RB 151 B3 V.3 UC-NRLF B H Efib >45Q End»crinol«gy and metabolism ENDOCRINOLOGY AND METABOLISM PRESENTED IN THEIR SCIENTIFIC AND PRACTICAL CLIN CAL ASPECTS BY NINETY- EIGHT CONTRIBUTORS EDITED BY LEWELLYS P. BARKER, M.D. (Toronto). LL.D. (QjjEENS; McGill) PROFESSOR OF MEHICIXE, JOHNS HOPKINS UNIVERSITY, 190.')-1914 ; PIIYSICIAN-IN-CHIEF, JOHNS HOPKINS HOSPITAL, 1905-1914 ; PKESIDEXT of ASSOCIATION- OF AMERICAN PHYSICIANS, 1912-1913 ; PUESIDENT OF AMERICAN XEUROtiOGICAL ASSOCIATION, 1915; PRESIDENT OK SOUTMERN MEDICAL ASSOCU- TlOX, 1919; PROFESSOR OF CLINICAL MEDICINE, JOHNS HOPKINS UNlVERtrlTT, 1914* 1921 ; AND VISITING PHYSICIAN, JOHNS HOPKINS HOSPITAL ASSOCIATE EDITORS ENDOCRINOLOGY R. G. HOSKINS PH.D. (HARVARD). M.D, (JOHNS HOPKINS) i PROFESSOR OF PHYSIOLOGY, STARLING-OHIO MEDICAL COLLEGE, 1910-1913 ; ASSOCIATE PROFESSOR OP PHYSIOLOGY, NORTHWESTERN UNIVERSITY MED- ICAL SCHOOL, 1913-1916 ; professor op PHYSIOLOGY, IBID., 1916-1918 ; ASSOCIATE IN PHY.SIOLOGY. JOHNS HOPKINS UNIVER- SITY, 1920-1921 ; professor and head OF DEPARTMENT OP PHY.SIOLOOY, OHIO STATE UNIVERSITY. 1921 ; EDITOR-IN-CHIEF "ENDOCKIH- OLOGY," 1917-. METABOLISM HERMAN O. MOSENTHAL M.D. (COLUMBIA UNIVERSITY) ASSOCIATE PHYSICIAN, JOHNS HOPKINS HOSPITAL, 1914-1918 ; ASSOCIATE PROFE-s%OR OP MEDICINE, JOH.VS HOPKINS UNIVERSITY, 1914-1918; AS- SOCIATE IN MEDICINE, COLLEGE OP PHYSI- CIANS AND SURGEONS, COLUMBIA UNI- VERSITY, 1910-1920; ASSOCIATB pro- fessor AND ATTE.VDING PHYSICIAN, NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL. VOLUME 3 D. APPLETON AND COMPANY NEW YORK , LONDON 1922 rp'?-- -ri^oj^m: Liii •#; vHY ^:^ANCH '■ :. ;r T-T^' ..'-kit;. V- Ti.. ■■.iC'^lfjV:^^ COPYRIGHT, 1922, BY p. APPLETOiSr AND COMPANY nvnvD m thb united states op America CONTRIBUTORS TO VOLUME III Graham Lusk, PIlD., Sc.D., F.R.S.E. PROFESSOR OF PHYSIOLOGY, CORNELL UNIVERSITY MEDICAL COLLEGE, SCIENTIFIC DIRECTOR RUSSELL SAGE INSTITUTE OF PATHOLOGY. A. I. Ringer, M.D. ASSOCIATE PHYSICIAN, MONTEFIORE HOSPITAL. NEW YORK: CONSULTING PHYSICIAN, DIS- EASES OF METABOLISM, LENOX HILL HOSPITAL. NEW YORK CITY; FORMERLY ASSISTANT PROFESSOR OF PHYSIOLOGICAL CHEMISTRY, UNIVERSITY OF PENNSYLVANIA; LECTURER IN PHYSIOLOGY AT CORNELL UNIVERSITY MEDICAL COLLEGE: PROFESSOR OF CLINICAL MEDICINE (DISE.VSES OF METABOLISM >, FORDHA^I UNIVERSITY SCHOOL OF MEDICINE. Walter Jones, Ph.D. PROFESSOR OF PHYSIOLOGICAL CHEillSTRY IN THE JOHNS HOPKINS MEDICAL SCHOOL; MEMBER OF THE J^ATIONAL ACADEMY OF SCIENCES. Louis Bauman, M.D. ASSOCIATE IN MEDICINE, COLUMBIA UNIVERSITY; ASSISTANT VISITING PHYSICIAN, PRES- BYTERIAN HOSPITAL, NTSW YOB«C. Walter R. Bloor, M.A., A.M., Ph.D. ASSISTANT IN BIOLOGICAL CHEMISTRY, HARVARD MEDICAL SCHOOL, 1008-1910; ASSOCIATE IN BIOLOGICAL CHEMISTRY, WASHINGTON UNIVERSITY, MEDICAL SCHOOL ( ST. LOUIS), 1910-1914; ASSISTANT PROFESSOR OF BIOLOGICAL CHEMISTRY, HARVARD MEDICAL SCHOOL, 1914-1918; PROFESSOR of biochemistry and HEAD OF THE DEPARTMENT OF BIOCHEMISTRY AND PHARMACOLOGY, UNIVERSITY OF CALIFORNIA, 1918-. Emil J. Baumann, B.S., Ph.D. IN CHARGE OF DmSION OF CHEMISTRY AND LABORATORY OF THE MONTEFIORE HOSPITAL; FORMERLY LECTURER IN BIOCHEMISTRY. U^^^TRSITY OF TORONTO. Philip B. Hawk, M.S., Ph.D. PROFESSOR OF PHYSIOLOGICAL CHE3IISTRY AND TOXICOLOGY, JEFFERSON MEDICAL COLLEGE AND PHYSIOLOGICAL CHEMIST TO JEFFERSON HOSPITAL. Harold L. Higgins, A.B., M.D. ASSISTANT PROFESSOR OF PEDIATRICS, UNIVERSITY OF CINCINNATI; ATfENDINO PEDIATRI- CIAN OF THE CINCINNATI GENERAL HOSPITAL. HI /25-S3 iv CONTRIBUTORS TO VOLUME III Henry A, Mattill, A.M., Ph.D. JUNIOR PROFKSSOR OF BIOCflFMISTI^Y, UiMVERSlTY OF KOCHESTKH, ROCHESTER, X. Y. ; PRO- FESSOR OF PHYSIOLOGY AND PHYSIOLOGICAL CHEMISTRY, UNIVERSITY OF UTAH, SALT LAKE CITY, UTAH, 1910-1915; ASSISTANT PROFESSOR OF NUTRITION, UNIVERSITY OF CALIFORNIA, 1915-1917. Helen Isham Matill, Ph.D. FORMFIBLY ASSOCIATE IN CHEMISTRY. UNIVERSITY OF ILLINOIS. Carl Voegtlin, M.D. PROFESSOR OF PHARMACOLOGY AND CHIEF OF DIVISION OF PHARMACOLOGY, HYGIENIC LABORATORY, U. S. PUBLIC HEALTH SERnCE, WASHINGTON, D. C. Isidor Greenwald, Ph.D. CHEMIST, HABRIMAN RESEARCH LABORATORY, ROOSEVELT HOSPITAL. Victor Caryl Myers, B.A., M.A., Ph.D. PROFESSOR OF PATHOLOGICAL CHEMISTRY, NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL; PATHOLOGICAL CHEillST TO THE POST-GRADUATE HOSPITAL. John R. Murlin, Ph.D., Sc.D, PROFESSOR OF PHYSIOLOGY AND DIRECTOR OF DEPARTMENT OF VIT^VL ECONOMICS, UNIVER- SITY OF ROCHESTER, ROCHESTER, N. Y.; CHAIRMAN, COMillTTEE ON FOOD AND NUTRITION, NATIONAL RESEARCH COUNCIL. Arthur Isaac Kendall, B.S., Ph.D., Dr.P.H. PROFESSOR OF BACTERIOLOGY, NORTH W?:STERN UNIVERSITY MEDIC^VL SCHOOL; DIRECTOR OF THE PATTEN RESEARCH FOUNDATION. Henry G. Barbour, A.B., M.D. PROFESSOR OF PHARMACOLOGY, MC GILL UNIVERSITY, MONTREAL. Arlie Vernon Bock, M.D. » ASSISTANT IN MEDICINE, HARVARD UNIVERSITY ; ASSISTANT IN MEDICINE, MASSACHUSETTS GENERAL HOSPITAL; ASSISTANT VISITING PHYSICIAN, COLLIS P. HUNTINGTON MEMORIAL HOSPITAL OF HARVARD UNIVERSITY. Herbert S. Carter, A.M., M.D. ASSISTANT PROFESSOR OF MEDICINE, COLUMBIA UNIVERSITY, NEW YORK; ASSOCIATE AT- TENDING PHYSICIAN TO THE PRESRYTEUIAX HOSPITAL, NEW YORK; CONSULTING PHYSICIAN TO THE LINCOLN HOSPITAL, NEW YORK. CONTRIBUTORS TO VOLUME III v George R. Minot, M.D. ASSISTANT PROFESSOR OF MKDrcINE, HARVARD UNIVERSITY; ASSOCIATE IX MEDICl^'E, MASSACHUSETTS CENER.\L HOSPITAL; PHYSICIAN TO THE COLLIS P. HUNTINGTON MEMO- RIAL HOSPITAL OF HARVARD UNIVERSITY. Thomas Ordway, A.B., A.M., M.D., Sc.D. DEAN AND ASSOCIATE PROl'ESSOR OF MEDICINE, ALBANY MEDICAL COLLEGE; ATTENDING PHYSICIAN, ALBANY HOSPITAL. Arthur Knud;'on, A.B., Ph.D. PROFESSOR OF BIOLOGICAL CHEMISTRY, ALBANY MEDICAL COLLEGE; ACTENDINO BIOLOGICAL CHEMIST, ALBANY HOSPIT^VL. E. C. Schneider, B.S., Ph.D., Sc.D. PROFESSOR OF BIOLOGY, WESLEYAN UNIVERSITY, MIDDLETOWN, CONNECTICUT, AXD DIRECTOK OF THE DEPARTMENT OF PHYSIOLOGY AT THE AIR SERVICE MEDICAL RESEARCH LABORATORY, MITCHEL FIELD, GARDEN CITY, NEW YORK; MEMBER OF THE ANGLO-AMERICAN PIKE'S PEAK EXPEDITION IN 1911 AND OTHER ALPINE PHYSIOLOGICAL EXPEDITIONS TO PIKE*S PEAK. Digitized by the Internet Archive in 2007 with funding from IVIicrosoft Corporation http://www.archive.org/details/endocrinologymet03barl91) recognized the analogy between the produc- tion of heat without Hame, botli in tlie l)ody and chemically outside the body, as had Aristotle and Galen l>efore him. He imagined the existence of a spirit, t h e Archa'us, which lived in the stomach and which there di- vided the foods into the good and the bad, the former being used by the body and the latter being eliminated in the excreta as evil and poisonous. Sanctorius (1561-1636), a professor of Padua, published in 1614 his celebrated '*De medi- cina statica aphorisrai," which was printed in Venice. Sanc- torius kept careful account of his body weight, noted also the weight of food and drink taken and of urine and excrement passed. He was thus able to discover that the major evacua- tion from the body was the '^insensible perspiration." He determined the considerable loss in body weight during periods in which no urine or feces were passed from the body. Section III of the Aphorisms treats "of Meats and Drink'' and contains the following quaint allusions, as rendered in a translation by John Quincy, published in London in 1712 and printed for William Newton in Little Britain. LXXV. "The Physician who has the Care of the Health of Princes and and knows not what they daily perspire, deceives them and will never be able to cure them except by Accident." LXXVI. "In the first four Hours after Eating a great many perspire a Pound or near; and after that to the ninth two Pound; and from the ninth to the sixteenth scarce a Pound." Fig. 1. Frontispiece of "De medicina statica aphorismi," showing Sanctorius seated on a cliair suspended from a large steelyard. 8 GKAHAM LUSK VIII. "Mutton easily digests and perspires; or it will waste in a niglit a third part of a Pound more than any other usual Food." XXIIT. "Pork and Mushrooms are bad both because they do not Perspire themselves and because they hinder the Perspiration of other things eat along with them." LIX. ''If a Supper of eight Pounds corrupts in the Stomach, the next Day the Body will be lighter than after a Supper of three Pound which does not do so." These aphorisms summarized signify that a well appreciated meat, such as mutton, increases the perspiration, whereas pork, which very likely then as now was an unpopular food in Italy, causes "corruption" and diarrhea and hence no increase in perspiration. This kind of investigation was continued by Dodart (died 1707) in France, who devoted thirty-three years of exhaustive labor to the subject. Then followed the first discovel*y of carbonic acid gas by Van Hel- mont in the seventeenth century. Van Helmont (1577-1644), a member of the ancient princely family of the Counts of Merode of Belgium, was one who consecrated his life to his laboratory. He discovered that when charcoal burned or wine fermented a gas w^as produced which was as invisible as respired air; that it is sometimes emitted from the bowels of the earth, in mines or at the Grotto del Carno (near Naples — so called because if a man enters it accompanied by a dog, the man lives but the dog dies, since carbon dioxid gas evolved is heavier than air and remains near the ground) ; that it is present in the waters of Spa and is evolved when vinegar is poured on chalk. This gaz sylvestre ("wood gas") does not maintain a flame nof life of animals. It promptly results in their asphyxiation and death. Jean Rey, bom about the end of the sixteenth century, died 1645, a physician of Perigord, found in 1630 that tin and lead increased in weight when calcined, but the significance of these facts was neglected in the subsequent enthusiasm over phlogiston. Key's work, ^^Essays sur la recherche de la cause pour laquelle Testain et le plomb augmentent de poids quand on les calcine," 1630, w^as reprinted after Lavoisier's dis- coveries in 1777. Nicholas Lefevre (died 1674), in his "Traite de Chimie," published about 1660, says, ''In the act of respiration the air does not confine itself to refreshing the lungs, but by means of the 'universal spirit' it reacts upon the blood, refining it and volatilizing all its superfluities." A hundred years later Haller had about the same viewpoint. Lefevre was. one of the founders of the Academie des Sciences and was physician- in-chief to Louis XIY. Eobert Boyle (1621-1679) in 1660 showed that the flame of a candle or the life of an animal was extinguished after placing them in an air pump. Between 1668 and 1678 he made numerous experiments with A IITSTORY OF METABOLISM 9 many animals of different species with a view of isolating that part of the air which was "eminently respirahle." Thus he suggests in a suh- division entitled "Of Air in Reference to Fire and Flame" in his work on "The General History of the Air" (1680) the following experiments: Tho hurning of candles under a glass hell. The burning of spirits of wine under a glass hell. The keeping of animals in the same instrument whilst the flame is burning. In the "Sceptical Chemist," which appeared in 1661, Boyle thus voices his opinions: Now a man need not be very conversant in the writings of chemists to ob- serve in how lax, indefinite and almost arbitrary senses they employ the terms salt, sulphur and mercury. . . . But I will not here enlarge upon this subject nor yet will I trouble you with what I have largely discoursed in the "Sceptical Chemist," to call in ques- tion the grounds on which chemists assert that all mixed bodies are compounded of salt, sulphur and mercury. Boyle lived in the period of the birth of national scientific societies. .The Academic des Sciences was founded in Paris by Louis XIV, who, after the peace of the Pyrenees in the fullness of his power, felt that his kingdom needed nothing further than to he fortified by science, industry and art, and he instructed his minister Colbert to carry out his desires. The members were given stipends from the state. This was the first example of state endowTuent of science. About the same time the Royal Society of London was established in England, which was the outgrowth of a gathering of men at first held surreptitiously. This older organiza- tion, of which Boyle was a member, is still perpetuated as the Royal Society Club. Among those influenced by Boyle was one J'ohn Mayow. John Mayow (1640-1679), "descended from a genteel family of his name living at Bree in Cornwall, was born in the parish of St. Dunstan- in-the-West, in Fleet Street, London, admitted as a scholar of Wadham College the 23rd of September, 1659, aged sixteen years," (Beddoes). Ilis scientific work was accomplished at All SouTs, Oxford. Some of his ex- periments may be thus recounted : Camphor placed in a capacious glass vessel inverted over water is ignited by a burning glass. After cooling, the air is reduced one-thirtieth in bulk. A second piece of camphor will not burn, "a clear proof that the combustion has deprived the air of its fire-air particles so as to have rendered it altogether unfit to support flame." ^ A mouse was put into a wire trap and this was placed on a three- legged stool which stood in water and the whole was covered with a bell jar. The volume of the air diminished one-fourteenth. 10 GRAHAM LUSK If a burning candle and an animal be put together in a bell jar both will go out sooner than one alone because flame is extinguished and an animal expires for want of nitro-aerial particles. "Air loses scmewhat of its elastic force during its respiration by ani- mals, as also in combustion. One nuist believe that animals, like fire, re- move from air particles of the same nature." And in another place he writes, "Breathing brings the air into contact with the blood to which it gives up its nitro-aerial constituent. Again the motion (of the muscles) results from the chemical action in the muscle with the combustible matter contained therein." Xiter contains the nitro-aerial particles and hence gim powder burns ^^ithout air. Many authoi-s have written "as if it had been ordained that niter should make as much noise in philosophy as in war, yet its properties are still concealed from our knowledg^e." Calcined antimony mixed with niter, when acted on by heat from a burning glass, increases in weight through addition of nitro-aerial par- ticles. As to Mayow^s death, at the age of thirty-nine it was written : "He paid his last debt to nature in an apothecary^s house bearing the sign of the Anchor in York Street near Covent-Garden, within the liberty of Westminster (having been married a little before not alto- gether to his content), in the month of September, 1670, and was buried in the Church of St. Paul, Covent-Garden." Beddoes, his biogi-apher, writes: "Mayow . . . silently and unper- ceived in the obscurity of the last century discovered if not the whole sum and substance, yet certainly many of those splendid truths which adorn the writings of Priestley, Scheele, Lavoisier, Crawford, Goodwyn and other philosophers of this day." "Should I ask you who of all your acquaintance is the person least likely to be overtaken by surprise you would, T think, name a certain Xorthern Professor. . . . Yet at the sight of the annexed representation of Mayow's pneumatic apparatus, this sedate philosopher lifted up his hands in compleat astonishment" The "sedate philosopher" was undoubtedly Black. Writing in 1790, however, Beddoes cannot escape from the absurd statement, "He (Mayow) has clearly presented the notion of phlogiston which rendered the name of Stahl so celebrated." Mayow's "Treatise on Respiration" was published in hi» twenty-eighth year. INewton invented the calculus when twenty years old; Black found "fixed air^' at twenty-four; li. ^[ayer formulated the Law of the Con- servation of Energy at twenty-six. flayer's paper containing the last-named doctrine was refused pul> lication in Liebig's AnnaJcn! These facts shonhl afFord a stimulus to the youn1>) in 1754 puhlished a Latin essay which, in its English form, is entitled ^'Experiments on ^lagnesia Alba, Quicklime and other Alkaline Substances." In this Black describes the discoverv of ^'fixed air'' or carbonic acid. Black writes of