence of oxygen is a significant event. 
Its occurrence has been confirmed by the later work of Meyerhof. 
In a series of papers which have appeared during the last. 
year, this author, who had previously identified himself with 
productive studies of general tissue-respiration, has made im- 
portant contributions to the subject of this lecture. Much of 
his work constitutes a confirmation of that of Fletcher and my- 
self, as also that of Hill and Peters; though; especially 
in connection with the effect of conditions on lactie acid 
formation, he has added precision to details. But he has also 
added facts, and especially one fact of great importance. 
Meyerhof repeated Parnas’s experiments on the oxygen con- 
sumption of the recovery period, estimating directly in the lactic 
acid which disappears. The conclusion that part of the energy 
arising from the oxidation is retained in the muscle was confirmed, 
but Meyerhof’s results differed quantitatively from those of 
Parnas, and the difference modifies the interpretation of the 


CHEMICAL DYNAMICS OF MUSCLE 227 


facts. Meyerhof agrees with Hill in finding that the observed 
heat of recovery is of the same order of magnitude as the heat 
of contraction, though his results suggest that the former is 
somewhat the greater, in the ratio, say, of five to four. He finds 
with Parnas that this value is considerably less than what would 
correspond with the lactic acid (or carbohydrate) burnt; but the 
figures he obtained for oxygen consumption indicate that not the 
whole, but no more than one-third to one-fourth, of the lactic 
acid is actually burnt; the remainder disappears without oxida- 
tion. This was Hill’s view. But Meyerhof has gone be- 
yond previous observers by showing what this disappearance 
means. The balance of the acid he finds is actually reconverted 
into glycogen. 

KE. J. Lesser,’? several years ago, showed that the glycogen of 
intact frogs was greatly reduced as the result of a comparatively 
brief deprivation of oxygen, and that when the animals were 
returned to normal respiratory conditions without receiving 
food the total glycogen returned in part to its original value. 
This might possibly indicate a resynthesis from lactic acid formed 
during the anoxybiosis. But the process in the whole animal 
might have been quite indirect, and involve other organs than 
the muscles. Meyerhof on the other hand, by simultaneous esti- 
mations of lactic acid and glycogen in excised muscles, before 
and after their recovery in oxygen from previous fatigue, has 
shown directly that during the process the one is actually recon- 
verted into the other. 

Meyerhof’s results have been fully confirmed in my labor- 
atory by the conjoint work of Miss D. Foster and Miss Moyle. 

Energy, it would seem is returned to the muscle along two 
lines; one involving a restoration of chemical potential, and the 
other the restoration of potential to a physical system. Each 
event has its own importance in the return to the status quo ante. 

From the chemical standpoint the equilibrium changes in- 
volved during activity and recovery resolve themselves ulti- 
mately into the simple reversible equation: 

Glycogen > Lactic acid 

So long as anerobic conditions prevail the production of lactie 

acid is an irreversible process; under the influence of oxygen it 


228 HARVEY SOCIETY 


becomes reversible, though at the cost of the oxidation of a part 
(say one-fourth) of the reacting materials. 

We may provisionally put the relations just discussed into 
quantitative form with the data of Hill and Meyerhof as a 
basis. Calculated as for one gram of muscle the average of 
Meyerhof’s results gives for the heat of contraction 0.75 cals; 
for that of recovery 1.0 cals; and for the heat of the lactie acid 
(or carbohydrate) actually burnt during recovery 1.75 cals. If 
we calculate in round figures the calories corresponding to one 
gram of lactic acid either produced or removed we get the data 
in a convenient form: 


Heat of anzrobic Heat of recovery Total heat of activ- 
contraction in oxygen. ity In oxygen. 
400 eals. 500 eals. 900 cals 


Heat of combustion 
of materials burnt. 


900 eals. 


This is a balance sheet which any Auditor would pass as 
satisfactory. The heat lost as a result of an exothermic change 
during the fatigue phase (400 cals.) is balanced by the absorp- 
tion of an equal amount of heat due to an endothermic change 
during the recovery phase. On the other hand the heat of com- 
bustion of materials actually shown to have been oxidized exactly 
provides the total loss of energy (900 cals.) during the whole 
cycle of change. Asa result of the recovery processes, therefore, 
the muscular system is restored to the condition which existed 
before activity, except for the fact that, in the disappearance 
of part of its glycogen store, it has lost chemical potential energy 
equivalent to the energy it has expended. 

