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Biographical Memoirs: Volume 56 (1987)

Chapter:Eli Kennerly Marshall, Jr.

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Suggested Citation:"Eli Kennerly Marshall, Jr.." National Academy of Sciences. 1987. Biographical Memoirs: Volume 56. Washington, DC: The National Academies Press. doi: 10.17226/897.
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ELI KENNERLY MARSHALL, JR. May 2, 1889-January 10, 1966 BY THOMAS H. MAREN TH E ~ D E A S A N D ~ D E A ~ S of the nineteenth century are embodied in many men anc! women born in late Victo- rian times, anc! so live on to the present. In this tradition was Eli Kennerly Marshall, ir., who servect the Johns Hopkins University School of Medicine for thirty-five years, first as professor of physiology, then of pharmacology and experi- mental therapeutics. Now near the end of our own century, it is fitting to review and celebrate the life of a scientist who macle giant strides towarc! the twenty-first. Marshall was born in Charleston, South Carolina, on May 2, TSS9. His father's family came from England in the early part of the century. His paternal grandmother, Susan, was the daughter of Eli Kennerly, a Virginian who migrated to South Carolina. His mother's family was more varied. One si(le of her family was English-his merchant grandfather (Brown) was a clescendant of the Rev. Samuel Andrew, a founder of Yale, ant] George Treat, one-time governor of Connecticut. His maternal grandmother (Beckmann) ap peared more exotic; Marshall's notes say her family included members of German, French, and Russian descent. He once mentioned that he was part Russian-a rather incongruous note and there was no whiff of the East in his character. He retained throughout his life the accent and many of the at 313

314 BIOGRAPHICAL MEMOIRS titudes common in Charleston, which in the days of his up- bringing was a somewhat unique cultural enclave. On both sickles his family was "in trade" in Charleston. His father ran the successful shoe business built up by his moth- er's father, and they all lived in the maternal granclparents' pleasant home, surrounded by aunts and (mostly) female children. Life moved in stately and routine fashion; there were large, early breakfasts; dinners at 3:00; and late, coIc! suppers. An isolated and shy boy, he went to private schools and graduated first in his class from Charleston High School. No effort seems to have been made to widen his horizons; he was sent to the small but excellent College of Charleston. He graduated at the age of nineteen in 190S, the only chemist in a class of eight men. As he describes those days: "I was cIevotec! to books, took no interest in athletics, ant! really led a rather narrow life of the mind. College, except in an intel- lectual way, was for me a failure. No lasting friendships were made, and as ~ see it now, my college was a high school and my post-gracluate years in chemistry, a poor makeshift for college." He embarkoct on these graduate years at Johns Hopkins in 190X; there had been some Hopkins teachers and ac- quaintances in the city of Charleston and at college. He lived in a boarding house near the old University on Little Rose Street; again he was quite isolated. It would be most agree- able to say, from the vantage of seventy-five years, that this unspoilect innocent found, at the golden dawn of Johns Hop- kins, the inspiration he craved and deservecI. Alas, this first year was "a shattering of illusions." bra Remsen, who hack been director of the Chemistry Department, was now presi- dent of the University ant] kept partial control of the de- partment, with no strong successors. Marshall was assigned to a thesis acivisor ant! a topic that he deemecl "unthinkable,"

ELI KENNERLY MARSHALL, JR. 315 and he returned to Charleston the next summer in the fierce indignation that was to become so characteristic. He ar- ranged to complete his graduate work at the University of Chicago, but his old college professor, Francis Parker, in- terceded at Hopkins and arranged for Marshall to choose his own thesis advisor, Associate Professor of Organic Chemistry S. F. Acree. He returned to Baltimore, but his notes about the time, written thirty-five years later, were full of excIama- tion points and attacks on those "old men" who ciared threaten his freedom. The next two years, finally, "were extremely happy and pleasant," despite the ebb of the department. Acree gave him plenty of independence and he read widely in the excellent library, including the works of Emil Fischer, Nef, and Gom- berg. He had planned to go into industry, but unaccountably he became interested in physiological chemistry. In 191~ he took an assistantship in that subject in the Medical School with Walter Jones, beginning the association in three de- partments that was to last forty-five years. He received the Ph.D. in chemistry and sailed to Europe in the summer of ~ 9 ~ 2, with a letter of introduction (but with no advance notice and no place to stay) to AbderhaIden at the Physiology Institute at Halle. He was accepted, but again seemed isolated: little English was spoken, his German was weak, and he did not care for the system in which Herr Pro- fessor gave directions each morning to the staff for the day's work. But the loner was to triumph: "I spent time reading in the small department library.... ~ wanted to study enzyme action . . . ran across literature on urease and decided to work with it when ~ returned to Baltimore in the fall." But if only Marshall could have visited Paul Ehrlich at Frankfort-am ~ "Walter Jones," in Biographical Memoirs of the National Academy of Sciences, vol. 20 (Washington, D.C.: National Academy of Sciences, 1943), pp. 79-139.

316 BIOGRAPHICAL MEMOIRS Main! Did he even know then of Ehrlich, whose name was to be coupled with his a quarter of a century later? Back in Baltimore that winter, Marshall did just as he planned and attacked the urease problem with great force. It turned from a purely chemical exercise into a methodo- logical triumph for physiology and chemistry (Section I be- low). Marshall wrote, "It was quite worthwhile to be on the mountaintop for a short time." Marshall thought Jones unimaginative and not interested in his work. Had he stayed with Jones, would he have slid off that mountain? Jones thought there wasn't much left to do in physiological chemistry, and he couldn't do much for Mar- shall anyway. But there was a dens ex machine, or more ac- curately, a godlike figure on the floor below John Jacob ~ ~ , Abel,2 professor of pharmacology, already a world figure. Abe! was a gentle farmboy and school principal from Ohio who had gone to Europe for seven years "to prepare myself for the JOth century." There he studied medicine, chemistry, physiology, and pathology before becoming one of the founding chairmen at Johns Hopkins in 1893. He had iso- lated epinephrine from the adrenal, begun work on the ar- tificial kidney, studied chemotherapy of trypanosomiasis with antimony compounds, crystallized insulin, pioneered work on the posterior pituitary, and founded both the American Society of Biological Chemists and the American Society for Pharmacology and Experimental Therapeutics. Most signif- icantly, he believed that "the investigator is the 1 r r ', inner llle IS tree. man whose Marshall had caught Abel's eye; indeed, the two depart- ments lunched together, an important tradition that was to last many years. Abe! arranged for Marshall to transfer to pharmacology, but with the most significant and serious pro 2 ''John Jacob Abel," in Biographical Memoirs of the National Academy of Sciences, vol. 24 (Washington, D.C.: National Academy of Sciences, 1947), pp. 231-57.