himself as follows: In the early days of my chymioal studies the author whose works made the most agreeable impression on my mind was Markgraaf (1709-1782) of Berlin; he contrived and executed his experiments with so nnich chymical skill that they were uncommonly instructive and satisfactory; and he described them with so much modesty and simplicity, avoiding entirely the parade of erudition and self-importance, with which many other authors encumber their works, that I was quite charmed with Markgraaf and said to Dr. Culleii that I would gather be the author of Markgraaf s Essays than of all the chymical works in the library. The celebrated ReaumuFs method of writing appeared to me also uncommonly pleasing. After three years spent with Dr. Cullen I came to Edinburgh to finish my education in medicine. Here I attended the lectures of Dr. ^Monroe, senior, and the other medical professors until the sununer of 1754 when I received the degree of Doctor of Medicine and printed my inaugural dissertation, "De Humore Acido a Cibis Orto, ct Magnesia Alba." Black finds that the carbonates yield "fixed air" on ignition and that caustic alkalis absorb the same air. Magnesia alba loses half its weight when heated and gives oif "fixed air" when treated with acids. Lime water does not combine with ordinary air but does combine with "fixed air." Black describes the new found kind of air as one "which is dis- persed through the atmosphere either in the state of a very subtle powder, or more probably in that of an elastic fluid. To this I have given the name of fixed air, and perhaps very improperly; but I thought it better to use a word already familiar in philosophy than to invent a new name, before we are. There fully acquainted with the nature and properties of this substance." This was the pioneer discovery in the field long known as pneumatic chemistry. "Fixed air" was produced in fermentation, in the cordbus- tion of carbon, and was eliminated in the respiration. The next gas to be discovered w^as hydrogen. Cavendish (1731-1810) was a nephew of the third Duke of Devon- shire. He was a man of wealth and of extremely eccentric character. It was he who discovered hydrogen in 1766 and gave it the name of "in- flammable air." He considered hydrogen to be phlogiston. Later, in 1781, he found that when two volumes of "inflammable air" and one volume of Priestley's "dephlogisticated air" (oxygen) were united by an electric spark the airs disappeared and water resulted. Cavendish con- cluded that dephlogisticated air was water deprived of its phlogiston. The French have ahvavs claimed that Lavoisier was the first to dis- 10 GRAHAM LUSK cover the composition of water. A discussion of the Water Controversy is given by Thorpe. DankS Eutherford (1749-1819) was a pupil of Black's and tlie uncle of Sir Walter Scott. Kuthorford in 1772 described ^^a residual air/' or nitrogen gais, as it is now called. He f(jund that when a candle burned in an inchj«ed i)lace until it went out and the ^'fixed air" was then ab- sorhed by ;i^kali, there remained a huge volume of air which extinguished life and iiame in an instant. Priestley (1733-1804) in 1771, a year before Ruther- ford's discovery of nitrogen, introduced a growing sprig of mint into an atmosphere in which a candle had burned out and after a lapse of several days found that another candle burned in it perfectly. Evi- dently the burning candle filled the space with phlogiston; the growing plant absorbed the phlo- giston and produced ^'dephlo- gisticated air." This could again receive phlogiston when the second candle burned. Shortly after this discovery (1774) Priestley submitted red oxid of mercury to the heat of a burning glass and foimd that an air was evolved in which a candle burned very vigorously. Priestley assumed that this air w^as pure dephlogisticated air, while com- mon air was only pai-tly dephlogisticated. And Priestley writes, *']My reader will not wonder that, after having ascertained the superior goodness of dephlogisticated air by mice living in it and the other tests above mentioned, I should have the curiosity to taste it myself. I have gratified that curiosity by breathing it, drawing it through a glass siphon, and by this means 1 retluced a large jar full of it to the standard of connnon air. The feeling of it to my lungs was not sensibly difierent from that of common air; but I fancied that my breath felt j>ecnliarly light and easy for some time afterward. Who can tell but that in time this pure air may become a fashionable article in luxury? Hitherto only two mice and myself have had the privilege of breathing' it." Priestley explained the presence of Black's "fixed air" in the ex- Fig. 2. Pri«!«tNy. From an engraving of a portrait by Gilbert Stuart. • A HISTORY OF METABOLISM ' - 17 pired air thus : "It will follow that in the precipitation of lime bj breath- ing into lime water the fixed air which incorporates with lime comes not from the lungs but from the common air, decomposed by the phlogiston exhaled from them.'' And Priestley, who was one of the discoverers of oxygen, was gathered to his fathers at Northumberland, Pennsylvania, in 1804, still believing the phlogiston theory of combustion. Crawford (1748-1795) was the first individual to publish experiments on animal calorimetry. In 1777 he found, after burning wax and carbon or on leaving a live giiinea-pig in his water calorimeter, that for evei-y 100 oz. of oxygen used the water was raised the following number of degrees Fahrenheit: Wax 2.1 Carbon 1.03 Guinea-pig 1.73 Crawford states, "Animal heat seems to depend upon a process similar to a chemical elective attraction." However, the theory of phlogiston renders Crawford's work quite unintelligible and in the second edition of his "Experiments and Observations — Animal Heat," published in 17SS, one still finds statements like this, "Now it has been proved that when an animal is surrounded by a medium at a low temperature it phlogisti- cates a greater quantity of air in a given time than when it is surro^^ a.ded by a warm medium." Scheele (1742-1786). — Independent of Priestley and before him, Scheele, a Swedish apothecary and eminent chemist, discovered oxygen by decomposing dioxid of manganese and other substances. Scheele be- lieved that the atmosphere was composed of "spoiled air" and "fire air." AYhen a body burned in air it lost its phlogiston, which united with "fire air." Heat consisted of "fire air" united with phlogiston. It passed through glass. In this way a portion of air could pass through glass. In 1771 Scheele (Scheele, 1793) had found that when silver carbonate was heated in a retort, "fixed air" was liberated as well as "fire air," while a residue of metallic silver remained. In 1775 he placed silver carbonate in a small retort connected with a collapsed bladder and then heated the substance. Two airs were evolved, **fixed air" which he re- moved with lime water, and "fire air" in which a flame burned brightly. In the interim between these two experiments he wrote Lavoisier in Paris a letter dated September 30, 1774, asking him to use his powei-ful burning glass upon silver carbonate, then to absorb the "fixed air" in lime water and observe whether a candle would burn and an animal live in the remaining air, and he beggeil Lavoisier to infonn him of the results. Scheele performed another striking experiment (Scheele, 1777). He placed two large bees together with a little honey in a small up^wr chamber 18 GUAIiA.M LI'SK Fig. 3. Scheele's apparatus showing bees in the upper chamber oi a glass apparatus filled with oxvgen. of a glass apparatus which he had devised. This upper chamber was in communication with a glass cylinder. The glass cylinder he filled with "fire air" and immersed its lower end in lime water. The volume of the air Vvithin the receptacle diminished day by day and the lime water whicli absorbed the carbonic acid rose in the tube. After eight days the bees were both dead and the lime water almost completely filled the space. It is evident that Scheele had intro- ^ duced bees into pure or nearly pure oxygen gas and that the carbon dioxid whicli they produced had been completely absorbed by the lime water. Scheele made no direct comment upon this truly beautiful experiment but in the general criticism of several experiments one may read the following hazy general- ization : Why do not the blood and lungs change "fire air" into "acid air"? I take the liberty to express my opinion concerning this, for what would such exacting experiments profit unless through them I had the hope to more nearly approach my ultimate aim, the truth. Phlogiston, which combines with most sub- stances causing them to become more fluid, more mobile and more elastic, must have the same influence, upon the blood. The blood corpuscles must absorb it from the air through delicate openings in the lungs. Through this combination they are expanded and in consequence become more fluid. In some part of the circulation they must give oflf this absorbed phlogiston and consequently be able to again absorb this fine principle when they next" reach the lungs. Whither the phlogiston goes during the circu- lation I will leave to others to find out. The affinity of blood for phlogiston caimot be as great as in the instance of plants and insects which take it from the air and ah?rr-the^ood cannet-convert it into "acid air," but it is changed into a kind of air which is midway between "fire air" and "acid air'*; it is "spoiled air." For it does not unite with lime water or water as does "fire air," though it extinguishes fire as does "acid air." Scheele's ""spoiled air" was nitrogen. The poor struggling apothecary who had made so many careful and accurate experiments and who was one of the greatest chemists of his time, was unable to interpret his results without adherence to the dominant fetisli of phlogiston. We have here the picture of two earnest men, Priestley and Scheele, both absorbingly interested in chemistry, both contributing important knowledge and ranking among the gi-eatest scientists of their day, and yet neither had the philosophical acumen to understand the meaning ol" his experiments. Priestley was a Dissenting cloi-gyman, earning his living by preaching, but in his old age his house was burned by Loyalists and he ■ } ■ ■ ^ ^ ; / A HISTORY OF METABOLTS]\[ 19 shprtly afterward fled to America. Scheele, though honored by scientific 'i men the workl over, remained a poor apothecary to the end of his days. , In the current parlance of to-day these two p:reat contributors to human knowledge would undoubtedly have been known outside their own circles as ^'narrow-minded scientists." This, however, could never have been said of Lavoisier, who repeated and extended their experiments, overthrew the phlosriston theory and established modern chemistry. Lavoisier (1743-1794). — The family of Antoine Laurent Lavoisier traced its ancestry back seven generations to Antoine Lavoisier, who was a post-boy* in the stables of the king and who died in 1620. Successive generations raised the position of the family name to ever higher levels until it was said of the great Lavoisier that it would require perhaps a hundred years for the appearance of his equal. Xative intelligence, a fine education, great wealth, combined wath the environment of the searchingly critical atmosphere of the Paris of his day, allowed of the vivid inspiration which filled his life. Lavoisier was elected a member of the Academie des Sciences in 17G8 at the age of twenty-four. About the same time, desirous of promoting his personal fortune, he became associated with Ja ferme generale, through whose activities the taxes were collected in France. Some of his fellow academicians looked askance at this undertaking, but the mathematician Fontaine is reported to have remarked, "Never mind, he. will be able to give us better dinners." (Grimaux, (A;) 1896.) In. the ferme gene rale the young man was the subordinate of one Paulze, a nephew of the then all-powerful Terray, Minister of State and Controller of Finance. At the age of twenty-eight Lavoisier married the fourteen-year-old daughter of Paulze. His own position and his marriage brought him gTeat wealth but in no way diminished his tireless activity. He congratulated himself that his patronage of the instrument makers of Paris had rendered France independent of Great Britain in the manu- facture of scientific instruments. Lavoisier's first paper before the Academie was "On the Nature of Water and on Those Experiments Which Pretend to Prove Its Trans- formation Into Earth." In this experiment he placed rain water in a flask and boiled it for 101 days. Mineral matter appeared in the flask but the whole did not change in weight and the mineral material which appeared was shown to be derived from the disintegi*ation of the flask itself, which lost in weight. Lavoisier used an extremely sensitive (fres exact e) balance, made by the official who was charged with the weighing of gold. Hero wo witness the overthrow of a dogma more than two thousand years old, a(»complished by the introduction of the quantitative method into ,• 20 GH.VIIA.\r LFSK chemistrj. One maj recall the words of Lavoisier written in his "Ele- ments of Chemistry" (Kobert Kerr, (m) 17DIJ) : ' As the usefulness and accuracy of chemistry depend entirely upon the de- termination of the weig-hts of the in^rredients and products both before and after experiments, too much precision cannot be employed in this part of the subject and for this purpose we must be provided with good instruments. ... I have three sets (of balances) of different sizes made by M. Fontin with the utmost nicety ; and excepting thase made by Mr. Ilamsden of London I do not think that any compare with them in precision and sensibility. Lavoisier had a bal- ance which could weigh 600 gm. within five mg. and another which was sensitive to within a tenth of a milligram, which were quite up to modem standards of ac- curacy. One may visit the Conservatoire des Arts et Metiers in Paris and see there a notable collection of Lavoisier ^s apparatus. One sees a gasometer for the accu- rate measurement of gases; there is the cele- brated ice calorimeter of Lavoisier and La Place ; there also are barom- eters of finest workman- ship, set in mahogany sup}X)rts decorated with gilded Qlagree work, re- minding one of the choicest furniture. These treasures were placed in the cellar of the Consei-vatoire during the bombardment of Paj-is by the Germans in the late war. Concerning the gasometers, Lavoisier wrote (Lavoisier, (m) 1799) : It becomes expensive because in many experiments, such as the formation of water and of nitric acid, it is absolutely necessary to employ two of the same machines. In the present advanced state of chemistry very expensive and com- plicated instruments are become indispensably necessary for ascertaining the analysis and synthesis of bodies with the requisite precision as to quantity and proportion. Fig. 4. Lavoisier and his wife, of a portrait by David. From an engraving A HISTORY OF METABOLISM It is strange that Lavoisier's insistence upon the use of ac '■ quantitative measurements through the application of which nea lunidred and tiftj years ago he brought about the "Chemical Revoluti. * .sli(nild appear as new truth when enunciated by some of our ultra mode scientists. In the heart of France near Puy-du-Dom, at Chateau de la Carriere, now (nvned by ^Fonsicur de Chazelles, there is a veritable museum of scientific apparatus which fonnerly belonged to Lavoisier (Tiiichot, (s) 1879). There are several thermometers of jn-eat accuracy and a fine , - <^ •* Jf Hi. t .'It linit.u\f II ^*^, J, u t^i Fig. 5. The burning glass of Tnidaine. From "CEuvres de Lavoisier," VoL Jl.r, balance, and there are three large glass globes, one capable of holding 15 liters of air, another 12 liters and a third 7 liters; also many another treasure of great historic value. Lavoisier made his experiments btfore the days when rubber and cork reduced laboratory expenses. His gL^ss tuljes and receptacles were united with finely polished brass joints. "We may imagine this accomplished Frenchman at work in his labora- tory, or his library, or receiving