Although at this stage we have arrived on solid ground it 
is clear that the mind cannot be satisfied to rest upon it without 
some attempt to visualize from a somewhat new and better stand- 
point the actual mechanism of muscular contraction. But the 
view ahead is not yet wholly clear and much must still be left 
to the imagination; though we have less reason than before to 


CHEMICAL DYNAMICS OF MUSCLE 229 


indulge in theories of contraction which are wholly speculative. 
To this extension of the subject I can here contribute little. My 
own ostensible task is indeed nearly finished for I have now ex- 
hausted the available facts of a strictly chemical nature. 

A few words may be said, however, in an attempt to relate 
these facts rather more clearly to the mechanical changes in 
muscle, premising that we at once enter a region of hypothesis. 
It is clear at any rate that we must dismiss all thought of the 
muscle as a heat engine. It works directly with chemical energy, 
taking especial advantage at some stage in a sequence, of the sur- 
face forces which its structure enables it to develop. The heat 
production is largely if not entirely irreversible. I need not 
press this claim. It is inherent in all that has been said, and you 
have an easily accessible statement supporting it in the Presi- 
dential Address delivered to the Society of Biological Chemists 
in 1913. The recently won facts affect but little the general 
arguments used by Professor Macallum on this occasion. 

It is very important to remember here that the work of Hill 
has confirmed in a highly quantitative way the statement of Blix 
that the amount of tension developed in a muscle depends upon 
the extent of the available surfaces. Hill has shown that the 
quantity of energy set free upon stimulation is directly propor- 
tional to the length of the fibres and not to the volume of the 
muscle; a relationship which was also found by Patterson and 
Starling to hold for the ventricular contraction of the heart. 
The prime chemical event would seem to occur at a boundary 
between two phases in the muscle structure. 

That the appearance of lactic acid (hydrogen ions) on the 
surface may be the efficient cause of the change of elasticity was 
urged by Mines when he was working at Cambridge some years 
ago, and I think the view is very generally though not universally 
accepted. The primary happening on contraction would seem 
to be clear. It consists in the sudden appearance of acid at a 
particular surface with the consequent development of tension. 
This does not necessarily mean that the breakdown of ecarbo- 
hydrate which yields the acid is quite so sudden, for there is a 
possibility not yet dealt with to which I must refer. Hill’s most 


230 HARVEY SOCIETY 


recent work has involved a closer analysis of the heat given out 
on a single contraction, and also a comparison of that which 
appears on very brief stimulation with that produced during 
more prolonged stimulation. He concludes from his results that 
within some closed location in the quiescent structure carbo- 
hydrate and lactic acid are in equilibrium; there exists, so to 
speak, somewhere, a certain pressure head of the acid before con- 
traction occurs. The first effect of a stimulus is to affect the 
permeability of the containing structures and lactic acid passes 
to the locus where it is effective in producing contraction. This 
result follows upon the briefest of stimuli; it also happens at the 
earliest stage of every stimulus 

[Carbohydrate —~ Lactic acid]?<— 
If the stimulation is prolonged beyond this point, what I have 
called the pressure head of lactic acid disappears, and the con- 
tinued production of lactic acid necessary for the maintenance of 
tension depends now on the steady progress of the reaction 

Carbohydrate—~»Lactie acid.* 

The conceptions just put forward are due to Hill. They are 
hypothetical, but they are supported, as I have said, by his latest 
analysis of the heat phenomena. The heat produced by a very 
short maximal stimulus and that evolved at the earliest period 
of any maximal stimulus is constant no matter what the external 
temperature. The process with which it is associated has there- 
fore no temperature cefficient and is represented by that sudden 
diffusion of preformed lactic acid of which Hill has conceived. 
If the stimulus be prolonged the later heat formation rises with 
the external temperature because we have now to deal with the 
temperature ceefficient of the reaction which continues to pro- 
duce fresh lactic acid. 

Part of the heat evolved during what we have agreed to call 
the active or fatigue phase is associated, as Hill has now also 
shown experimentally, with relaxation. What kind of event gives 
rise toit? If contraction follows upon the appearance of acid at 
certain effective surfaces, relaxation will follow upon its leaving 


* The intervention of the hexose phosphate is here omitted for the sake 
of simplicity. 