ELI KENNERLY MARSHALL, JR. 317 viso: that Marshall would study medicine. Rather compli- catecT arrangements tract to be macle, because at that time faculty were not permitted to study for a clegree. Marshall ended up (loin" the basic sciences (except biochemistry, phys- iology, and pharmacology, which he never took!) at Wisconsin and Chicago cluring the summers, but somehow the rule was relaxed so that he did his clinical work at the Johns Hopkins Hospital. Marshall's medical training had profound implica- tions for him, as well as for generations of his students; he never ceases! to bless Abe! for this advice. He received the Hopkins M.D. in ~ 9 ~ 7. During those years he lived most contentecIly at the oIc! Johns Hopkins Club at the corner of Monument and Howard streets. Intellectually and socially, it was a rich period. There was a host of young scholars from the medical school and the university, who tradecl shoptalk, gossip, and beer on Saturday nights. Much later he recalled Barnett (statistics), Mustard (Latin), and Lovejoy (philosophy). An appealing scene is that of Ecigerton, a Sanskrit man and later professor at Yale, react ing Hindu stories to Marshall at midnight, over crackers and cheese. This episode in Marshall's life encled with three events: his graduation from medical school, service in World War I, and marriage to a Hopkins classmate, Berry Carroll, of Co- Jumbus, Ohio. She later macle a career as psychiatrist to the Children's Court in Baltimore, while raising three children. Marshall was assigned, with the rank of captain, to the Chem- ical Warfare Service in Washington, where he worked until the enct of the war. In this unlikely setting, Marshall macle a motion indenen ~ ~ - ~ --- -- -A dent discovery Homer W. Smith,3 who was clestinect to be 3 "Homer W. Smith," in Biographical Memoirs of the National Academy of Sciences, vol. 39 (New York: Columbia University Press for the National Academy of Sciences, 1967), pp. 445-70.

318 BIOGRAPHICAL MEMOIRS come the world leader in renal physiology. But in 1918, Smith was an enlisted man from Cripple Creek, Colorado, where he had sold vacuum cleaners. Marshall noticed that a light always burned late in the back laboratory; investigation one night revealed a tall skinny young man (not unlike the cap- tain himself) who stuttered and had a passion for chemistry, literature, and music. If the captain was burdened with two doctorates, the sergeant had none at all, and Marshall re- solved to repair this. Meanwhile, they published three excel- lent papers on mustard gas, prepared in the quantitative and chemical spirit that was to characterize the work of both in the years ahead. There was some effort to get Smith into medical school after the war, but he ended with the D.Sc. from the Johns Hopkins School of Hygiene and Public Health, where he worked on the pharmacology of arsenic. Seven years later, when both were involved in the study of renal physiology, they met again in Maine, where they collab- orated briefly in a pioneering study of vertebrate evolution in light of the development of the glomerulus. They were neighbors, friends, antagonists, colleagues, and rivals at the Mount Desert Island Biological Laboratory for thirty-five years. To ask for more would be unrealistic, in view of their very different characters. Back at Hopkins in early 1919, Marshall and his new fam- ily happily faced a gas-lit apartment on West Baltimore Street, a low budget, and some interesting decisions. He thought of going with a drug company as research director, but there were no offers and Abel was unsympathetic to this. He was offered a professorship in the Peking Union Medical School, with responsibility for the combined departments of physiological chemistry, physiology, and pharmacology (the curriculum of the twenty-first century?), but turned it down with little thought. Only at the close of his life did he speak

ELI KENNERLY MARSHALL, JR. 319 sadly of this quite out of character for him as a great missecI opportunity. He took the more conventional way and accepted the chair of pharmacology at Washington Univer- sity in St. Louis. But in less than two years, too little time for lasting impressions on Marshall or Washington, the offer came from Hopkins, through Abel, to succeed Howell in the chair of physiology. His single, short journey outside Hop- kins was over. His only reservation in returning was that somehow he had never taken a course in physiology, but he reasoned that he had never taken physiological chemistry or pharmacology either and had aIrea(ly taught both. There must have been a very special quality in Marshall that brought him to this ctistinguished chair at age thirty-two and led Hopkins to pass over the more orthodox cancliclates. His papers up to that time were surely of good quality, but there were no outstanding contributions to physiology. Of course, his training was remarkable; it may be notect that he was not an M.D.-Ph.D. in the modern sense of a combined degree. He tract two separate anti significant tracks to a career in pharmacology: chemistry and medicine. His scholarship, vigor, singleness of purpose, and forthright honesty couIcI not have failer! to impress. His bibliography from 1910 to 1920 charts his gradual transition from pure chemistry to physiology and pharma- cology. The urea method! hack opened the cloor to these later studies, notably on the effects of adrenalectomy on the kid- ney (Section I). It was not long before this promise and these gifts came to fruition. In October 1922 he react to the Johns Hopkins Medical Society the "Proof of Secretion by the Con- voluted Tubules": he had discovered active transport! Some details of this fincting and the ensuing controversy are given below (Section Il). In the published paper (1923) he seems to have leapt fifty years over the heads of his contemporaries

320 BIOGRAPHICAL MEMOIRS to bring an entire new field into focus. It was to be another twenty-five years before it gathered the great impetus that it has now. In January 1923, just as his great paper with Vickers on the proof of secretion was published, Marshall sailecI to Eu rope "carefree and happy" with his family. In this mem- orable year he met most of the scientists who had been only names to him. "E. H. Starling of University College was par- ticularly nice to me . . . we sat in his little office in front of a small fire . . . we discussed Physiology . . . my going into it without orthodox training. Starling said 'we need men bring- ing gifts, a new point of view.' I then felt that maybe I could do something." The next few months were spent in Cambridge. "Here, I worked with Joseph Barcroft (with whom I tract had much correspondence, cluring the war, on gas warfare). This was a clelightful time. We took a furnished hole se had a 'general' and excellent nurse for the children. 1 enjoyed dining in Col- lece at the high table. My wife says that if I had not been ~ ~ . · ~ T ~ 1 ~ ~ 1 1 _1 ~ ~ ~ ~ ~ ~ ~ ~ 1 ~ ~ ~ ~ ~ ~ A married, 1 snoulcl nave pulled eVeI y sr~-~g, ~v~ an t~J~V111~ a Fellow of one of the Cambridge Colleges anti live the (le- lightfu! life there." He went to Edinburgh to confront Arthur R. Cushny, whose book, The Secretion of Urine, and "modern theory" were wi(lely accepted. The theory embraced filtration and reab- sorption only, even though Bowman and Heidenhain had spoken of secretion much earlier. Cushny was unmoved by . Marshall's visit, or his papers, and still rejectee! secretion in the 1926 edition of his book. It is clear that Cushny could not accept the idea that cells reabsorbed and secretes] or that clif- ferent substances could be handled in different ways. Marshall spent "several delightful weeks" in the reacting physiology laboratory of Europe August Krogh's in Copen- hagen. "This was his old laboratory, an old house machine