information from visitors to the fashion able and brilliant capital of France. It is related (Thorpe, (r) 1908) that Priestley dined with Lavoisier in Paris in October, 1774, and informed him concerning the production of "pure dephlogisticated air'' from oxid of mercury, and we may also recall that Scheele, on September 30 of the same year, w^rote to Lavoisier, asking him to expose silver carbonate to J- GFLVHAM LUSK ' ^ . Axoat rays of a large burning glass and produce "fixed air'' and "fire air" from them. Ten days after his conversation with Priestley, and again during the month of the following March, Lavoisier went to Montigny to visit his friend Trudaiiie, who was the owner of an immense burning glass 42 ins. in diameter, which had cost 15,000 livres (about $3,000), and lie here repeated Priestley's experiments. In the paper read before the Academic des Sciences at Easter, 1775, Lavoisier (a) stated that he took the red mercury calx and heated it w'ith carbon and obtained "fixed air," and wlien he heated the same without carbon a gas was evolved in which a flame burned with the splendor of phosphorus in air, and that this gas was the "air eminently respirable." The loss in weight of the mercury calx was equal to the weight of the "air eminently respirable" given off. He concluded that "fixed air" was the result of the union of carbon with "air eminently respirable." In a subsequent paper he reported that it was this "air eminently respirable" which was absorbed by phosphorus and siilphur when they burn with the production of phosphoric and sulphuric acids (ft). Having discovered these facts, Lavoisier (c) proceeded to determine the effect of a sparrow upon the content of air in a confined space. In a , brief memoir published in 1777 he enunciated the principles that during respiration it was only "air eminently respirable" (oxygen) which dis- appeared from the atmosphere when an animal was put into a confined space and that this air was supplanted by expired "aeriform calcic acid" (carbon dioxid) ; that when metals were calcined in air oxygen was absorbed until its supply was exhausted; that if after an animal had perished in a confined space and the carbon dioxid in the atmosphere was absorbed by alkali the "foul air" remaining was the same kind of air as that found after metals had been calcined in air in an inclosed space. All the former qualities of this air could be restored by adding to it "air eminently respirable." Three years later Lavoisier and La Place made another step in ad- vance. (Lavoisier and La Place, {n) 1780.) They noticed that a guinea- pig produced 224 grains of carbonic acid in ten hours, and that what would now hx5 called the respiratory quotient was 0.84. Then they put another guinea-pig in their recently constructed ice calorimeter and found that the heat given off by the animal melted 13 oz. of ice in a period of 10 hours. Kext they calculated that if carbon was oxidized so that 224 grains of carbonic acid were produced, 10.4 oz. of ice would have been melted. They realized that in the case of the guinea-pig allowances would have to be made (1) because the legs of the animal became chilled during the experiment; (2) because the water of respiration was added to that of the melted ice; and (3) because the influence of cold increased the heat production of the animal. But they nevertheless stated that "Since w^e have found in the preceding experiments that the two qualities of lieat A IirSTORV OF :METAF>0LISM 23 obtained are nearly the same, we can conclude directly and without hypothesis that the conservation of animal heat in the animal body is due, at least in greater part, to the transformation of ^air pur' (oxygen) into ^air fixe' (carbonic acid) during the process of respiration." Here bo it noted that Lavoisier refers to the conservation of animal heat more than fifty years before the general law of the conservation of energy was enunciated. He also observed that two sparrows produced about the same quantity of carbonic acid in the unit of time as did a guinea-pig. About a year after these experiments (ITSl) Cavendish in England found that when 'inflammable air'' (or hydrogen) and Priestley's "dc- plilogisticate-l air'' were united by an electric spark the airs disappeared and water resulted. It is said that Lavoisier, hearing of these experiments from Blagden, secretary of the Royal Society of London, repeated them. ;he im- ])ortant point is that Lavoisier {d) was the first really to understand the phenomenon. In a memoir presented to the Academie des Sciences in 1783 he stated that water is merely a combination of ^'inflammable air" and oxygen and that any heat or light produced by their union is imponderable. In the same year Lavoisier (e) completely demolished the phlogiston hypothesis and concluded his memoir "Reflections upon Phlogiston" with these w^ords : " My object in preparing this memoir has been to record the new developments of the theory of combustion which I published in 1TT7, to show that the phlogiston of Stalil, which he gratuitously supposed existed in metals, sulphur, phosphorus and all combustible substances, is an imaginary creation. All the phenomena of combustion and calcination are much more readily explained without phlogis- ton than with phlogiston. I understand that my ideas will not be suddenly adopted. The human mind conforms to a certain manner of vision and those who during a portion of their lives comprehend nature from a given point of view have difBculty in acquiring new ideas. In good time the opinions I have set forth will be confirmed or destroyed. In the interim, it is a great satisfaction for me to see that young, unprejudiced minds among those who are commencing to study science, such as mathematicians and physicists who have a new sense of chemical truths, no longer believe in phlogiston as presented by Stahl but regard the whole doctrine as scaffolding which is more embarrassing than it is useful for the continuance of the structure of the science of chemistiy. And the wonder of it all is that the great chemists of his time outside of his own country persisted in their narrow viewpoint. Priestley and Cavendish refused to be converted. Scheele wrote in 1783, ''Is it im- possible to convince Lavoisier that his system will not find universal acceptance? The idea of nitric acid from nitrous air and pure air, of carbonic acid from carbon and ])ure air, of sulphuric acid from sulphur and pure air, of lactic acid from sugar and pure air!! Can one believe such things? Rather will I support the English." 24 GKAHA^E l.USK Only Black, professor of chemistry at Edinburgh and the discoverer of "fixed air/' saw the truth. Lavoisier wrote to Black on Xovemhcr 13, 17C>0, a letter (Richet, (p) 1887) composed six months after the reading of his last memoir to the Academie ^les Sciences, lie concluded the letter with the truest French courtesy: *Mt is only right that you should be the first to be informed of progress in a field which you ojx?ncd and in which we all regard ourselves as your disciples. We do the same kind of experiments and I have the honour to connnunicate to you the results of our recent discoveries. I have the honour to remain, with respectful attachment, etc.'" And to this Black replied in 1701, '^The numerous experiments which you have made on a large scale and which you have so well devised have been persued with so much care and with such scrupulous attention to details that nothing can be more satisfactory than the proofs you have obtained. The system which you have based on the facts is so intimately connected with them, is so simple and so intelligible, that it must become more and more generally approved and adopted by a great number of chemists who have long been accustomed to the old system. . . . Having for thirty years believed and taught the df^ctrine of phlogiston as it was understood before the discovery of your system, I for a long time felt inimical to the new system which represented as absurd that which I had hitherto regarded as sound doctrine, but this enmity which springs only from force of habit has gradually diminished, subdued by the clcarneafs of your proofs and the soundness of your plan." In reading of the overthrow of the old doctrine of the fire principle phlogiston one must feel a throb of the impending horror of the Fi-ench Kevolution when one considers the statements of ^farat written in 3 701. Ararat at one time had declared that a flimie, when placed in a confined vessel, went out because the heat of the flame suddenly expanded the air, causing such a pressure on the flame that it was extinguished. Lavoisier refuted this doctrine. Marat, "L'Ami du People,'^ under the title ''Mod- ern Charlatans,-' published the following: *^Lavoisier, the putative father of all the discoveries that are noised about, having no ideas of his own, snatches at those of others, but having no ability to appreciate them, he quickly abandons them and changes his theories as he doe& his shoes." Certainly words of unqualified, contemporaneous disapproval ! Lavoisier's new system of salts and oxids led him to forecast the discovery of sodium and potassium, for in his "Elements of Chemistry" (Lavoisier, (m) 1700) he wrote, "It is quite possible that all the substances we call earths may be only metallic oxids irreducible by any hitherto known process." A eulogist of Lavoisier has likened this to the vision of Copernicus before Galileo's invention of the telescope. Lavoisier had now progressed so that he was able to lay the funda- mental basis of njodem chemical physiolog;^'. Thus, in 1785, he stated A HISTORY OF METABOLTSllit 25 tliat the discrepancy between the quantity of expired carbonic acid and inspired oxygen, wliich lie had observed in 1780, was accounted for by the fact that a part of the absorbed oxy^^en was utilized to oxidize hydrogen in the hini»s. This oxi(hition woidd produce additional heat and account for the discrepancy between the heat direotly measured from a guinea-pig and the heat calculated as being derivable from the oxidation of carbon by oxygen. It is interesting to recall that eighty years later, in 18G0, Eischoff and Voit still calculated the heat value of the metabolism from the heat which would be produced in burning the carbon and hydrogen dements of the metabolism. Respiration experiments on a human being constituted the final con- tribution in the culmination of this gi-eat career. The w^ork is presented l)y Scguin and Lavoisier (t) in the memoirs of the Academie des Sciences during the year 1780. In this paper the authors remark: ''This analogy between combustion and respiration did not escape the attention of the poets and philosophers of antiquity, of which they were the interpreters and spokesmen. Fire taken from the heavens, this flame of Prometheus, not only represents an idea that is ingenious and poetical but it is a true picture of the operations of nature on behalf of animals who respire; one can say with the ancients that the fire is lighted the moment a baby takes its first respiration and is not extinguished until its death." Before giving the details of the experiments on man the authors state that a guinea-pig respired in pui'e oxygen and in a mixture of oxygen and hydrogen gas just as it did in ordinary air; respiration, circulation and the intensity of combustion were uninfluenced. Nitrogen had nothing to do with respiration. In the experiments on man Segiiin himself was the subject. The results are given in the accompanying table: RESUT.TS OF EXPERIMENTS ON ^VIAN Condition { 1 ) Without food (2) Without food (3) With food (4) Work (n,195 foot pounds) without food.. (.">) Work (9,750 foot pounds) with food Environ- mental Tempera- ture Degrees 26 12 Oxygen Absorbed per Hour Pouces 1210 1344 1800-1900 3200 4600 Liters 24 27 38 65 91 Here are the basic facts regarding metabolism. The basal metabolism was increased 10 per cent after exposure to cold ; 50 per cent after taking food; 200 per cent by exercise; and 300 per cent on combining the influ- ences of food and exercise. We now know more details and w^e may also calculate that Lavoisier's determination of 24 liters of oxygen absorbed 26 GRAHAM LFSK per hour in this first historical experiment on the hasal niotaholism was 25 per cent too high. As for tlie experimental plan, it is as moilcrn as the work of to-day, and yet it was executed 140 years ago by the first man who really understood the sigiiiiicanc-e of oxygen. It is only in the last decade that the summation of the individual stimuli caused by food and muscular work and noted by Lavoisier has been verified. Lavoisier (/>) also observed a constant i-elation between the quantity of oxygen consumed and the rate of the pulse multiplied by the number of respirations. How Lavoisier achieved these remarkable results is not known, for the times iu which he lived became too troubled to allow further work in pure science. We find, however, the following statement in the original memoir: ^'It would have been impossible to accomplish these exact experiments upon respiration before the introduction of a simple, easy and rapid method of gas analysis. This service ^l. Segiiin has rendered to chemistry." If, now, one turns to the report of Seguin (Seguin (q), 1791) one finds that he states that in his work with Lavoisier he used eudiometers 8 to 10 inches high and an inch in diameter in order to determine the "vital air" or oxygen in the respired air. The tube was first filled with mercury and inverted over mercur}', a little of the gas to be analyzed was introduced and then a bit of phosphorus, which phosphorus was later ignited by bringing a burning ember in the vicinity of the glass. The rest of the air to be analyzed was gi-adually admitted and when the tube cooled the voliune of the air remaining could be measured. The loss in volume represented the quantity of oxygen absorbed. Carbonic acid could then be absorbed by potash. Seguin stated that the older method, as originally introduced bv Priestley, had twenty sources of error but that his method merited attention on account of the very great exactitude with which he could determine the gases which are contained in respired air. He furthermore truly stated that "if we enter into a room containing a large number of people we immediately smell a strong, suffocating odor, but if we use eudiometers to analyze this foul air and compare it with ordinary atmospheric air we find hardly any difference in the proportions of gases which are contained in them." After Lavoisier's death Madame Lavoisier drew from meniorj^ the apparatus used by her husband. The drawings were retouched by J3avid, Madame Lavoisier's instructor in art. There are two pictures quite dis- similar. Good reproductions are to be found in Grimaux's "Lavoisier." In both pictures Seguin sits naked in a chair, breathing througli a mask into a series of globes or bell jars. In both pictures ^Madame Lavoisier is shown seated at a table, taking notes of the experiment. In both pictures the pulse is being counted. In one experiment a weight is placed on Seguin^s instep. The arrangement of the apparatus is quite different in the two pictures. In the experiment showing Seguin at work it seems as A IIISTOEY OF METABOLISM 27 though valves were indicated through wliich inspired air was received from the atmosphere while the expired air was driven through a tube into a hell jar under water. Nysten (Xysten, (o) 1817), working in Paris in 1811, described the method by which he caused tuberculous and other patients to respire through valves into a previously collapsed bag for half a minute and then analyzed the expired air by a method similar to that of Seguin. These are the knowTi historical facts about the apparatus used in the first respiration experiments on man, but the exact details of the method hv which results were established and which still are the basis of metab- olism studies are unknown. In contemplating his results Lavoisier (/) said: ^'This kind of obser- vation suggests a comparison of forces concerning which no other repoi^t exists. One can learn, for example, how many pounds of weight lifting correspond to the effort of one who reads aloud or of a musician who plays a musical instrument. One might even value in mechanistic terms the work of a philosopher who thinks, the man of letters who writes, the musician who composes. These factors, which have been considered purely moral, have Boraething of the physical and material which this report allows us to compare with the activities of a man who labors with his hands. It is not without justice that the French language has united under the common expression worh the effort of the mind with that of the body, the work at the desk with the work at the shop. . i , Thus far we have considered respiration only as a consumption of air, the same kind for the rich as for the poor, for air belongs equally to all and costs nothing. The laborer who works enjoys indeed in great measure this gift of nature. But now that experiment has taught us that respiration is a true process of combustion which every instant consumes a portion of an individual, that this combustion is greater when the circulation and respiration are accelerated and is augmented in proportion to the activity of the individual life, a host of moral considerations suggest themselves from these determinations of physical science. What fatality ordains that a poor man» who works with his arms and who is forced to employ for his subsistence all the power given him by nature, con- sumes more of himself than does an idler, while the latter has less need of repair? Why the shocking contrast of a rich man enjoying in abundance that which is not physically necessary for him and which is apparently destined for the laboring man? Let us take care, however, not to calumniate nature and accuse her of faults undoubtedly a part of our social institutions and perhaps inseparable from them. Let us be content to bless the philosophy and humanity which unite to promote wise institutions which tend to bring about equality of fortune, to increase the price of labor, to assure to it just recompense, to offer to all classes of society and especially to the poor more pleasures and greater happiness. Let us trust, however, that the enthusiasm and exaggeration which so readily seize men united in large assemblies, that the human passions which sway the multitude, often against their own interest, and sweep the sage and the philosopher like other men into their whirlpool, do not reverse an outlook with such beautiful vistas and do not destroy the hope of the country. ... 