CHEMICAL DYNAMICS OF MUSCLE 231 


those surfaces. But relaxation precedes the recovery phase and 
occurs without oxygen. What then removes the acid from the 
contractile surface? MHaving reached a certain local concentra- 
tion it will certainly tend to diffuse away into places of lower 
concentration, and unless, as during continued stimulation, the 
concentration is maintained at the contractile surface. relaxation 
may be expected, at some moment or other, to follow. Meyerhof 
takes the view that diffusion is indeed the sufficient cause of 
relaxation and considers that the heat of the relaxation is ac- 
counted for by the effect of diffusing acid upon the colloids of the 
muscle plasma. Hill, on the other hand, postulates a more defin- 
itely chemical event at this point and bases his view upon the 
fact that he finds a high temperature cefficient for the relaxation 
process. There are difficulties I feel in either view. The heat 
given out during relaxation forms, as Hill and Hartree have 
shown, a large proportion of the total heat of the fatigue phase. 
It is difficult to understand this upon Meyerhof’s view; and even 
if we agree with Hill in thinking that the acid which has initiated 
contractions is, so to speak, inactivated by the formation of some 
fresh compound, it is hard to picture what type of compound this 
might be. Doubtless simple neutralization by the carbonates 
of the muscle plasma plays a part here, but it seems to be a small 
one. If some other compound is formed it would seem to have 
a high heat of formation, and yet it must be some loose compound ; 
for, after all, it is lactic acid itself which analytical methods 
extract from fatigued muscle. The process of relaxation is not 
yet, I think, fully understood. 

The significance of oxidation in the recovery phase is much 
more easily grasped. Whatever the condition of the lactic acid 
at the end of the fatigue phase it is easy to see that its oxidative 
removal is an important factor in the preparation for the next 
contraction. If the acid during relaxation diffuses from the con- 
tractile surfaces into adjacent elements of the muscle structure 
then in the absence of the oxidative removal, the diffusion grad- 
ient would get less and less; acid would therefore tend more and 
more to accumulate at the surfaces and relaxation would become 
increasingly incomplete as we know it does during the progress 


232 HARVEY SOCIETY 


of fatigue. On Meyerhof’s view an important consequence of 
the recovery processes is the restoration of the diffusion gradient 
for the translocation of acid. On Hill’s view the events would 
have just the same significance; for oxidation of the combined 
lactic acid will prevent the saturation of whatever substance it 
may be supposed to combine with. 

In any case we see that the function of oxygen in the life of 
muscle is not to provide directly the energy of its specific physi- 
ological activity. It rather restores potential when it has run 
down, and clears the mechanism so that the actual sources of 
energy can be efficiently drawn upon. 

We shall not, however, understand the whole of the fascinat- 
ing chemical system which has occupied our attention if we think 
only of its energy exchange, and the material events which sup- 
port them. 

All the Dynamic phenomena we have considered, though they 
may be displayed to perfection for long periods by muscles ex- 
cised from the body, are of course displayed only while a certain 
equilibrium is maintained among a complicated set of factors; 
the equilibrium which is associated with, and necessary for, the 
property of irritability. 

So long as this is maintained, or, if lost, is capable of restora- 
tion, so long are we justified in attributing life to the tissue. A 
moment comes when the necessary equilibrium is no longer main- 
tained, and this moment is usually—though, as we are to see, 
not always—associated with, and marked by, a happening which 
seems to have a more or less critical character—the rigor of death. 
This may arise, even in quiescent muscle, as the final result of 
oxygen lack alone; but we have learnt to make no sharp distine- 
tion between the onset of rigor mortis and that gradual progress 
of fatigue which in active muscle may lead up to it; a progress 
which is accelerated by deprivation of oxygen and delayed by 
a proper oxygen supply. 

It is the accumulation of products of change and not the 
exhaustion of supplies of oxidizable material which leads to fa- 
tigue and ultimately to death in rigor. Fletcher’s early work 
and the work we did together as well as such observations as 


CHEMICAL DYNAMICS OF MUSCLE 233 


those of Joteyko left little doubt that the prime if not the sole 
cause of fatigue, and, no less, of death in rigor, is the accumula- 
tion of lactic acid. Both phenomena are due to the effect of this 
upon the colloid machinery of the muscle. Fatigue increases as 
the accumulation increases and the critical moment of rigor mortis 
(in so far as it is critical) corresponds with the attainment of a 
certain concentration of acid. 

These are the common and obvious events. When they occur 
they overshadow other failures in equilibrium which may never- 
theless be as fatal to what we call the life of the tissue. An 
excised amphibian muscle when quiescent in an atmosphere of 
oxygen does not accumulate lactic acid, and never displays rigor 
mortis at all. Yet though it lives surprisingly long it is certainly 
not immortal. It ultimately ceases to be irritable and we must 
then speak of its death; but it is death without rigor. What 
now is the cause of death? Miss D. L. Foster and Miss D. M. 
Moyle have carried out in my laboratory some experiments which 
bear upon the answer to this question and the results seem to be 
of great interest. 