ELI KENNERLY MARSHALL, JR. 321 shop and 'diener's' quarters on the ground floor, laboratory on the second floor, and Krogh's living arrangements on the top floor. There were no cupboards in the laboratory and one could roam around and see all the apparatus Krogh had made and used on high shelves. Krogh used to say that if one could theorize and reason correctly for five or ten minutes in physiology without doing an experiment, one was very lucky." He returned to Baltimore greatly invigorated and no longer worried about his lack of training. The secretion prob- lem occupied and stimulated him. The Physiology Depart- ment at Hopkins under Marshall was small and appears to have taken social as well as midday nourishment from Abel's pharmacology group. Like Abel, Marshall gave relatively little time or energy to medical school teaching. Their idea of curricular reform was probably to move toward the small- est number of class hours possible; at one time Abel was run- ning about eighty hours for the entire course. Both anon made their influence felt by force of character and example in subtle ways. In those far-out and very active days, Marshall appeared intense and somewhat remote to his colleagues; he is said to have changed little between 1925 and 1955. He enjoyed reading, and in younger days, walking, but had no hobbies. He liked good company in small doses and looked forward to lunches and dinners at the Hamilton Street Club in downtown Baltimore with a small and select group of law- yers, writers, businessmen, and Hopkins professors. He was something of an ascetic; the life of an English don would have been eminently suitable for him. His physical presence matched his cast of mind. Tall, thin, handsome, well-groomed, and formal, with a strident voice bearing the accent of Charleston, he was uninhibited in giv- ing opinions or criticism of scientific peers. He was famous for his (well-placed) profanity, but this too was selective and

322 BIOGRAPHICAL MEMOIRS emphatic. Three old-fashioned staples were user! with such skill (clamp, hell, anti bastard) that he never needec! or even hinted at the sexual expletives. He had the social graces of his "caste," but no social ambitions or "snobbery." He was a very private person and wouIcl not share personal or family . . . adversities. As he grew older, his photophobia and intermittent cIau- dication worsened, so he die! not enjoy the outdoors. As we shall see, his scientific world expandecl, but his private intel- lectual world continued to be less than that of the usual aca- demic. In the 1920s and after he seemed to revert to the isolates! ways of his boyhood. He hac! little interest in litera- ture, art, religion, music, sports, or philosophy; thus he re- mainect at a distance from most of us. The key was science, and to realize that despite his austere and (to some) fright- ening presence, he was fundamentally kind, supportive, and optimistic about himself and his close colleagues. In 1932 Abe! retired and Marshall was appointee! to his chair, which was renamed Pharmacology and Experimental Therapeutics. There were several reasons for this rather un- usual academic shift; dominant were the desire "to be the oIct man's successor," and the feeling, strong in Marshall at age forty-three, that his destiny lay closer to chemistry than to physiology. There followed an unusual time, for at the peak of his intellectual power and prestige Marshall idled, waiting for chance or observation to point to the future. He was finisher! with the kidney; secretion was proved and accepted by all, and it interested him no longer. In this time of waiting, he die! make an important observation in a different area from all his other major work: that in respiratory depression an- oxia provides a major ventilatory drive mediated through the sino-aortic mechanism (Section III). This tract the mark of

ELI KENNERLY MARSHALL, JR. 323 Marshall's contributions a fundamental discovery and a firm base for human medicine. Marshall held his chair until his retirement in 1955. Dur- ing the twenty-three years of his tenure, he passed through three separate phases of research, which are consiclered be- low (Sections {V-VI). In the first, the sulfonamides, he be- came a principal actor at the dawn of chemotherapy and achiever! world renown. His multiphasic and powerful train- ing was brought to bear on the chemical, physiological, anct pathological aspects of the subject. He was fortunate or prescient in having talented ant! cledicatecl young col- leagues in meclical pharmacology (Winclsor Cutting and Ken- ciall Emerson), bacteriology (Harold White), chemistry (Cal- vin Bratton), and chemotherapy ~ John Litchfielcl). These men, with Morris Rosenfelct, were the nucleus of an aclvanced teaching anc! training department, responsibilities that were not forgotten even though the guiding passion was research. For thirty-five years he sat on the Advisory Board of the Johns Hopkins Medical School and fought, among other things, for freedom in curricular matters, free time for stu- lents, departmental autonomy, and the highest standarcls for faculty selection. He was one of the first to realize the im- portance of clinical pharmacology and began to train men in this area as far back as 1936. While he recognized that such men must be good doctors, he was convinced that they must also be able to take their place as scientists in the pharmacol- ogy departments; this is now the pattern of this "new" field. He believer! that basic pharmacologists should also have med- ical training; after World War II he sought and receiver! pri- vate funds for a program to create pharmacologists by "train- ing medical men in chemistry, or training chemists in medicine." Each man's three-to-six-year program fit inctivicl- ual requirements; the products of the plan are now nearing

324 BIOGRAPHICAL MEMOIRS the ends of their careers in university, governmental, or in- dustrial pharmacology. It was characteristic of Marshall that no matter how pas- sionately he felt about a subject, when he ctroppecl it, he never lookecI back. This was his pattern with the study of renal secretion, sulfonamides, malaria, ant! cinchoninic acids. He scorner! some of his followers who were "looking for the sec onc! clecimal place," but some of those addec! depth to what he began. It freed him from the intellectual torments that Homer Smith surrey! as he followed and classified the twist- ing trails of renal physiology clecade after decacle. Marshall retired in 1955, and in the next clecacle served a variety of useful functions. He became an industrial consul- tant and an advisor to the National Cancer Institute. For four years he spent a month each year teaching at the new Uni- versity of Florida College of Medicine. He continued to ra- ctiate the same intangible love for his subject ant! hope for its future that was the legacy of Abel's lunch table, anct reached back to Schmiecleberg and Buchheim. Each year he gave sev- eral lectures on the kiciney4 and on chemotherapy using an historical perspective and a spare, clear delivery. It pleased him to say that he had known all the significant men in renal physiology after Heiclenhain. There was no other formal teaching, but a string of pleasant days, given to consideration of icleas, observation of experiments, and pronouncements- often spiced with his well-acljusted profanity in the direc- tion of poseurs and incompetents. He became interested in the teaching program and in several of the medical students and kept his appointment until he could see "my first class graduate." There was a most significant part of Marshall's life that was all but concealect from his colleagues in Baltimore and 4 Reprinted in The Physiologist, 9, no. 4 (Nov. 1966).