28 GRAHA;]^! LITSK We end this memoir with a consoling reflection. To merit well of liumanity and to pay tribute to one's country it is not necessary to take part in brilliant public functions that have to do with the organization and rej-Tcneration of em- pires. The naturalist may also perform patriotic functions in the silence of his laboratory and at his desk; he can hope through his labors to diminish the mass of ills which afflict the human race or to increase its happiness and pleasure; and should he by some new methods which he has opened up prolong the average life of men by years or even by days he can also aspire to the glorious title of bene- factor of humanity. These are words written by the greatest scientist of his day under the spell of the French Revolution. They are words of an educated, culti- vated man of middle age spoken in the Academic des Sciences in the year of the fall of the Bastile and at a time when Edmund Burke from the other side of the Channel said. '*In the groves of their Academy at the end of every vista you see nothing but the gallows." Lavoisier and Franklin had been intimate friends, living near each other in Paris and Franklin dining frequently with the great French chemist and his wife. In a letter written to Franklin, then in America, on February 5, 1790, during the early days of the French Revolution, Lavoisier says: "After having recited what has transpired in chemistry it is well to speak of our political revolution. We regard it as accom- plished, well accomplished and beyond recall. There still exists, howeverj an aristocratic party which is making vain efforts but is evidently feeble. . . . We greatly regi-et at this moment your absence from France. You could be our guide and mark the limits beyond which we ought not to pass." . And in 1790 Lavoisier (g) concluded his last scientific communication to the xVcademie with these words. "Up to the present time we have learned only to conjecture as to the cause of a great number of diseases and as to the means of their cure. Before hazarding a theory we propose to multiply our observations, to investigate the phenomena of digestion and to analyze the blood both in health and in disease. We will draw ujwn medical records and the light and experience of learned physicians who are our contemporaries and it will be only when we are thus completely ai'med that we will dare to attack a revered and antique colossus of pi'ejudice and of error." No person of understanding can escape a thrill at this vision of modern medicine expressed by him who had overthrown phlogiston, discovered the composition of the air and its relation to combustion and to life, wl)o had created calorlmetry and revolutionized the whole of chemical thought. True to his enthusiasm we find him drawing up the conditions for an international prize of 5,000 livres offered by tlie Academic des Sciences in 1792 to the author of the best experimental treatise on the livei" and the bile (t). Lavoisier's life outside his laboratory had been that of a public A HISTORY OF METABOLISM 29 official, a tax gatherer, and lie had also been associated with the national iiiaiiufactiu'o of iiunpowder, the finality of which he had greatly improved. He piuchased a large landed estate and made experiments in scientific agricnltiiro, doubling the wheat crop, (piintupting the number of beasts en the land anxl earning thereby the enduring gratitude of the peasants. However, as before remarked, he liad ineurj-ed the bitter hatred of ^Marat and he was a tax gatherer. In iSTovember, 1703, he was arrested at the Arsenal in his lal)oratory there, npon which he had spent a large portion of his fortune. Just a little while before, in August of the same year, the Acadomie des Sciences had been closed as inimical to the welfare of the state. Les amis du peupJe are notoriously suspicious of the "intelli- genzia,'' and the Academic was abolished. Just prior to his execution Lavoisier wrote to a friend, "I have had a sufficiently long career, always a very happy one, and I believe that my memory will be thought of with some regret and perhaps as having some- thing of glory. What more could I desire? The circumstances which surround me would probably lead to an uncomfortable old age. ... It is certainly true that all the social vii-tues, important services to the country, a useful career employed in promoting ai*t and human knowledge, have not sufficed to save me from a sinister end or to prevent me from perish- ing as a criminal," One of the charges against Lavoisier was that he had allowed tho collection of taxes upon the water contained in tobacco. On May 8, 1794, at the age of fifty years, he was tried and found gliilty. Twenty-eight fenmers-generaux were executed in the Place de la Rcpublique at the same time. He witnessed the execution of his father-in-law, Paulze, who was fourth on the list, and he was the fifth upon whom the ax of the guillotine fell. Such was the Terror. His friend Lagi*ange whispered that night to an intimate, "It took but an instant to cut off his head ; a hundred years will, not suffice to produce one like it!'' Writing a hundred years later, Berthelot (y) (1890) exclaimed, "It is our right to admire the positive work which he accomplished. The uni- versal jiulgment of the civilized world increasingly reveres his establish- ment of chemistry, one of the fundamental sciences, upon a fixed and definite basis. There is no gi-ander accomplishment in the history of civilization and hence the name of Lavoisier will live forever in the memory of humanity." It is interesting to consider the difl^erences in the lives of the men concerned in the great discoveries of the last quarter of the eighteenth century. Priestley, an indigent clergyman ; Cavendish, of whom it was said that he was the most wealthy of learned men and the most learned of the wealthy ; Scheele, a poor Swedish apothecary ; and Lavoisier, a man of 30 graha:m lusk affairs, a noble of high social jxisitioii, in receipt of huge pergonal i-cvennes. What is it, then, that makes for greatness in science ? Would l^avoisier have accomplished more had lie been on a "full-time'^ basis willi a restricted income ? It is a question of individual opinion, but to most people it would appear that scicnlilic greatness depends primarily upon the quality of the intellectual piotoplasm of the brain, npon the advantages offered to the functioning of that brain l\v a favoring mental environment, and on the }X)Ssession of a good conscience. Olio may well understand that the clarification of the work of Black, Rutherford, Cavendish, Priestley and Scheele by the brilliant mind of Lavoisier might lead others than they to tlie expression of national scientific self-consciousness. Thus, \Vurtz*s ''Histoirc des doctrines chimiques," published in Paris in 18G1, begins with the proud statement, "La chimie est une science fran^aise; elle fut constituee par Lavoisier." It is needless to state that this caused reverberations of disapproval from England. The personal opinion of national worth finds still more intense modern expression in the Manifesto of the Intellectuals (1915), ^^Thc German Mind is, in our opinion, beyond all doubt our one supremely valuable- asset. It is the one priceless }X)Ssession amongst all our posses- sions. It alone justifies our people's existence and their impulse to main- tain and assert themselves in the world; and to it they owe their supei-iority over all other peoples.'' A historic case in which a generous attitude was taken occurred Avhen the French Academy in 1806, just prior to a declaration of war between France and ITngland, conferred its newly established Volta medal upon Humphrey Davy. A French delegation went to London to deliver the medal while the war was in progTess and Davy, in acknowledging it, said, "Science knows no country. If the two countries or governments are at war, the men of science are not. That would, indeed, be a civil war of the worst description. We should rather through the instrumentality of men of science soften the asperities of national hostility." Perhaps this "old-fashioned'' courtesy was a relic of the days of a bygone chivalry. At any rate, it affords a delightful example of human behavior. Science after the French Revolution Kapoleon, during the winter of 1707-1 703, attended the regular course of chemical lectures delivered by Berthollet, who had been an associate of Lavoisier. At a later date Berthollet and Monge, the mathematician, organized a company of one hundred scientists to accompany JSTapoleon to Egypt. At least the scientific men of France had no cause to complain of lack of recognition. And perhaps partly in consequence of this one finds living in Paris in 1823, the year Liebig studied there, such men as La A HISTORY OF 3IETAB0LISM 31 Place, Berthollet, Gay-Liissac, Tlicnard, Ciivier, Ampere, Laennec and. ]\rai^pn(lie. Thori>e writes of them (1D08) : "That constellation has set — 'The world in vain Will hope to look ii],x>n their like again.'" The atmosphere for the development of French science reached at this time a maximum of power to stimulate. One of the few mistakes (;f Lavoisier was his conception that oxidation took place in the lungs. Lagrange, the illustrious mathematician, a friend and associate of La- voisier, reflecting that if the heat production took place in the lungs their temperature must be higher than elsewhere in the body, concluded that heat was generated wherever the blood circulated, that oxygen dissolved in the blood, combined with hydrogen and carbon there, and that carbonic acid was eliminated. This interpretation of Lagi'ange w^as published in 171)1 before Lavoisier's death by Lavoisier's pupil Ilassenfranz (I), who agrees that the caloric necessary to maintain animal heat is liberated in the blood by the combination of carlx)n and hydrogen wath oxygen, with which the blood is mixed. Humphrey Davy (1778-1829) was the first to obtain oxygen from arterial blood by warming it to 93° C. and carbonic acid from the venous blood by warming it to 45° C. He was apparently not well acquainted with Lavoisier's work, and his own work, published in 1799, remained long forgotten. To him oxygen occurred as "pliosoxygcn," a combination of heat and light. In his experiment XVII he shows that "phosoxygen'' can be absorbed by venous blood in the dark without the liberation of light, but with the result that the color of the blood changes from dark red to bright vermilion. Experiment XVIII. — A phial containing- about 12 inches, havinjr a pneumatic apparatus affixed to it, was filled with arterial blood from the carotid arterj' of a calf. The phial was placed in a sand bath at a temperature ol 90" and the heat gradually and slowly raised. In about ten minutes the temperature of the bath was 108° and the blood began to coagulate. At this moment some globules of gas were perceived passing through the tube. Gas continued to pass in very small quantities for about half an hour when the temperature of the sand was about 200° ; the blood had coagu- lated perfectly and was now almost black. About 1.8 cu. in. of gas \vere collected in the mercurial apparatus; of this LI cu. in. were carbonic acid and the re- maining 0.7 phosoxygen. From this experiment it is evident that the arterial blood contains phosoxy- gen, and we have proved before by synthesis that it is capable of combining with it directly. We are possessed of a number of experiments which prove that phosoxj'gon is consumed in respiration. It has been likewise proved that gases can penetrate through moist membranes like those of which the vessels of the lungs arc composed. We may therefore conclude that phosoxygen combines 32 GRAIIA:\[ Ll'SK with the venous blood of the system in the pulmonary vessels. As no light was liberated in Experiment XVII there cannot be even a partial decompo- sition of phosoxygen in respiration, Davy's iiiferpretatioiis are far from clear, as will be seen in the followinc: paragraph: ''Jtespirali»;n ihon is a chemical process, the com- bination of phosoxygen with tlie venous blood of the Inngs and liberation of carbonic acid and acpicous gas from it. From the combination and decomposition ai'ises an i'.icrease of repulsive motion which, combined with that pi'oduced by the other chemical processes taking place in the system and that generated by the reciprocal action of the solids and flnids, is the cause of animal heat; a heat which the other systems have supposed to arise chiefly from the decomposition of phosoxygen (oxygen and caloric)." About the same time that Davy was experimenting in England Spal- lanzani in Italy was inquiring into the validity of Lavoisier's ideas. Spallanzani (1729-1799). — The experiments of Spallanzani were published in 1804 after his death. Ilis biogi-apher states: ^'When the Empress Maria Theresa had reestablished the University of Pavia on a more extensive plan she w^ished to render it at once celebrated by the attainments of its professors; she empowered Count Firmian to invite Spallanzani to give lectures on natural history." Spallanzani says that ox\'gen is transported by the blood to the heart and is necessary for the heart beat, but he is not convinced that oxygen is necessary for the production of carbonic acid. He put snails into two tubes filled, respectively, with atmospheric air and with nitrogen. "On removing them from the tubes at the end of twelve hours I found the animals still alive; I examined the two aerifonn fluids and was astonished to discover that the quantify of carbonic acid gas was gieater in the azotic gas (nitrogen) than in the common air.'' He obtained the same result when he used hydrogen gas and says, *T shall only conclude from these experiments that it is clearly proved that the carbonic acid gas produced by the living and dead snails in common air resulted not from atmospheric oxygen, since an equal or even a greater quantity of it was obtained in azotic and hydrogen gas." This is very nearly the same as Davy's conclusion. Of his method of work Spallanzani says: ''Being engaged in similar experiments, it was natural for me to attend to this part of the subject uninfluenced by the opinion of those celebrated men, in order that I might obsei-ve only nature herself. This is at least the mode T have always pui'sued, when it was possible, with respect to the most universally received opinions, however respectable the quarter whence they proctx'ded; I have always myself examined the facts on which they were built." William F. Edwards (1776-1842) confirmed the work of Spallanzani, finding that frogs when placed in hydrogen gas eliminated in a few houj-s a A HISTORY OF :\rETABOLTSM 33 volume of carl)OTiic noid equal to tlicir own vohuuc and larger ill quantity rhun they would have expired Jiad they hrcatlied in air. lie concluded rhat eiirhon dioxid was not foiined hy oxidation in the lungs but must have 1 ('cn exen^ted from the hhxid, and he supports this conclusion by ritini:- unpuhli8heeriment& hy Vau(pielin in which bh)od was exposed r.. a ]ivdr<»iivii atmo.si)here with the result that carbonic acid was eriven Magnus (1802-1870) repeated the experiments of Vauquelin, shaking ]il.;«)d in hydrogen gas, and he also placed blood in a complete vacuum iiiid n»)ticed the elimination of a great volume of gases. There was more • arlionic acid eliminated than could be accounred for by the bicarbonate ]>re^f'nt. Gay-Lussac (1778-18.50) criticized these results and stated that the .