If frogs’ limb muscles are kept in oxygen at 0°C they remain 
irritable for periods which vary with the season from about a 
fortnight to three weeks. The irritability declines relatively 
fast immediately after the first few days, then remains constant 
for a period, and later declines more rapidly to zero. But the 
muscles when, finally, they fail entirely to respond to the strong- 
est electrical stimulus show no signs of rigor mortis. In their 
flaccidity and in their general appearance they resemble perfectly 
fresh muscles. Corresponding with this they are found to con- 
tain only that original ‘‘resting minimum”’ of lactic acid which 
must have been present when they were originally removed from 
the frog. In parenthesis it may be stated that this failure to 
accumulate lactic acid is not due to the complete inhibition by 
the low temperature of the chemical processes concerned. In 
nitrogen the muscles at 0°C accumulate lactic acid at a steady 
rate, a circumstance which is associated with a much earlier 
loss of irritability. Its failure to accumulate is still the effect 
of oxygen. But the remarkable fact is that wholly non-irritable 


234 HARVEY SOCIETY 


muscles may be essentially mtact in respect of their chemical 
mechanism. Whatever stimulates chemical change in a normal 
muscle stimulates the same change in muscles which have lost 
irritability during exposure to oxygen, though throughout all 
stimuli fail to produce a mechanical response. If kept at 40°C 
their glycogen is converted into lactic acid with a normal rapidity 
and the usual maximum is reached. If exposed to chloroform 
vapor the usual chemical response is seen. If chopped up the 
usual acceleration of lactic acid production is displayed. It is 
noteworthy, moreover, that though when electrically tested they 
show no current of action, transmitting no diphasic change of 
potential, they yet display a demarcation current as another in- 
dication of their chemical integrity. By chemical criteria we 
should say they were alive, electrical stimulation decides they 
are dead. These would seem to be a dislocation in the normal 
sequence of stimulation and energy discharge. Can we picture 
any physical basis for such a dislocation? I would offer a pro- 
visional view: Nernst’s theory of excitation as extended by the 
work of Lucas and Adrian at Cambridge postulates the free move- 
ment of ions. The attainment of a certain concentration of these 
upon a surface or surfaces within the tissue determines the con- 
dition of excitation. Now in an isolated system containing e¢ol- 
loids and dissolved electrolytes there is a tendency with flux of 
time towards an increase of stability in the relations which exist. 
Ions which start free gradually form relatively stable association 
with the colloids. This, I would suggest, is what occurs when the 
muscle gradually loses irritability under the conditions described. 
During the long survival period in oxygen at 0°C there is none 
of that clogging of the machinery with metabolic products which 
ordinarily precedes the death of the tissue, but there is a gradual 
immobilization of ions. This makes impossible that movement 
towards an efficient concentration at a surface which is postulated 
in the Nernst theory of excitation. An examination of the osmotic 
properties of the unfatigued yet non-irritable muscles supports 
this view. Though the actual loss of material which they have 
suffered during their survival life in oxygen consists solely of a 
small proportion of their glycogen store, the osmotic pressure in 


CHEMICAL DYNAMICS OF MUSCLE 235 


the fibres is markedly lower than that observed in muscles freshly 
removed from the body. The living condition demands the main- 
tenance of a proper equilibrium in the Colloidal apparatus of 
a tissue as well as the continuance of chemical reactions which 
proceed in that apparatus. The nature of the apparatus plays 
doubtless an important part in the organization of the reactions, 
and it is necessary to study them together. 

Much doubtless has to be learnt before the total activities 
of the contractile tissues can be fully described in terms of 
Physics and Chemistry, but I think that the knowledge already 
won with which I have dealt very partially, should encourage 
the belief that the essential phenomena involved are far from 
elusive. If the biochemist duly respects his materials while he 
applies quantitative methods to their study he need not be dis- 
mayed by the circumstance that they are only interesting 
when alive. 

1. Fletcher and Brown: J. Physiol., 1898, 23, 10. 

2. Vernon: Science Progress. 

3. Fletcher and Brown: J Physiol., 1914, 48, 177. 

4. Fletcher: Ibid, 1902, 28, 474. 

5. Fletcher and Hopkins: Ibid, 1907, 35, 247. 

6. Danilewski: Pflitiger’s Arch., 1889, 45, 353. 

7. Hill, A.V.: J. Physiol., 1910, 40, 389 with series of later papers 

in same journal. 

8. Peters, R.A.: J. Physiol., 1913, 47, 243. 

9. Meyerhof: Pfliiger’s Arch., 1919, 175, 20 & 88; Ibid, 1920, 182, 

232 & 284. 

10. Embden and Laquer: Ztschr. Physiol. Chem., 1916, 98. 1921, 113. 

11. Parnar, Centralb. f. Physiol., 1915, 30, 1. 

12. Ztschr. f. Biol., 1908, 51, 287. 


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