ELI KENNERLY MARSHALL, JR. 325 his confreres in Washington. This was his role at the Mount Desert Island Biological Laboratory, at Salsbury Cove, Maine, where he summered for forty years. After he completed his renal work in the early 1930s, he stopped working at the laboratory, but at his home, looking over the western aspect of Frenchman's Bay, he read, wrote, talked to friends, ancT gathered energy and enthusiasm for the fall ahead. He fol- lowed the work in the laboratory with his usual attention to detail and provided an astonishing amount anti quality of guidance for generations of investigators. It often seemec! that most of the ongoing work in the laboratory had been presaged, at least qualitatively, by his thinking in those rich, early years. Sometimes these early observations were in his memory, sometimes in his notes, and surprisingly often in the literature; this last to the profound discomfort of the hapless investigator who had rushed off to Maine without a session in the library. Marshall was a somewhat different man in Maine than in Baltimore. At Hopkins, he persisted in the oIcI fashion of calling departmental colleagues and students by their last names, and he kept aloof from their family af- fairs, except for one fine party each year in his home. In Maine, he slipped naturally into first names and showocI true affection and interest for the younger men, as well as their wives ant! children. He and Mrs. Marshall were favorites at parties, and gatherings at their home were greatly enjoyed. Although administration was a distant second to research in his life, Marshall could be most effective when required. This was evident in his directorship of both departments in Baltimore and at two occasions in Maine: the first cluring the reestablishment of the laboratory after World War IT (along with Homer Smith and Roy Forster) and the second when he was president of the laboratory from 1960 to 1964. In these roles he appeared ruthlessly efficient, as if he realized so well how these tasks rankoct compared with science.

326 BIOGRAPHICAL MEMOIRS Marshall's character was perhaps susceptible to (using a favorite word of his) more clean-cut analysis than most, for he possessed absolute integrity. In the light of this undilutec! quality, his occasional (or frequent, clepending on the com- pany) lapses from the amenities shouIct have surprised or ctisturbed no one. He was profoundly loyal to all the men who tract ever worked with him. He was the antithesis of the organization man. Self-reliance was the key; he was an Emerson-like hero. In a certain cast of the stern face, he even resembled the Concord philosopher. Marshall stayed in his laboratory and workocI; he shunned all the ordinary appa- ratus of success. Some of these came to him anyway; he was president of the Pharmacology Society in 1942 and was edi- tor of its journal from 1932 until 1937. He was a member of the American Philosophical Society and the American Asso- ciation of Physicians and received the LL.D. from the College of Charleston in 1941. Astonishingly, in view of all that he pioneered ant! accomplished, he won no prize, received no awards or special honors. Was this related to his utter inde- pendence, his forthright manner, his lack of political ambi- tion, his disregard for compromise, his avoidance of com- mitment to a single field? Such a man will not come again, for the times that pro- cluced him have vanished. He was a bridge between the nineteenth and twentieth centuries for science, medicine, manners, the South, Johns Hopkins, ant! Maine. The phar- macologists now training for the twenty-first century might turn to his scientific life and principles as guides to their fu- ture. . I. UREA AND EARLY KIDNEY STUDIES When Marshall was in AbJerhalclen's laboratory in 1912, he became interested in enzymes anct decided to work on urease, entirely as an academic exercise. Back in Baltimore

ELI KENNERLY MARSHALL, JR. 327 he got some soybeans from an Italian market on Gay Street, and was amazed at the ease and quantitative specificity with which the extracts decomposect urea. He knew iT]hat C.S. Hudson had used the enzyme invertase to determine cane sugar, and I was suddenly struck with the idea that urease could be used to determine urea and that the procedure would be extremely simple. That evening I left the laboratory with L.G. Rowntree and walked with him across Monument Street to the old Johns Hopkins Club. I asked Rowntree if there were any need for a simple, quick method of determin- ing urea in urine, blood and body fluids. He said he was at the time very much interested in determining urea in blood, but the known methods were very difficult, cumbersome and time consuming (Folin's micrometh- ods had just been published and had not come into general use). I told Rowntree I had a very simple method or at least could devise one in a few weeks. He replied that if I did that I could have a Chair in Physiological Chemistry in a very few years. This conversation with Rowntree was a sufficient stimulus to make me go at the matter with great enthusiasm. I believe I talked to Walter Jones about the matter, but he was not at all interested. In a week or 10 days the job was done and my first publication from the Medical School was being prepared. I recall that during this exciting week, I never left the laboratory until 1:00 to 3:00 a.m. It was quite worthwhile to be on the mountaintop for a short time. One of the greatest compliments I have ever had was paid me by Otto Folin at our first meeting. It was at the Philadelphia meeting of the Bio- chemical Society (Christmas 1913~. When I was introduced to Folin, he said that when he had read my paper on the determination of urea by using urease, he thought it was perfect rot. He continued and said that he had tried my method and it was o.k., and he wanted to congratulate me. This from Folin! only a few months after my first paper on Physiological Chemistry had been published. Using this method, Marshall and Davis studied the clistri- bution of urea in tissues and found that it was distributec! evenly and rapidly, except for fat. They also measured its renal clearance. This was a signpost to much later work in kidney physiology and the pharmacology of sulfanilamide.