|uanrity of oxygen found in the bh)od was sixteen times larger than could 1 e dissolved by water and that no differences api>eared in the analyses of arterial and venous bloods. ^FagnTis (1845) replied that 100 parts of gas extracted from blood contained: Arterial Blood Venous Blood Carl)onic acid C2.3 71.6 Oxygen 23.2 15.3 Xitrogen 14.5 13.1 100 100 He found also that when blood was pumpeil out it could again al^orb sixteen volumes per cent of oxygen. Berzelius (1779-1848) announced in 1838 that little oxygen could be a<]ded to blood serum freed from corpuscles, but when the serum was mixed with the coloring matter of the blood it was absorbed in large volume. Berzelius attributed the affinity of ^'hematin'- for oxygen to its content '.tf iron. Dumas in 1840 found that on replacing blood serum with a solution "f sudium sulphate the blood corpuscles suspended therein still changed in '•"liir after shaking with oxygen. It was Liebig in 1851 who gave expressit;n to modem thought iijxjn the sulfject of the respiration in saying, "The absorption of a gas by a liquid is due to two causes, an external consisting in the pressure exerted 1 y the gas u|K)n the liquid, and a chemical, an attraction manifested by the f^-onstituent particles of the liquid;" F>»r complete references to this story, consult "Lecons sur la physiolo- liie." by II. .Milne-Edwards, Volume 1, printed in 1857. Tiiese volumes treat the subject of physiology with a thoroughness lately thought to be ♦•xelusivelv German, 34 GKAnA:\[ LUSK The Be^innin^s of Calorimetry The work of Lavoisier concerning the source of animal heat was in- STifficicntly convincing, and so the French Academy of Science offered a pfiw to any one wlio w«.n]d produce the hest tliesis on the subject. Tl)e prize was compered for by Despretz and hy Dulong. It was awarded in 1823 to the former^ although in the light of modern knowledge it would seem that the latter had a greater insight into the problem. Despretz (17U2-1803) gives the following account (1824): "Xo phenomenon in physiology is more capable of attracting attention than the singidar property enjoyed by man and warm-blooded animals of pre- serving an almost constant temperature*, although the tem|>erature with which they are surrounded is subject to continual variations. All bodies tend constantly to seek heat equilibrium; reciprocal exchange tends to establish a uniform temperature between dilferent bodies. *' Warm-blooded animals, en the contrary, though they are e<]ually exjK^sed to heat loss occasioned by contact, radiation and the evaporation of water, possess within themselves a power to produce heat wdiich main- tains their temperature as a rule at about 30° above the melting point of ice.'' The resources of modern science were lacking in the days of Galen, Boerhaave and Ilaller. The author cites Lavoisier (n) (1780) and criti- cizes Crawford's (1779) very imperfect method. He states tbat Brodie (1812 Philosophical Transactions) thought the brain proiluced heat through the nerves, citing the heat loss after decapitation. This was denienl by Le Gallois, who maintained artificial respiration in a decapitated animal. Type of experiment by Despretz: Subjects, three guinea-pigs. Ventilation, 55 to 60 liters per 2 hours, the air being purified by- passing through potash. Condition of the environmental air, 0 j>er cent CO2 and water saturation. Experiment 1 : CO2 formed, 2,587 liters. Oo unaccounted (i. e., not in COg), 0.700 liter. The three animals raised the temperature of 23310.5 g. water 0.03 . Animal beat as measured, 100 per cent. Heat due to formation CO2 60.0 per cent. Heat due to formation water, 19.4 per cent Total heat as calculated, 89.3 per cent. A IIISTOKY OF ]\IETAB0LIS:M 35 The modern calculation would be: 0-2 CO2 E. Q. Calories Calories indirect direct liters liters 3.30 2..>1> 0.78 15.86 14.68 Or 8 j>er cent too much calculated heat instead of 11 per cent too little. The conclusions of Despretz were : 1. That the respiration is the principal cause of the development of animal heat; that assimihition, movement of the blood, friction in different parts, can easily produce the small residual amount. 2. Although oxyoen is employed in forming carbonic acid, a certain quantity, sometimes considerable in amount, disapi>ears; it is generally thought that it is used in the combustion of hydrogen. 3. There is an exhalation of nitrogen in the respiration of both carnivorous and herbivorous animals. The following animals were used: Ducks, chickens, cocks, young and old pigeons, gulls, buzzards, owls, magpies, dogs, cats, rabbits and guinea- pigs. •/'Dulong (1785-1838) presented the second paper in competition for the prize of the Academy, of which a resume follows : The author, who is both physicist and chemist, proposes to determine if the quantity of oxygen intake is sufficient (in health) to repair the heat loss by animals under natural conditions of life; in other words, whether animal heat is entirely due to combustion which takes place within the animal through respiration. He calls attention to the fact that Lavoisier used two different guinea- pigs, one in the calorimeter and another for the determination of the gaseous exchange. He uses the water calorimeter of Rumford, The temperature of the water is the same as that of surrounding air at the start ; at the end, higher. The animals can move at will. Cat, dog, kestrel, capibara (water-hog), rabbit, and pigeon are used. He finds that in the cat, dog and kestrel the volume of oxygen inspired is one-third more than that of the carbonic acid expired, whereas in rabbits, capibara and pigeons the oxygen is only one-tenth more than the carbonic acid. There- fore he thinks this difference is due to food or to a difference of animal organization thrrugh food. He finds that nitrogen is exhaled. The heat from carbonic acid in carnivora is 40 to 55 per cent of the total heat measured; in herbivora, 65 to 75 per cent. Calculated inclusive of the heat produced from the oxidation of hydrogen, it equaled 69 to 80 per cent. The experiments were repeated many times. One source of error in the calculations of Despretz and of Dulong 3G GKAHAAL LUSK lay in the fact that the ealori',' values attributed to the oxidation of carbon and hydro«ion were wronir. Ouo may compare the values used nt different I)eriods as follows : Favre and Lavoisier Despretz Silberuiann 1780 1823 1852-53 calories calories calones yields . . . 22.170 23.G40 34.402 viehJs. . . 7.237 7.014 8.080 1 gnu IT oxidized 1 gm. C oxidized The agreement berweeii Despretz and Dulong that nitrogen was present in the expired air in an amount larger than that inspired Avas accepted for many years ]»y many wTiters. ]\Iagendie, in his ^'Elements of Physiology," in 1830, thus expresses the thoughts of his time: ^"^Accord- ing to the experiments of M. Despretz upon herbivora, the respiration furnishes only 80 per cent of the animal heat, and in carnivora only 80 per cent. Therefore, other sources of animal heat must exist in the economy. It is probable that these occur in the friction of various parts, in the movement of the blood, the friction of the blood corpuscles u}X)n one another and finally in nutritive phenomena. This supposition is not forced, for it is known that most chemical combinations give rise to heat, and it is doubtless true that combinations of this nature take place in the organs, both during secretion and digestion.'^ It is evident that ignorance of the Law of the Conservation of Energy hampered progress at this time. Dumas (1800-1884). — In the year 1823 a paper was published by Prevost and Dumas pjiiiting out the fact that if the kidneys were ex- tirpated in cats and rabbits, urea rose to high concentration in the blood. This experiment proved that urea was not formed in the kidney. Rouelle in 1773 had found urea in the urine. • It was the year 1S23. the year of the publication of the work of Despretz, of Dulong and <'.f Dumas, that Liebig, at the age of twenty, came to Paris to study. This should be remembered as the story of the deveh'pmcnr of the French school is unfolded. The part Liebig played will be tohl later. Diunas was an organic cheinist of high repute. Concerning his influ- ence, the words of Pasteur, spoken in 1882, may be recalled: "^ly dear ^fastei-, it is indeed forty years since I first had the happiness of knowing you and since you first taught me to love science. **I was fresh from the country: after each of your classes I would leave the Sorbonne tran?|X)rted, often niove^l to tears. Fro;n. that moment your talent as a professor, your immortal labors and your noble character have inspired me with an admiration which has gTOwna with the maturity of my mind," A HISTORY OF METABOLISM 37 Dumas came into freqiiciit intellectual conflict with Liebig and Wohler in Germany and Berzeliiis in Sweden. In 1828 Wohler produced uiea synthetically from ammonium cyanaie, delivering the final death Mow to the doctrine that organic compounds arise only through the inter- vention of living things. JVIagendie (178:5-185;-)) was among the first to differentiate between various kinds cf foods. This distinguish**! physiologist fed dogs cane sugar or olive oil or butter and fouuil tlwit death occurred in 31 days ( Magendie, 1830). He rightly coneluilcd that the nitrogien of the organs of the body arose only from the nitrogen «;f tlie food, that the nitrogen-free food-stuffs were not transformable into nitrogen-containing food-stuffs. He rendered great service in i>ointing out the nitrogen content of rice, maize and potatoes, foods upon which jjeoplc live. Magendie also found that dogs fe^l with bread alone lived only a month. The second gelatin commission of tlie French Academy (Magen- die, 1841), sitting in 1811 under the pi-esitlency of Magendie, determined that bread and gelatin given together to eitlker dog or man constituted an insufficient diet. Boussingault (1802-1887). — Organic analysis, which was founded by Lavoisier, was further advanced by Gay-I-ussac and Thenard (1810-15), by Berzelius in 1814, and was perfected l>j Liebig in 1830. This work led to that of Boussingault, who curioii:s!y eiicugh had been previously for several years in the employ of an English mining company in equatorial South America. The experirnents of Boussingault in 1839 may be considered to be [U'ophetic of the future evohition of metabolism studies. Boussingault compares the quantities of carbon, hydiX)g€^n, nitrogen and oxygen in the fodder constituting a maintenance ration of a milch cow, with the quan- tities of the same elements eliminated in the urine, feces and milk. The difference between these quantities wciuhl he available for the respiration. He gives the following account (Boussingault, (h) 1839) : 'Tt is generally recognized to-day that the food of animals must con- rain a certain amount of nitrogen. The j>resence of nitrogen in a larg-o number of vegetable foods forces thr* coHclusion that herbivora receive nitrogen in their food, which enters into tlieir constitution. ^*In ordinary alimentation an individwid does not change his average weight ; this state of affairs exists wlien an animal takes a maintenancG ration {ration d'entretlen).^^ Lender these conditions the food of the animal should be found in his excretions. During gi'owth, or the jnx3cess of fattening the conditions would be different. Cows were given a maintenance ration of known elementary com- position and the elements recovered \n tlie urine, feces and milk were .-subtracted from those in the fodder, with the following results: H 0 N Salts lAiC) 1035 201.5 8S9 M2 20S3 174.5 021 38 GK.VllAxM LUSK C Elements in the fodder 4813 Elements in tlie urine, feces and milk. 20(^3 —2211 —203 —1052 --27 +32 Unitinir the oxyiren of the food with the livdrogen in such a proportion as to form water, there* would remain 10.8 «ni. of hydrogen requiring inspired atmo.-pheric oxyiren for its conversion into water. The loss of carbon equaling 2211 pn., it would require 4052 liters to convert it into 7000 gin. of carbonic acid. A cow would therefore deprive 10 square meters of air of its oxy^rc-n. Boussingault states that one nitrogen determination is not sufficient to decide whether nitrogen as a gas enters into the metabolism of protein. The same kind of work is done with a horse (Boussingault, (a) 1S30). It. is concluded tliat 45S4 liters of oxygen would be required to form, the carbonic acid produced. There were 24 gm. less of nitrogen in the excreta than in the food. It seems clear that atmospheric nitrogen is not assimilable by the body. In a subseqtieiit experiment published in 1843 Boussingault (c) gives food to a turtle-dove and estimates the carbonic acid elimination as he had done with the horse, but he also determines directly the carbonic acid given off. By the first method 0.211 gm. of carbon were estimated to have been expired and by the second method an average of 0.198 gm. were actually found. This closely approaches modern technic. Boussingault and Le Bel (1830) made the first complete analyses of cow's milk. They conclude from their work that the nature of the fodder does not aiTect the quantity or the chemical composition of the milk, provided the cow receives the same relative nutritive equivalents in the fodder. The nutritive equivalents, however, were based on the nitrogen content of the fodders, thu^ 13.5 kg. of hay Avere accounted the nutritive equiva- lents of 54 kg. of beets or 27 kg. of potatoes. It is evident that at this date there was no real understanding of the nature of the different food- stuffs. Barral (I81D-l>iS4) in 1840 applied the principles of Boussingaidt's method to the analysis of the nietal>olism of human beings. He thus presents his problem: ^'Knowing the amount and the eleinentary com- position of the food, both solid and liquid, taken each day, determining the elementary comjx)sition of the excreta and perspiration, one may calculate the gains and losses of the human body.'' His experiment on himself lasted five days, with the following results per day: A HISTORY OF METABOLISM 39 Water Salts CI C H N O Total In the food lOOS.G 31.3 7.8 300.2 57.3 28.0 205.7 2754 9 In the excreta. .. . 1177.8 15.4 5.0 30.5 5.4 13.7 10.0 1204.7 Differences — 820.8 — 15.0 — 2.8 —33.5.7 — 5L0 —14.3 —248.8 —1490 2 248.8 g. O, -f- 31.1 g. IT, = 279.0 g. H,0 20.8 g. Hj -f. 1G0.:J g. inap. 0, = 187.1 g. II^O 335.7 g. G -1- 805.2 g. insp. O, = 1230.9 g. CO, It is evident that 1001 inn. of oxygen would have been inspired and 1231 gin. of carbonic acid expireni^ and of Despretz could I>e sieeounted for fiom the oxidation of carhon and hydrogxm calculated a«.*c<;rdin<^' to the method of Lavoisier. The more modern cah)ric values fwr hydrogen were liere employed as later in lSr>^ hy Gavarret. Liehiii' jdso points out that if one of the dog\s exj)erimeided upon hy DuloniT ha4 was director of the Sevres porcelain manufactory. He Avas a strict disciplinarian of students and up to the outbreak of the war in 1014 his memory w^as held in tradition as representative of the highest pedagogical severity. In 1841) JlegmmU and Beiset published their celebrated monograph upon the respiration of animals. The apparatus which they used consisted of a closed system, from which the carbonic acid produced by an animal placed within the system could be absorbed, and into which oxygen could be admitted as the atmcvspheric air was consumed by the animal. This is the ^'closed system af Regiiault and Heiset," the principle of which is employed in modem calorimeter work (vide Atwater and Benedict, 1005)1 '^ The i-esults obtained were usually accurate and their interpretations were within the compjiss of the knowledge of the time. Their main conclur^ions as they enumerated tliem, together with some of their experimental data, are presented in the following abstract: For anitnals tf Winrm blood, mammals and birds: 1. Xormally nourished animals constantly expire nitrogen but the quantity eliminated is very small, never exceeding two per cent and often being less than one pin cent of the total oxygen consumption. 2. If animals fast they fre(]uently absorb nitrogen. The proportion of nitrogen al)?orbed varies within the same limits as the exhalation of nitrogen by animals regularly fed. This absorption of nitrogen takes place in almost every instance in the case of birds but scarcely ever in manmials. ... (In experiment 10 performed on a rabbit the quantity of nitrogen absorbed was 0.08 per cent of the quantity of oxygen absorbed. In the text of the article they remark that the enormous elimination of nitrogen A HISTORY OF METABOLISM 41 rrpoilf'(] by Diilong- is inipossihle and that Liebig had pointed out [p. 40] that when one considered rlie loss of nitrogen in tl»e urine and feces, an animal expiring in addition the amount of nitrogen found hv Dulono- would tlnis in a few days liheiate all the nitrogen contained in the organic iiiafcMial of its own body. They also state that the respiration cannot contain rnoi-e than extremely .-mal} quantities of ammonia. ) 4. ... 'J'ho alternating elimination and absorption of nitrogen found in the same animal under various conditions is favorable to the opinions _^, — J — 3- /■/' *.^— ^ - / a.;,,. i ^r--i=^ I in Fig. 6. The closed circuit apparatus of Rofrnaiilt and Reiset. From **Annales de Cliimie et de Physique/' Series "i. Vol. XXVI. PI. ITT. Water rising in the glass recep- tacle drives oxygen into the glass bell jar. A pump alternately raises and lo\v»'rs two cylinders. The lower cylinder fills with alkali at the expen&e of the upper one, and this movement of the liquid forces air from one cylinder into the bell jar and draws a corresponding amount from the bell jar into the other cylinder. of Edwards, who believes tlnit an elimination and an absorption of nitro- gen constantly takes place during respiration, and what one finds is the resultant of these two contrary processes. 5. The relation between the quantity of oxygen exlialed as carbon dioxid and the quantity of total oxygen consumed appears to dejX'ud more on the nature- of the food than on the si)ecies of the animal. This ratio is higher in the animals whicli live upon grain and in them it may exceed unity. When they are given meat, the ratio is less and varies between 0.02 and 0.80. TJ^>on a diet of legumes the ratio is between that found after giving meat and that after giving bread. 0. This ratio is nearly constant in animals of the same race, such as dogs when they are given the same diet. 42 GKAIIAM LUSK 7. Fasting animals show about the .same ratio (R. Q.) as they do when fed with lueat, though usually a little less than under latter con- ditions. Durin**: inanition fastina: animals live off their own flesh, which is of the same nature as the flesh whicli they eat. All fasting animals present the picture of carnivora. 8. The fact that the relation betweei) the volumes of oxygon absorbed and carbonic acid exhaled varies between 0.02 and 1.04 according to the kind of food whicli the animal takes in, destroys the validity of the hypothesis of IJrimner and Valentin (1840), attributing the respiration to the simple ditfiision of gases through membranes according to the laws of Grahaiii (which calls for a constant ratio of 0.85). Tu the text they describe how they placed the bodies of animals (fowls, dogs, i-abbits) in an impermeable robber sack and found in mammals, as well as in birds, that the total quantity of carbon dioxid eliminated from the skin and intestine of these animals was practically negligible, rarely exceeding two per cent of that found in the pulmonary respiration. 9. Lavoisier tiried to prove that the heat of the body came from the oxidation of cailjon and hydrogen. RegTiault and Ileiset do not doubt that the heat is in fact derived entirely from chemical reactions in the body. But they tMnk the reactions are too complex to be compiled on the basis of the oxygen intake. ^'The substances which are oxidized are composed of earlKWi, nitrogen, hydrogen, and often contain a considerable amount of oxygen. Though they be completely oxidized in the lespiration process, their own c^xygen content contributes to the production of water and carbonic acid, and the heat which is liberated is necessarily different from that whieli would have been evolved by the oxidation of carbon and hydrogen supposedly liberated. ^Moreover, the food substances are not completely destvoyed, for portions are converted into other materials which play a special part in the body's economy and portions are trans- formed into urea and uric acid. In all the transformation and assimilative processes which tla'se substances undergo in the organism there is either liberation or absorption of lieat ; but the proi'esses are evidently so complex that it is very \inlikely that one will ever be able to calculate them.'' (They found in fowls that the volume of carbon dioxid was often greater than the volume of oxygen, which rendered the proposition of estimating the heat production from the oxygen impossible.) 10. The quantity of oxygen varies during different periods of diges- tion bec*auso of muscle work, and numerous other circumstances. In ani- mals of the same species and the same weight the quantity of oxygen is larger in young individuals than in adults. It is greater in healthy, thin animals than in fat ones. 11. The consiuiiption of oxygen absorbed varies greatly in different animals per unit of body weight. It is ten times greater in sparrows than in chickens. Since the diffei'cnt species have the same body temperature A HISTORY OF METABOLISM 43 aiul the smaller animals present a relatively larger area to the environ- mental air. they experience a substantial cooling effect, and it becomes necessary that the sources of heat production operate more energetically and that the respiration increases. 11. Awakening marmots consume oxygen in very largely increased quantity. 1 7. Reptiles consume much less oxygen per unit of body weight than do warm-blooded animals, but do not differ from them in the relative quantities of oxygen and carbon dioxid. 18. Frogs without lungs respire just as well as frogs with lungs. 19. Frogs and earthworms show nearly the same metabolism per kilogi'am of body substances. 20. The respiration of insects, such as beetles and silkworms, is very much more active than that of reptiles. For equal body weights they consume as much oxygen as mammals, and a proportionately large amount of nourishment. We are comparing insects with animals two to ten thousand times heavier than they. A thermometer placed in the midst of a mass of active beetles inclosed in a sack show^ed a temperature of two degrees higher than the sur- rounding air. The results of the work on these low^er forms of life may be tlius summarized: Temp. 37 Beetles . . . Weight gm. . 37. R.Q. 0.82 Oxygen per kg. per hr. 0.1)62 18 Silkworms . . 42.5 0.79 0.840 25 Chrysalides.. — Earthworms, 21. . 112. 0.64 0.78 0.240 0.101 2 Frogs . 127.5 0.75 0.105 21. Animals of different species respire just the same in air con- taining two to three times the usual quantity of oxygen, and do not per- ceive the difference in oxygen content. (The air contained 72.6 per cent of oxygen.) 22. If hydrogen replaces nitrogen of atmospheric air there is very little difference in the respiration process. (The air contained 77 per cent of hydrogen and 21.0 per cent of oxygen.) There were 104 experiments in all. Reg-nault and Reiset exemplify their natural instincts of friendsliip and courtesy when they write that experiment 26, in which they varnished a dog with gelatin, was done at the suggestion of "cet habile physiologiste -^^agendie," and that M. Bernard **dont Phabilite est hi en connue de tons les physiologistes'' had extirpated the limgs of the frogs about half an hour before placing them in their apparatus. 44 GPixVIIA:M LUSK In the closin*^ -words of tliis masterpiece the authors write: We are far from conckulini^ that our work presents a complete study of respiration. Wc consider ourselves happy if we have established the principal facts and if our methods are useful to ijhy.riologisti> who, through their special learning, may he able to extend them. Tlie animals were never inconvenienced in any wa}^ in the apparatus. Thouiih sin^iile animals were often ii-cd in mafiy exjK^riments, there was never any deleterious effect upon their liealtli. It will be noticed that there are two regrettable omissions in our work, ex- periments on the respiration of fish and of man. We have not made experiments on fish because we knew that Valenciennes was doing this. Eegarding the res- piration of man it was our intention to accomplish this in a special research. We proposed to study not only healthy men under various conditions of diet and at rest or at work, but also patient^ affected with different diseases and we hoped to associate ourselves in this important work with one of the skilled physi- cians of the large Paris hospitals. Unfortunately, the new apparatus which was to have served for this investigation, on account of the special conditions it had to satisfy, cost more money than we had at our disposal and we had to renounce our project. The study of the respiration in man in its various pathological phases ap- pears to us to be one of the most important subjects that could occupy those who follow the art of healing the sick; it can give a precious means of diagnosis in a grertt number of diseases and render more evident the transformations which take place in the organism. . . . Our desires will be fulfilled if our work provokes study that will be of such great importance to humanity. The Rise of German Science ^ Justus von Liebig (1S03-1873). — It has already been stated that Liebig was in Paris during the greatest period of French scientific achieve- ment. Liebig had been a dunce at school and was laughed at by hig teacher^ when, as a boy, he expressed his determination to become a chemist. Liebig attended the university of Erlangen, where he Avas duly educated in the spirit of the phlogiston hypothesis. lie heard witli im- patience the lectures, of the renowned philosopher Schelling, and fonnd no satisfaction until, in the autimin of 1822, he went to study in Paris (see p. 3G). Both Liebig and Dumas were introduced into the scientific circles of Paris by Alexander von Humboldt. Liebig, dedicating a French edition of one of his books to Thenard, a former master, thus expresses his appreciation: "To Monsieur le Baron Thenard, Member of the Academic des Sciences. Monsieur : "In 1823 when you presided over the Academic des Sciences a young foreign student came to you and begged you to advise him concerning the fulminates which he was then investigating. A IITSTOIIY OF METABOLISM 45 "Attracted to Paris by the immense reputation of those celebrated masters wliose glorious researches established the foundations of the sciences and elevated tliem into an admirable edifice, he had no other introduction to you except his love of study and his fixed desire to profit from your teachinjrs. ''You bestowed on him a most encourasinjr and flattering welcome, you dirc^'ted his first researches, and through your influence he had the honor to communicate them to the Academie. "It was the session of the 28th of July which decided his future and opened a career in which for seventeen years he has labored to justify your benevolent patronage, "If his labors have been useful, it is to you that science is indebted for them, and he feels obliged to express publicly to you his ineffaceable sentiments of gratitude, esteem and veneration." Justus Liebig. Giessen, 1 January, 1841. Through the influence of Alexander von Humboldt, Liebig was ap- pointed professor of clieniistry at Giessen in 1S24 at the age of twenty- one. Wilhelni Ostwald writes in his '^Grosse Miinner'' that this gave him free water to swim in. Here lie built the first nioilem chemical re- search laboratory and attracted to it men, many of whom afterward became distinguished. J.iebig's "Thierchemie in Ihrer Anwendung auf Physiol- ogie und Pathologie'' was first published in 1840 and jxissed through nine editions. Comparison should be made between it and the publications of Boussingault already described. Liebig divided the foodstuffs into protein, fat and carbohydrate, and stated that protein could take the place of body protein, while carbo- hydrate and fat could spare body fat. He believed that muscular work caused the metabolism of protein, while oxygen destroyed fat and car- bohydrate. In the introduction he states tbat in fifty years it will be as impossible to separate chemistry from physiology as it was then to separate cbemistry from physics ; that he had endeavored to bring chemistry and physiology together in a single book. In one of his writings Liebig says that the acceptance of principles, like the application of chemistry to physiology, all dei)eiids on the mental development, that the great Leibnitz refused to accept Xewton's doctrine of gravitation, which is now understood by every schoolboy. The time w^s propitious for the writing of Liebig's book. He himself had been more largely the creator of organic chemistry than any man then living. Chemical compounds of carbon were becoming known, Sclieele had discovered uric acid and lactic acid in 1776 and glycerin as a com- ponent of fat in 1778; Fourcroy and Vauquelin in 1779 and Prout in l>^i)?j had analyzed urea; Clievreul announced the chemical constitution of fat in 1S23 and Thenard investigated the composition of bile; Berzelius, the composition of the secretions in general. In 1828 Wohler prepared 46 GIfAIIAAE LUSK urea synthetically, and in 1837 Liebig and Wolilcr, working togctlier, described the dcconiixjsition products of uric acid. Carl Voit, writing in 1865^ thus describes Liebig's services: AH these chemical discoveries, to which Liebig so largely contributed, gave him his fruitful conceptions concerning the processes in the animal body. Be- fore him the ob.