328 BIOGRAPHICAL MEMOIRS Two other significant studies were done in this decade, the first on the tI]nfluence of the adrenals on the kidney. In it is stated, "The excretion of some substance by the adrenals which is necessary for normal kidney function, and the consequent interrelationship of the two glands serves as a very probable explanation of the results which are presented in this paper. Should it be found possible to prevent the renal changes in animals deprived of their adrenals by injection of adrenal extracts, it would sup- port this hypothesis." About fifteen years later, others found it possible to prevent renal changes by injection of adrenal cortical hormone or extract. I recall clearly that in the first draft of this paper the adrenal cortex was implicated, but in revisions a more cautious statement was made. Another series of observations resulted from my interest of the effect of the adrenals on the kidney. These were done with Kolls during the years 1915-1917. Essentially the important observation was that unilateral sec- tion of splanchnic nerve (or unilateral denervation at the renal pedicle) resulted in anesthetized dogs in the excretion of a much greater amount of water, chloride, bicarbonate, urea, sulfate and phosphate, but of the same amount of creatinine and phenol red by the denervated kidney as com- pared to the normal. In addition, compression of the renal artery could bring about a decrease of water and chloride with no change in the excre- tion of creatinine. The conclusion arrived at was that the changes were caused by vasodilation of renal vessels and increased blood flow to the kidney after section and that secretory action could not be attributed to the renal nerves. Some years later, others found that unilateral nerve sec- tion in the unanesthetized dog produced no change in the excretion of water or chloride. The interpretation then was that renal vessels were not nor- mally in tone, but were put in tone under anesthesia. About a third of a century after our experiments on nerve section, I reconsidered the evi- dence. It seems that the above explanation cannot be correct as no change in the creatinine means no change in glomerular filtration rate and no change in phenol red, no change in renal blood flow. Others have now confirmed this by unilateral nerve section in anesthetized dogs. It looks as if the nerves are actually secretory in the sense of influencing reabsorption by the tubule but why only in anesthetized and not unanesthetized ani- mals? I have been puzzling for years to see how to attack this problem anew.

ELI KENNERLY MARSHALL, JR. II. RENAL SECRETION 329 Marshall came to this work from the urea-acirenal-kidney- renal nerve progression described above. Adclitionally and significantly, his friend Rowntree had twelve years earlier in- troclucecI phenol rec! as a test for renal function-50 percent of the dose was eliminatecT in the first hour. But since fiItra- tion rates were not known (unti! Rehberg, 1926), it was not apparent to anyone (except perhaps Marshall) that the phenol rect data implied a second process. The epoch-making paper with Vickers in 1923 contained two simple observations. Following intravenous injection in the clog: · Phenol red was concentrated in the kidney to 12 x that of plasma. · The amount in the urine was greater than drug (un- bound) fiIterecT, even assuming that all the plasma was fiIterecl. and using a very high value for renal blood flow 300 mI/min, a "safe maximum." The authors concluded that "the problem would appear to be clefinitely settled, and satisfactory evidence would seem to exist that . . . filtration, reabsorption ancT secretion all play a role in the elimination of urine." But it was not so easy new ideas are dangerous and threatening. For one reason or another, these experiments were attacked by Cushny, Starling, A. N. Richarcts,5 Rehberg, Oliver, and Ekehorn. If Marshall tract any supporters (Homer Smith?), they are not in the record. A 1930 paper by Richards and Walker ~ journal of Biological Chemistry, 87:479) records 5 "Alfred Newton Richards," in Biographical Memoirs of the National Academy of Sci- ences, vol. 42 (New York: Columbia University Press for the National Academy of Sciences, 1971), pp. 271-318.

330 BIOGRAPHICAL MEMOIRS "an experiment technically one of the best," in which the ratio of phenol red in frog gIomerular urine/plasma was 16. The astonishing comment follows: "It is impossible however to accept the result." There is no reference to Marshall in the paper. His further work with Crane in 1924 supported secretion, but more interesting events lay ahead. In his wide reading, Marshall came across the fact that certain fish lack gIomeruli; even better, his friend Alan Chesney (later dean and historian of Hopkins) told him that one of these, the goosefish (Lophaus piscatorius), lived in the waters off Maine. Another, the toact- fish (Opsanus taut, lived in the nearby Chesapeake. Accordingly, Marshall went to Maine, anct at the Mount Desert Island Biological Laboratory, with his student AlIan Grafflin (later to become professor of anatomy at Hopkins), showed that phenol recI was excreted in the goosefish without a gIomerulus, along with many other low-molecular-weight substances, sugars excluclecI. He later found the same for the toactfish. The fight was nearing its close; the comparative method tract paid oh. But not before the redoubtable Rich- ards criecI out after Marshall's paper at the XIII Physiolog- ical Congress in Boston- "he found the one beast in the world that will support his theories." In 1931 Marshall wrote his final paper on the subject, bringing the 1923-1924 work into focus with new experi- ments in which gIomerular filtration was measured. The sup- porting data from fish were cited and, most importantly (then and for the historians), there are three pages of rebut- tal to his opponents of the past decacle, the names a roll call of the renal establishment. He finished this era with a masterly review (1934) of the comparative physiology of the kidney. Data on anatomy, physiology, and evolution were synthesized to show the un

ELI KENNERLY MARSHALL, JR. 331 questioned power of the comparative approach, a view that was to be vindicated and amplifiect over the next fifty years. III. INTERLUDE: RESPIRATORY AND CARDIAC PHYSIOLOGY AND PHARMACOLOGY, 1932-1936 We hear best in Marshall's words an account of the rather unusual transition, when he walkocI upstairs from one Hop- kins department to another and began a new academic life at age forty-five. In 1932 when I transferred from the Chair of Physiology to the Chair of Pharmacology and Experimental Therapeutics, the main problem which had interested me for more than a decade in regard to renal phys- iology active secretion by the convoluted tubule was settled. It was an- swered in the affirmative due mainly to the investigations of myself and coworkers. A great number of problems were now apparent and waiting for solution in regard to renal excretion. These were, however, mainly a quantitative study of the qualitative framework which had been established in the past quarter of a century. I deliberately decided not to engage on them, but to seek a new field of research. Some time was spent in 1932- 33, in reorganizing the laboratory course in pharmacology. This led to an interest in respiratory stimulants which lasted until the fall of 1936. One important outcome of this work was the rediscovery of the depression of respiration by oxygen and an analysis of its mechanism. Like so much else of Marshall's work, this study had direct clinical significance; it is a prime rule in accident rooms not to give oxygen to patients depressed with morphine, barbi- turates, or allied drugs. With Rosenfeld he showed that ox- ygen removed the sino-aortic respiratory drive, which had recently been (discovered by Heymans. In a typical vein, Mar- shall invokes the comparative method by recognizing that when the mammal is threatened with anoxemia, "it may adapt itself . . . to a primitive type of respiratory control (the sino-aortic rather than central) which is normal for lower vertebrates."