^erviitions. were like single building-stones without interrelation, and it required a mind like his to bring them iulo ordered relation. It is a service which the physiologists of our own day do not sufficiently recognize. In order to appreciate tlii< one has only to read physiulogical papers written before the publication of his books and afterward in order to witness how his writing changed the mental attitude toward the processes in the organism. The chemical discoveries on Avhich he based his conclusions were, in fact, matters of general knowledge, but it was he who applied them to the jjroctcsscs of living things. Scientific progress is determined by the establishment of correct interpretations and the creation llierehy of new pathways and problems. A school-boy has a better knowledge of many things than the wisest man had formerly; and he laughs at the ignorance of his forefathers because he does not understand the history of the human mind. The m^m of science ought to realize the factors which have given him the vantage which he holds. But there are textbooks on physiology in which the chapters on the animal mechanism do not even mention the name of Liebig. This anomaly is possible only for those who do not understand history, and who hold onlj' the new to be worthy of consideration. Liebig was the first to establish the importance of chemical transformations in the body. He stated that the phenomena of motion and activity which we call life arise from the interaction of oxygen, food and the components of the body. He clearly saw the relation between metabolism and activity- and that not only heat but all movement was derived from metabolism. He investigated the chemical processes of life and followed them step by step to their excretion products. The following quotations from Liebig's (b) ^^Thierchemie" appear to be significant cf his attitude (Cambridge, 1842; Braunschweig. IS-lrG) : It is clear that the number of heat units liberated increases or decreases with the quantity of oxygen giveii to the body in a given time through the respiratory process. Animals whi«.'h respire rapidly and are therefore able to absorb a great deal of oxygen can eliniinate a larger number of heat units than those which have the same volume but absorb less oxygen. Of metabolism in fasting -rewrites: The first action of hunger is a disappearance of fat. This fat is present neither in the scanty feces nor in the urine, its carbon and hydrogen must have been eliminated through the lungs in the form of oxygen-compouuds. It is clear that these ''onstituents are related to the respiration. Oxygen enters every day and takes away a part of the body of the fasting person with it. ^[artell found that a fat pig lived 160 days without food and lost 120 pounds. A HISTOKY OF METABOLISM 47 In herbivora tun volumes of oxygen absorbed result in nine volumes' of carbon clioxid eliniinaterocess but also have a part in the processes which take place iii the animal body, and if further investigations demonstrate that the cause of the decomposition of sugar into alcohol and carbonic acid in alcoholic fermentation is dependent '•n the development of a lower order of vegetation, and that the metabolism of complex molecules with the production of new substances can be caused by • Miitact with certain particles which are in the state of vital movement, it is rl* ar that a pathway has been constructed which leads to a vision of the mysteri- '•u> processes of nutrition and secretion. As to tbe energy production, he says : The lack of a correct viewTpoint regarding energy and activity and their rtlation to natural phenomena, has led people to ascribe the production of animal h» at to the nervous system. If one excludes tha metabolism within the active nenes. the above proposition would be merely s j^ing that movement would arise i'roni nothing. But out of nothing no power or activity can arise. Liebig asks: What is the use of fat, butter, milk-sugar, starch, cane-sugar in the diet? Through these non-nitrogenous food-stuffs a certain amount of carbon and in ^}m' case of butter a certain amount of carbon and hydrogen are added to the Jiitrogen-containing materials and form an excess of elementary substances which ••aiinot be used to generate nitrogen- and sulphur-containing substances, which latter are contaiiKxl preformed in the food. Hardly a doubt can be entertained 48 GRAHAM LUSK that this excess of carbon or of carbon and hydrogen is expended in the pro- duction of animal b(^at and serves to protect tlio orp:nnisni fr-tjn hcing attiickcd by atmospheric oxyg,en. Fiirthei- on he remarks: In their final forms meat and blood which are consumed yield the greater part of their carbon to tlic respiration, their nitrogen is recovered as urea, and their sulphur as sidphuric acid. Before this occurs the dead meat and blood must be converted into living flesh and blood. The food of carnivora is con- verted into blood which is destined for the reproduction of organized tissue. We know that the nitrogen-containing products of metabolism are not sus- ceptible of further change and are eliminated from the blood by the kidney. Differences in the quantity of urea secreted in these and similar experiments are explained by the condition of the animal in regard to the amount of the natural movement permitted. Every movement increases the amount of organ- ized tissue which undergoes metamorphosis. Thus, after a walk, the secretion of urine in man is invariably increased. In the animal body the comi)onents of fat are used for the respiration process and hence for the production of animal heat. If the condition and the weight of all parts of a carnivorous animal are to be maintained it must daily receive a certain definite measure of sulphur and nitrogen-containing food substances as well as of fat. The difficulties of calculating the metabolism are discussed. The weight of the ingested materials must be the same as those eliminated in the forms of uric acid, urea, carbonic acid and water. The weight of the ingested fat must be the equivalent of the fat eliminated in the form of carbonic acid and water. From this it follows that the quantity of oxygen absorbed cannot be a measure of the amount of the living substance destroyed in a given time. The oxygen absoi-ption expresses the sum of two factors; one the destruction of nitrogen-free substances and the other the destruction of nitrogen-containing substances. It has already been frequently stated that the measure of the latter can be determined from the nitrogen content of the urine. He later consider^ die metabolism of a horse: "A horse preserves itself in a state of healrii if he be given Ti/^ kg. hay and 2(^4 kg. oats. Hay contains 1.5 per cent and oats 2.2 per cent of nitrogen. Assuming that all the protein in the food is transformed into the lil)rin and seriini albumin of the blood, there would be produced daily 4 kg, of blood, con- taining 20 per cent of water and 140 gin. of nitrogen. The quantity of carbon combined with tlie protein and ingested at the same time would have been 448 gm. Of this only 24G gin. could have served for the respira- tion, for 05 gm. are eliminated in the form of urea and 109 gm. in the forai of hippuric acid. . . . The experiment of Boussingault which shows that a horse expires 2450 gm. of carbon in a day cannot be very far from the truth.'* The nitrogen-containing substances of the fodder of the horse do not con- tain more than one-fifth of the carbon necessary for the nuiintenance of the A HISTORY OF :^i:E:TABOLIS^r 49 respiration, and wc see that the wisdom of the Creator has added to all the foods tho remainder of the carbon in tlie form of sugar, starch, etc., which is necessary for the renewal and maintenance of animal heat and for the conversion of inspired oxygen into carbonic acid. If these substances had not been present in the food and th(M'e had been the same intake of oxygen, then the materials of the animal's own body would have been used instead. J.iebi«i: says that only a small fraction of the bile is unabsort)cd and cannot contribute ji^reatly to the formation of tlie feces. As to tho formation of fat, Liebig argues as follows: A spider, fierce with hunger, sucks the blood of the first fly, but is not to be disturbed by a second or third fly. A cat eats the first and perhaps a second mouse, and will kill but not eat a third. Lions and tigers react the same way, driven by hunger to devour their prey. IIow different with a sheep and a cow in the pasture, which eat almost without intermission as long as the sun in the heavens shines upon them. The herbivorous animals eat in such excess that the ingestion of starch is greater than is necessary for union with oxygen, and hence the animals fatten through conversion of starch into fat. Concerning alcohol, he makes the following comments: "Alcohol is oxidized in the body, the carbon dioxid elimination decreases after alcohol (Vierordt) because relatively more oxygen unites with hydrogen." Liebig has been informed that in England all servants are given beer, or where the Temperance Society is influential the money equivalent of beer. Under the latter conditions more bread is eaten, so that the beer is paid for twice, once in money and once in extra food containing the ?amo carbon and hydrogen equivalents as the beer. Liebig enters into the calculation of the oxidation of various foods in the body and gives the following values (p. lOG) : 100 Liters of O^ And they warm liters of combine with water from 0° to 37° 120.2 gm. starch 28.356 48.8 iiin. fat 27.04 Liebig also calculates the caloric value of meat. lie prepares a table • >f isodynamic equivalents which are given below, contrasted with the \alu('s given by Rubner (r/) later in 1S85 (p. 75). Liebig writes: Since the capacity of these substances (the respiratory materials) to develop luat through union with oxygen is dependent on the amount of combustible t'loiuents which equal weights contain, and since the amount of oxygen neces- sary for their combustion increases in the same proportion, therefore it is pos- >il>le to calculate approximately their relative heat producing power or respira- tory value. The following table contains the respiratory materials arranged in '•no possible order. The figures express the relative amount of each substance uhich a given amount of oxygen would convert into carbonic acid and water or 50 GILVIIAM LirSK approximately how inuch one must eat in order to maintain the body tempera- ture at a given lev(;l of metabolism during a given time: Table of Isodijmimic Values Liebig Eiibner in 1846 in 1885 Fat .300 100 Starch 242 232 Cane-sugar .....* 249 234 Dried meat 300 243 This, surely, i$ a divination of Itiibner's su])scquc'ntly enunciated isodj- namic law. As regards the oxygen requirement for the combustion of different foods, comparisons may be made between the findings of Liebig in 1846 and those of Loewy in 1011: To oxidize . requires Oo m c.c. I^iebig Loewy Fat, 1 gm .T~2050 2019 Starch, 1 gm 832 828 It is evident that Liebig clearly understood that it was protein, car- bohydrate and fat which were oxidized in the body and thai they were the source of energ;^' and not carbon and hydrogen supposed to be pro- duced from them, Liebig divides the foodstuffs of man into two classes, the nitrogenous and the non-nitrogenous. The first class can be converted into blood; the other cannot be. The constituents of organs of the body are built up from those foods which are conveitible into blood. In the state of normal health the other foodstuffs are used merely for maintaining the respira- tion process. He calls the nitrogen-containing foods the plastic food- stuffs and the non-nitrogenous, the respiratory foodstuffs. They are as follows : Plastic Foods Bespindonj Foods Plant fibrin Fat . Vegetable albumin Starch Vegetable casein Gum Meat and blood of animals Sugars Pectin Bassorin. Beer Wino Brandv A HISTORY OF METABOLISM 61 "It is a fimdamental fact, so far without a contradictory experiment, that the sulphur- and nitrogen-containing constituents of plants have tlie same cheinical cumposition as the principal comj)onents of the blood. We know of no nitrogen-containing material of a comjx>sition different from tihrin, alhumin and casein which is able to sustain life. ''The animal organism is certainly able to construct its membranes and cells, nerves and brain, the organic materials of ribs, cartilages and bones nut of the constituents of its own blood, but these constituents must be already constructed in proper form or the production of blood and life itself is brought to an end. ''Looking at the matter from this standpoint, it is easily understood wliv gelatin is not a builder of blood or a supjxjrter of life, for its com- position is different from that of the fibrin and albumin, of the blood." Concerning the ultimate disposal of the products of metabolism, Liebig writes : The kidneys, skin and lungs cannot be the only ways tbrougli which products of the metabolism are eliminated from the body. The intestinal canal functions also as an organ of excretion and its relation to the respiration process must not be misunderstood. If the quantity of oxygen absorbed in a given unit of time is that which is exactly nece3sa:y to convert the products of metabolism present during the same period into carbonic acid, urea and water, then the intestinal canal will contain only indigestible substances. ... In general it must be assumed that all of the nitrogen- and sulphur- containing constituents of the food of man are completely digestible, are brought into solution and absorbed into the circulating blood, for a property belonging to some pa.rts.must belong to all. In such cases it is undoubtedly true that the discover^' of nitrogen-containing materials in the feces signifies that they can • •nly be the products of the metabolism of the intestinal canal itself or products which have escaped normal metabolism and have been excreted from the blood by the intestinal wall. Just before the publication of Liebig's gi-eat work Dumas, in glowing language, pictured similar interpretations without giving Liebig credit tV)r the ideas. He utilized a formula similar to tbat given by Liebig without stating its derivation. Thus, in 1842, Dumas and Cahours pre- M iited the following penetrating conception: • The food of an ordinary nraintenance ration contains 16 to 21 gm. nitrogen. This nitrogen is almost entirely recoverable in the urine in the form of urea. Ignoring the intermediary^ phases, protein breaks up as follows: ^^sHg A^O,^ + 100 O = C, ll,J^,,0, urea ^42 ^84 carbon dioxid Hog O25 water C,,-K,,-N,fi,,, llie only object in giving this formula is to enable one to calculate the heat of c«.>iiihustion of protein. Allowing for the daily production of urea from protein, 52 GRAHAM LUSK there would remain 50 gin. of carbon and 6 gm. of hydrogen suitable for oxida- tion; this would yield 575 calorics. Since calculations based on the carbonic acid elimination and oxygen absorption show that a man produces between 2,500 and 3,000 calories daily, it follows that he needs an additional 200 gin. of carbon and 10 gm. of hydrogen to complete the required quantity of heat. The writings of Dumas brought Liehig (h) to the defense of his priority in an article entitled, '^Antwort anf llerrn Dumas' Eechtfertiginig wegen eines Plagiati*/' published in 1842. He recited "how, in the winter of 184CM1, he Lad lectured to his students upon: (1) the respiration process in its relation to the bile, (2) the nitrogen-containing substances of the vegetable kingdom are identical with those of the blood; and (3) sugar and starch are not food materials but serve for respiration and for fat production. A young Swiss student of Geneva came to Liobig with a letter from Dumas, attended the lectures, and afterward carried the in- formation to Dumas in Paris. With volume 41 of Liebitr's Annalen the name of Dumas as collaborator disapj)ears from the front page. Berzclius sided with Dumas in this historic controversy^ greatly increasing the bit- terness of Liebig. The feeling between the two men, however, must have died down, for in a dedication to Dumas of his "^ouvelles lettres sur la chimie," dated Giessen, 1851, Liebig speaks in the most flattering terms of his old associate and brilliant antagonist. Charges of plagiarism are contemporaneous with the progress of hu- man thought. Wlien two people work together they may find it possible to make the pleasing statement of Bidder and Schmidt, "As the result of mutual exchange of ideas and through intellectual metabolism, we find ourselves in entire agreement.'' But as regards the controversies regarding the priority of discoveries, such as grouped themselves around the person of Lavoisier and the person of Liebig, no such self-abnegation was pos- sible. Wohler writes to Liebig regarding another matter in the following words (Moore, 1018) : To make war upon Marchand (or any one else for that matter) is of no use. You merely consume yourself, get angry, and ruin your liver and your nerves — finally with Morrison's Pills. Imagine yourself in the year 1900, when we shall both have been decomposed again into carbonic acid, water and ammonia, and the lime of our bones belongs perhaps to the very dog who then dishonors our grave. Who then will care whether we lived at peace or in strife? Who then will know anything about your scientific controversies — of your sacrifices of health and peace for science? No one: but your good ideas, the new facts you have discovered, these, purified from all that is unessential, will be known and recognized in the remotest times. But how do I come to counsel llie lion to eat sugar 1 This is the correct interpretation to be placed upon rights of priority. The influence of an individual is evidently the result of the sum total of all activities of his life. If he contributes to the ideas of others, the A HTSTOPcY OF METABOLISM 53 results may be of three kinds: (1) the donor may be publicly acknowl- edged; (2) the donor may be honestly forgotten and the recipient may honestly believe that he has for years held the same views; or (3) the (h)nor may be well known to the recipient but be deliberately and sys- tematically ignored. The last-named reaction is the one most difficult to k^ar with l)ecoming humility of spirit, but, interpreted in the light of history, it signifies but little. It matters little to the world at large whether Hacon wrote Shakespeare or Shakespeare wrote it himself. The heritage of the masterpieces is what matters. Before Licbig's deatli he wrote to Wohler concerning the publication of their correspondence as follows: "When we are dead and gone these letters which united us in life will be as a token for the memory of man of a not frequent example of two men who, without jealousy or envy, strove in the same field and always remained intimatelv united in friend- ship.