332 BIOGRAPHICAL MEMOIRS His interest in respiration was coupled to an exercise in physical chemistry in the work (again with Rosenfelcl) on cy- anohycirin equilibria. The goal was to take advantage of the widely varying rates of reactions between CN- and alclehydes or ketones to find a compound to detoxify HCN, and also one that would slowly release CN- as a nontoxic respiratory stimulant. Belonging intellectually to this period, but done earlier, was the first measurement of cardiac output in an unanesthe- tize(1 laboratory animal, using the Fick principle. His col- league GrolIman extended this work ant! applied it to man, using acetylene rebreathing. These papers made considerable advances in their several fields. They show breadth, economy of style, attention to im- portant issues, and high technical competence in both phys- iology and chemistry. None of this work was clone by tech- nicians, ant! the entire budget of the Physiology Department was about $10,000 per year! Fecleral grants, of course, were unknown. IV. CHEMOTHERAPY, 1936-1941 Looking back in 1952, Marshall wrote: It was amusing to be a free lance no held of work waiting for some accidental observation to point out a promising lead.... Then around 1936, I began to read of streptozon (Prontosil) and how it cured human cases of streptococcal and staphylococcal septicemia. Would that my friend Charles Hooper, Research Director of Winthrop (Metz or Bayer it was called) had not died a year or so before of pneumonia, which the new drug could have cured! Hooper used to come down two or three times a year and tell me of the new things cooking at the I. G. at Elberfeld, but always said, "That's what the German Johnnies say, I can't vouch for it. Do you want some of this new drug?" He would have brought Prontosil to me at least two years before I became interested in it. In St. Louis in 1919-1920, I had become interested in the chemother- apy of bacterial infections. Nothing came of this interest except an unpub

ELI KENNERLY MARSHALL, JR. fished address before the St. Louis Section of the American Chem 333 rical So- ciety. When successful bacterial chemotherapy arrived, I was ready for it; partly, I think on account of my meditation in St. Louis eighteen years before and, I think some of my best contributions with my able collab- orators have been in this field. As I can see it, our significant contributions to bacterial chemotherapy were as follows. A simple, accurate and specific method was devised for the determination of sulfonamides in blood and tissues. Using this method, a quantitative study of the absorption, excretion, distribution and degra- dation of sulfanilamide was completed. These results had the effect of devising a rational basis of dosage an initial loading dose and then a maintenance dose every four hours day and night. Soon dosage of the sulfonamides was based on blood concentrations rather than on number of grams administered by mouth. Quantitative methods were devised for studying the effectiveness of the sulfonamides on experimental bacterial ntectlons In mice. As a result of our fundamental studies in bacterial chemotherapy, two new sulfonamide drugs were introduced by us into clinical use. In each instance, this has not only been the introduction of a new drug but of a new principle in bacterial chemotherapy which would be applicable to many other drugs. The chemical and pharmacological properties of the sodium salt of sulfapyridine were first described in a publication from my laboratory. This compound was introduced clinically for intravenous use and was the precursor of the use of sodium salts of other sulfonamides. Sulfanilylguanidine (sulfaguanidine) was prepared here. It had the unique properties of being fairly soluble in water, poorly absorbed from the gas- trointestinal tract and highly active against various bacteria in vitro. This suggested that this drug or one having similar properties might prove useful in the treatment of bacterial infections confined to the intestinal tract, and not exhibit any toxicity on account of poor absorption. Both of these drugs were useful after their introduction; although, now utilizing the same principles, better ones have been found. Sulfaguanidine was sent to the Near East in 1941. Hamilton Fairley was much impressed by it. In "Medicine in Jungle Warfare" (Proc. Roy. Soc. Med., 38:195, 1945) he states that it was the considered opinion of many officers in the Australian Medical Corps that sulfaguanidine saved Port Moresby from the Japanese. This description modestly recalls the facts, but not the excitement, triumphs, and significance of these five years.

334 BIOGRAPHICAL MEMOIRS Marshall and his collaborators were the architects of quanti- tative chemotherapy, and showed the direct line from labo- ratory to clinic. These observations anct measurements were extraordinarily solid anct precise and are still useful. Accu- rate chemistry was dominant in this thinking, and the stan- ard was applied to bacteriological and pathological mea- surements. The blood level concept and practice were born here, along with the idea of drug distribution and decay. It is extraordinary how Marshall's work on urea a quarter century earlier prepared him for sulfanilamicl~e. The discovery of compounds more active and less toxic than sulfanilamide was anticipates] by the quantitative data showing that cure of septicemia in mice was accomplishecI at different blood levels, depending on drug structures: sulfa- ctiazine was sixty-four times as active as sulfanilamicle in vitro, ant! eleven times in viva. These techniques and conclusions hac! a profounct effect on development of sulfonamicles in the drug industry. Even the incidental findings, such as that sulfanilamicle causer! an alkaline urine ant! metabolic aci- dosis, were important. This was on the road to discovery of the carbonic anhycirase inhibitors. V. MALARIA, 194 1-1946 WorIct War II brought sulfonamicle research to an end in Marshall's laboratory. Malaria was "the number one meclical problem of the war" and attacked through a complex ar- rangement under the Emergency Management Act anc! the Office of Scientific Research ant! Development (OSRD), whose medical arm was the Committee on Medical Research (CMR). This interlocked with advisory committees of the Na- tional Research Council and the National Academy of Sci- ences. But it all worked! The CMR was headed by A. Newton Richards, the ctistin

ELI KENNERLY MARSHALL, JR. 335 guished professor of pharmacology at the University of Pennsylvania, ant! Marshall's great antagonist in the battle about renal secretion. There is every evidence that they workoc! beautifully together in the war years. The National Research Council held an organizing conference through their Division of Meclical Sciences in July 1941, at which the following occurred: "After extensive discussion of possible lines of research, various reports were requested. Of those submitted, that of Dr. E. K. Marshall, Jr., foreshadowect what was to become the principal line of work. Special researches were immectiately begun by several of the conferees." Thus it transpired that Marshall became a prime mover in the government malaria program, which expanded enor- mously in the years to come ant! involved universities, indus- tries, and exchange of information with our allies. Commit- tees, panels, and conferences in Washington multipliecI to an astonishing degree, covering the territory from basic parasi- tology to biochemistry to clinical medicine. They were headect by the most eminent (often also the best) men in the fielct. Baltimore became a secondary hub of the vast enter- prise with the establishment of the Survey of Anti-Malarial Drugs, heeled by Dr. Frec;lerick Wiselogle. This office arranged the testing of 13,000 substances re- ceived from hundreds of sources, and codified their activity over a four-year period. The work was accomplished by a clevotecI staff; there was no computer. Marshall was a con- sultant to this unit also, which was about 200 feet from the Pharmacology Department. Investigators who thought they (or their drugs, which came to the same thing) had been slighted in the program referrer! toughly to "the high com- manc! in Baltimore." But unlike most of his colleagues at these councils in the two cities, Marshall also had a very busy laboratory run

336 BIOGRAPHICAL MEMOIRS ning, in which chemicals were screened for their activity in the avian malarial. New methods of analyses were worked out; structure-action relations were analyzecI; distribution of drugs in the body was measured. He was unsparing of him- self and his younger colleagues; it was a crucial wartime ef- fort, seven days a week with no holidays. Rigorous quantification of the experimental avian infec- tions was badly needed. Marshall was often at octUs with the parasitologists; on some he vented ire laced with his usual expletives. Typically the chemists were his allies and friends. He reliecI heavily on Kenneth BlancharcI, a polymath in all branches of chemistry who was to join Marshall's department after the war. It was all exciting and full of high iclealism, but scientifically frustrating. Marshall ctic! not like the idea of bird malaria it represented not only an alien class but organisms alien to human malaria. But it was, at the time, the best they could do. Marshall's close scientific friend, Tames A. Shannon (later the enormously successful director of the National In- stitutes of Health as it became a major force in world re- search) was head of the Research Group at GoIc~water Hos- pital in New York. These two had also an earlier boncI, renal physiology. This curious link of topics was also common to the younger colleagues in the program: Berliner, Taggart, and EarIe. It was Shannon, along with Alf Alving at the Uni- versity of Chicago, who definect the role of the 4-amino and 8-amino quinolines in the human malarial. These men, along with Robert Loeb, Lowell Coggeshall, Leon Schmidt, and many others, were dedicated to the closest attention to ciata obtained from the laboratory anct human volunteers- it was a triumph of true cooperation. It was frustrating that there was no time to work out the many problems that arose almost ciaily. Yet scientific issues were not ignored, and one of great theoretical and practical importance emerged and captured Marshall's imagination. ShouIcl drugs be given to maintain a

ELI KENNERLY MARSHALL, JR. 337 constant bloocI concentration in infectious disease? Marshall, having introduced this concept for the antibacterial sulfon- amicles, was nevertheless convincer! that this ctid not apply to the quinolines in malaria, which had a different pattern of distribution and mechanism of action. It was typical that he was flexible, realistic, and outspoken in such an argument. The situation was indeec! critical. Supplies of quinine were cut off, anct atabrine (quinacrine) turned the skin yellow and was the target of many unfounclec! rumors, typical of war- time, so the troops would not take it. Furthermore, it did not seem to be working well until the Shannon group showed that a loacling dose was essential an early triumph of what is now rather elaborately called pharmacokinetics. This surely reflected Marshall's principle of a loading dose for sul- fonamides, now curiously forgotten in the use of anti- infective agents. Thus quinacrine was found superior to qui- nine and became the most important single contribution to the control of malaria in the Pacific War. Meanwhile, the search for new agents continued. The clis- covery of chIoroquine was a major accomplishment, resulting from study of some 200 4-aminoquinolines. This class sup- presses vivax malaria and is a radical cure for fatciparum ma- laria. A main goal of the program was to find a radical cure for vivax malaria, which was made particularly difficult by lack of basic knowledge about the exoerythrocytic cycle in man, ant! lack of a proper mode! in bircts. Nevertheless, fol- lowing an early German leacI, intensive screening ant! phar- macology was clone on several hundred S-aminoquinolines, leading to the discovery of primaquine, still the chief drug for cure of this clisease. In April 1946 at a Symposium in Wartime Pharmacology at the Federation of American Societies for Experimental Biology, Marshall said farewell to this vexing anct exciting period. It was about his average time for a subject, no matter

338 BIOGRAPHICAL MEMOIRS how passionately pursued. He dropped malaria and never looked back. VI. THE LAST DECADE: METHODS, CINCHONINIC ACIDS, ETHANOL In the fall of 1946 the past had been cleared away, and Marshall at fifty-seven faced fresh problems with new vigor. He was interested in rational dosage schedules for chemo- therapeutic agents, and still rather enraged that his dictum of constant blood levels for sulfonamides unthinkingly had been transferred to the antimalarials and to penicillin. He thought (but Tim Shannon did not agree) that he had de- molished the malaria argument, and now with Gordon Zu- brod he turned to penicillin and showed that a moderate dose interval does not weaken the effect, and that cure is a func- tion of total dose. This was related to its {ytic or bacteriocidal action and still guides use of the drug. Marshall's heart was still in chemistry; he would have loved to develop an analyt- ical method for penicillin, but failed. He did succeed with streptomycin, however, and went on to a full-dress stucly of its pharmacology. In the course of using a selection of cinchoninic acids as fluorescent ligands for antibiotics, Marshall noticed their anti-diuretic effect. (l had come to his laboratory in 1946 as a medical student and trainee: graciously he had allowed me two years to study and finish work of my own on arsenic and antimony left over from war work on tropical diseases.) He now asked me to find if the cinchoninic acids worked through the posterior pituitary or directly on the kidney. To his great disappointment (since no drug of the latter type was known), it was the former. Nevertheless, it introduced us to the hy- pothalamus and then the anterior pituitary; it was the dawn of their relations in the work of Geoffrey Harris of London. Now came a shared excitement, still felt a third of a century

ELI KENNERLY MARSHALL, JR. 339 later; some of the cinchoninic acids synthesized by Blanchard (a clean-cut structure-action relation was found) stimulated the pituitary-adrenal system! It was also the year of ACTH (adrenocorticotropic hormone) and we had (possibly) a new drug for the rheumatoid and other connective tissue dis eases. Once again, it was as if Marshall had been waiting for this, and he sprang into action, mobilizing his clinical associates and students. He and ~ took an unusual step a train trip out to Chicago to attend the first ACTH conference. But the clinical trials of 3-OH-2-pheny~cinchoninic acid were dis- appointing: there was some beneficial effect, but also enough toxicity to end the study. Marshall had no further interest in the theoretical aspect. He left it to his plodding student to section the hypothalamus of the rats (under the tutelage of David Bodian) with pituitary lesions and to guess that these drugs might be working at the level of the naraventricular nuclei. ~1 In the last years, Marshall's luck and judgment continued to hold. He continued with talented and devoted young col- leagues as he had for forty years, particularly Albert Owens, who was also his physician. He still selected important and unsolved problems. Marshall was always intrigued by etha- nol; he now showed that the classical zero-order kinetics of decay trom blood following the usual size dose changes to ~ . . . ~ .. . . first order when the dose is small or at the tail-end of the curve. In the first case the systems for drug metabolism are saturated; in the second they are not. Finally, as a result of his own hospitalization and taking of chIoral hydrate, he be- came interested in its metabolism, neglected since its intro- duction as the first synthetic drug ~ 00 years before. The chief findings were that a very large fraction is oxidized to trichIor- acetate; the smaller amount reduced to trichiorethano! is re- sponsible for the narcotic effect. TrichIorethano} and ethanol