^' - Liebig's Munich Period. — In 1852, at the age of forty-nine, Liebig moved to ^[unich to become professor of chemistry there. His creative work ceased and a period of literary activity set in. He engaged in violent polemics with Pasteur, maintaining that alcoholic fennentation was a purely chemical phenomenon and not one of biological origin. He gave popular lectures in court circles and, with Rfchard Wagner, shared the popular adulation of the town. When Liebig's new gluten bread was put upon the market the townspeople stood in long lines before the bakeries to receive the precious product. It may be of interest to pass here to the viewpoint of Liebig ex- pressed in 1870 just before he died. In the interim the work of Bidder and Schmidt, of Bisehoff and Voit, of Voit, and of Pettenkofer and Voit, had appeared, material which is still to be recorded. Liebig writes as follows : "On the basis of general experience I for- merly expressed the opinion that the source of mechanical work of the animal body nmst be sought in the metabolism, especially in the metab- olism of the nitrogen-containing constituents of muscle. The capacity for work in two individuals would therefore depend upon their respective mass of muscle tissue, and the endurance of each would depend on his capacity to rebuild the broken-down muscle substance from the inflowing food material. "It is well knoA\Ti that hard-working men eat much meat. An em-* ployee (Briiuknecht) in Seldmeyer's large beer brewery consumes daily 810 gm. of meat, 600 gm. of bread and 8 liters of beer. One should be cautious in adopting the jwpular Bavarian idea that it is the beer which gives muscular power, for the beer drinkers are also the gi'eatest con- sumers of meat. The question regarding the source of muscle power has been confused through a conclusion which has been shown to be false and for which I am to 54 GRAHAM LUSK blame. It was an error to assume that, if urea were an end-product of the oxidative metabolism of muscle, then one could measure the intensity of the work done by the quantity of urea in the urine. The first facts contradicting: the idea that urea is a measure of muscular activity were communicated by BischotI and by Jiischoff and Voit of Munich, which researches are to be considered as the extension of work accomplished in Giessen. It is hardly ueeessaiy to state that these experiments always excited my keenest interest because tliey were effected with my method of urea determi- nation. . . . These experiments firmly establish the fact that, although urea elimination is a measure of protein ing^estion and metabolism, it is not a measure of the work done by the body. When one thinks these matters over it is apparent that the facts could not be otherwise. For if the metabolism of the muscle increased with work a man could exhaust his entire supply of muscle tissue^ because work is directed by the will. He criticizes Frankland's comparison of the muscle with a steam engine, as follows: It is certain that the wonderful structure of the animal body and of its parts will long and perhaps forever remain an insoluble riddle. But the proces- ses within the organs are of chemical anc^ physical nature, and it is incompre- hensible that oxygen and combustible materials are under the control of nerves to induce their union. The factor of voluntary nerves upon muscle activity must be of a different order. . . . X consider that those investigators who have busied themselves with the question of the source of muscular power have thought its solution too simple and that it will be many years before a proper viewT)oint leads to clarity in the solution of this subject. I have no desire to enter into the dispute. Liebig discusses the activity of the yeast cell as follows: A close consideration of the behavior of the yeast cell may be desirable in order to give a more definite idea of what transpires in living muscle. It is certain that motions occur within the yeast cell through which it is enabled to accomplish external work. This work consists in the cleavage of carbohydrates and similar substances. This is chemical work; it would be mechanical work if the yeast were able to split wood, which is likewise carbo- hydrate. One part of yeast can destroy sixty parts of its weight in sugar, according to Pasteur. A gram of yeast can produce the heat equivalent of 148,960 gram meters of work without the intervention of oxygen. The cause of all these activities lies in the motions of the contents of the yeast cells. In similar maimer the motions of life are present in muscle cells, without muscular contraction resulting. When the movement within the muscle cells rises. above a certain limit, muscular contraction follows. Liebig enters into a defense of the use of Liebig's extract of meat. At one time he had regarded it, when mixed with potatoes, as the equiva- lent of meat. He quotes Hippocrates: A HISTORY OF METABOLISM 65 "Soup and pap were discovered because experience has taught mankind that fio'l^ which are good for healthy people are not good for the sick." One need only compare the capacity for work of the German Avorkman, who live? on bread and potatoes, v/ith the English or American workman, who eats meat, in order to gain a clear insight into the importance of the kind of food taken. The partaking of meat raises the capacity, the power and the endurance fr.r work. Or compare an English statesman who may speak for five hours or nK're in a Parliamentary debate, and who in the full possession of youth may ■i'^iii engage in a strenuous hunt at the agc» of sixty, with a German professor oi the same age who sparingly conserves the rest of his physical powers and v.h:- is exhausted by a walk of a few hours. Liebig cannot understand the modern expressions, "organized protein" ah' I "circulating protein"; they confuse him to such a degree that he oannut tell his right hand from his left. It is right to investigate a single phase in order to comprehend the existence and activity of a whole process, but in order to interpret correctly the results of investigations one must have a clear picture of the manifold phenomena and the limitations affecting the entire problem. I have a general knowledge (Icb w^eiss so xiomlich) of how to estimate the importance of experiments and facts, and of their inequality as far as draw- ing' conclusions is concerned. The simple observation of a natural phenomenon arranged without our assistance is more important and often much more diffi- cult than the phenomena obsen'cd in an experiment produced by our will. In the first reality is mirrored, while an experiment represents the imperfection of our understanding. I remember that many years ago during a walk between Berchtesgaden and the Konigssee, a very simple observation led me to the conclusion of the source of carbon in plants. At that time there was great confusion in the subject, and it was difficult to exclude humus from consideration as a factor. But on this walk Nature gave the proof that the carbon of the plant could arise only from carbonic acid. For one finds rocks there which had been dislodged and had fallen from the higher mountain side, aiid trees thirty or forty feet high grow on the rocks, sending their roots between the crevices while the rocks are covered only with moss and a layer of dust. It was impossible to con- ceive that humus could have conveyed carbon to vegetation of this sort. Similar observations can be made in the laws of nutrition if one has but the good-will to see them. It appears to me to be almost unthinkable that the high value placed by the French family upon their "Pot-au-feu'" is merely based on custom; or that OTie of the greatest military physicians of the French army. Dr. Baudens (Bau- deiis, 1S5T) would dare to say "La soupe fsiit le soldat" unless he was absolutely C'-.nvinced of the high potency of meat soup coutaining the necessary vegetables which the French soldier often prefers to meat. Licbig laments the criticism of his extract of beef and quotes Goethe, "The word of a wise man teaches me that if a person once does a thing wljioh is good for the world, the world takes pains to see that that person «l"f s nnt do it a second time." One may annotate Liebig's opinion of Voit's "circulating protein" and •'organized protein" by citing a letter which Liebig wrote to Wohler 56 GRAHAM LUSK in 1870, ill which he says that he is considering giving up his lectures during the summer semester upon the subject of animal chemistry and nutrition and continues, ^'I find so little to interest me in what others are doing in this subject I lose all desire to take part in it. They per- form nothing hut small expeiiments which lead to nothing. ^AFodern phy-;iologists lack a great idea upon which all investigations depend." Wilhelm Ostwald comments that this i-; tjie usual experience of parents with their children, and is the greater the more capable and important the children become. It may be of interest in this connection that I heard Voit tell my father in 1801 that there were no young, promising physiologists of about forty in Germany at that date, a generalization which would have in- cluded Kubner (born 1854), Kossel (born 1853) and Ilofmeister (born 1850). The happy ideas obtained as the result of Liebig's walk between Berchtesgaden and the Konigssee recalls the statement made by Ilelm- holtz at a festival given in honor of his seventieth birthday, in which he told that he had never had a great thought come to him at his desk nor when he was tired nor after taking a glass of wine, but usually wdien he was walking in the garden thinking of other things. All the quotations of Liebig's later views are from writings pub- lished in the year of the Franco-Prussian War of 1870. In his ''Thier- chem.ie" of 1840 and in several other of his publications at that period occur the following memorable words : "Culture is the ecoTiomy of power, the sciences teach how to produce the greatest results by the simplest means with the least expendituie of energy. Every unnecessary use of energy, every waste of power in agriculture, industry, science, or in state- craft is characteristic of crudeness or lack of culture." Concerning the results of the ccnfliet of 1870, Liebig moralized as follows: "It was a battle between knowledge and science on one side and empiricism and routine on the other, in which, as in agriculture, knowledge won." Hear this realizing cry of Pasteur (Vallery-Iiadot, 1002) which fol- lowed the defeat of France in 1870 concerning the "forgetfulness, dis- dain even, that France had had for gi'cat intellectual men, especially in the realm of exact science." He says, "Whilst Germany was multiplying her universities, establishing between them the most salutary emulation, bestowing honors and consideration on the masters and the doctors, cre- ating vast laboratories amply supplied with the most perfect instniments, France, enervated by revolutions, ever vainly seeking the best form of government, was giving but careless attention to her establishments for higher education. "The cultivation of science in its highest expression is perhaps even more necessary to the moral condition of a nation than to its material prosperity." A HISTORY OF METABOLISM 57 Xor was the development of German science ignored in England, for Matrhcw Arnold wrote in INOS: ''Petty towns have a nniversity \vhose Teaching is famous throughout Europe, and the King of Prussia and (oiijit iiismarck resist the loss of a great savant from Prussia as they w. Ill Id resist a political check. ^' I..t us not forget the environmental conditions under which men like Lif l>ig may be fostered and developed. Bidder, P. W. (1810-1894) and Schmidt, C. (born 1822).— In order to rM.niplcte the story of Liehig's life this history has been diverted from its chronological sequence, and it is now necessary to tell of the activity nf the period essentially coincident with the date of the publications of iic^^uiudt and Itciset. At the same time that these men were at work ill Paris, Bidder and Schmidt (a) were active in the German university ortahlished at Dorpat in Kussia. In 1852 they published their book, -Die Verdauungssiifte und der Stoffwechsel." Voit often referred to This book as a veritable mine of information. The book, However, has nevev been as well known as it should be. The statement still found in textbooks on physiology that the influence of food upon the bile flow has never been investigated finds its refutation in this volume, published in the middle of the last century. Here, also, one finds the method of computing the metabolism used by those who employed the Pettenkofer- Voit respiration apparatus. Bidder and Schmidt were much more profoundly influenced by the doctrines of Liebig than were Regnault and Reiset. Had the methods of the four investigators been combined, much of value would probably have been rapidly uncovered. But Reiset's publication of 1868 on the metabol- ism of farm animals shows no knowledge of the publication of Bidder and Schmidt. To promote science one must know of contemporaneous activi- ties in many lands, as well as of the older historical happenings. C. Schmidt, who had been a pupil of Liebig and Wohler, began w^ork -ix years before (1845) the completion of the combined work of Bidder ;iT)d Schmidt. Schmidt had planned an experimental critique of the iiif rabolism of the higher vertebrates. His idea was to study in a few typical forms the following main factors: oxygen absorption, carbonic acid mtd urea elimination and the energy statistics of fasting animals, ac- ' 'inplished upon the same individual under identical conditions. Having ;''Miimuh\ted this mass of observations concerning the typical intensity of rlif respiration and the protein consumption on the more prominent types "f vertebrates, it was planned to investigate in similar fashion the size of the intermediary metabolism, the effect of external temperature and in*' effect of partaking of protein, fat and carbohydrate, and then to iiMluce the sum total of all the observations to a systematic whole. It was beyond the power of a single individual to accomplish this I'lan. A preliminary investigation established the specificity of the 58 GRAHA:\I LUSIv cnzyineSy that yoi\st can act only on sugar and produces only alcohol and carhonic acid, eniulsin acts only on aniygodv protein itself. The larger part is eliminated in o)'