340 BIOGRAPHICAL MEMOIRS share common oxidative pathways, to aldehycle and acid. The data suggested that trichIorethano} itself is a more potent ancI reliable hypnotic than chIoral hydrates it is now marketed as trichIofos sodium, the salt of the phosphate ester of trichior- ethanol. In this last (1955) work, we find again the inspiring char- acteristic of Marshall's work since 1912: the synthesis of the basic sciences in the service of medicines ~ THANK Drs. Robert W. Berliner and C. Gordon Zubrod for their review of this memoir, particularly their help with the malaria story. I am grateful to Dr. I. Wendell Burger for some personal insights into Dr. Marshall's character. The passages quoted in the text are from Dr. Marshall's manuscript memoir, written at various times between 1942 and 1955.

ELI KENNERLY MARSHALL, JR. B IBLIOGRAPHY 1910 341 With S. F. Acree. Uber die quantitative Bestimmung van Diazoal- kylen. Ber. Dsch. Chem. Ges., 33:2323-30. With Sidney Nirlinger and S. F. Acree. Note on the reactions of diazoalkyls with 1-phenyl-2-methylurazole. Am. Chem. }., 43: 424-25. 1911 On the reaction of diazoalkyls with urazoles and their salts. Ph.D. thesis, The Johns Hopkins University. 1913 With S. F. Acree. On the reversible additions of alcohols to nitrites catalyzed by ethylates. I. Am. Chem. i., 49:127-58. With Julia Peachy Harrison and S. F. Acree. On the reactions of both the ions and the nonionized forms of electrolytes. The reversible addition of alcohols to nitrites catalyzed by sodium ethylate. II. J. Am. Chem. Soc., 49:369-405. A rapid clinical method for the estimation of urea in urine. }. Biol. Chem., 14:283-90. On the self-digestion of the thymus. I. Biol. Chem., 15:81-84. On the preparation of tyrosine. I. Biol. Chem., 15:85 -86. A new method for the determination of urea in blood. I. Biol. Chem., 15 :487-94. The determination of urea in urine. I. Biol. Chem., 15:495-96. With L. G. Rowntree. The action of radium emanation on lipase. I. Biol. Chem., 16:379-84. 1914 With H. W. Plaggemeyer. A comparison of the excretory power of the skin with that of the kidney through a study of human sweat. Arch. Intern. Med., 13: 159-68. With L. G. Rowntree and }. T. Geraghty. A study of the compara- tive value of functional tests in the surgical diseases of the kid- ney secondary to obstruction in the lower urinary tract. Surg. Gynecol. Obstet., 18: 196 -202.

342 BIOGRAPHICAL MEMOIRS On soy bean urease: The effect of dilution, acids, alkalies and ethyl alcohol. l. Biol. Chem., 17:351-61. With David M. Davis. Urea: Its distribution in and elimination from the body. l. Biol. Chem., 18:53-80. With L. G. Rowntree and A. M. Chesney. Studies in liver function. Trans. Assoc. Am. Physicians, 29:586 - 625. With A. M. Chesney and L. G. Rowntree. Studies in liver function. I. Am. Med. Assoc., 63:1533-37. 1915 The therapeutic value of organic phosphorus compounds. I. Am. Med. Assoc., 64:573-74. With M. Clark and L. G. Rowntree. Mushroom poisoning. Some observations in a case due to Amanita phalloides. ]. Am. Med. Assoc., 64:1230-32. With L. G. Rowntree and W. A. Baetjer. Further studies of renal function in renal, cardiorenal and cardiac diseases. Arch. In- tern. Med., 15:543 -54. With B. B. Turner and Paul D. Lamson. Observations on plasma- phaeresis. I. Pharmacol. Exp. Ther., 7:129-55. The toxicity of certain hirudin preparations. I. Pharmacol. Exp. Ther., 7:157-68. With L. G. Rowntree. Studies in liver and kidney function in ex- perimental phosphorus and chloroform poisoning. J. Exp. Med., 22:333-46. 1916 With I. G. Mateer. Urease content of certain beans, with special reference to the jack bean. }. Biol. Chem., 24:xxx. With I. G. Mateer. The urease content of certain beans, with special reference to the jack bean. l. Biol. Chem., 25:297-305. With David M. Davis. The influence of the adrenals on the kidneys. I. Pharmacol. Exp. Ther., 8:111-12. With David M. Davis. The influence of the adrenals on the kidneys. I. Pharmacol. Exp. Ther., 8:525-50. 1917 With A. C. Kolls. The effects of unilateral excision of the adrenal, section of the splanchnic nerve and section of the renal nerves on the secretion of the kidney. J. Pharmacol. Exp. Ther., 9:346.

ELI KENNERLY MARSHALL, JR. 343 With A. C. Kolls. The effect of nicotin on the two kidneys after unilateral section of the splanchnic nerve. I. Pharmacol. Exp. Ther., 9:347. 1918 With Vernon Lynch and H. W. Smith. On dichlorethylsulphide (mustard gas). I. The systemic effects and mechanism of action. I. Pharmacol. Exp. Ther., 12:265-90. With Vernon Lynch and Homer W. Smith. On dichlorethylsulphide (mustard gas). II. Variations in susceptibility of the skin to di- chlorethylsulphide. I. Pharmacol. Exp. Ther., 12:291-301. 1919 With A. C. Kolls. An apparatus for the administration of gases and vapors to animals. i. Pharmacol. Exp. Ther., 12: 385-91. With Homer W. Smith and George H. A. Clowes. On dichloro- ethylsulfide (mustard gas). IV. The mechanism of absorption by the skin. }. Pharmacol. Exp. Ther., 13: 1-30. An Institute for Cooperative Research as an aid to the American drug industry. I. Ind. Eng. Chem., 11 :64. With A. C. Kolls. Studies on the nervous control of the kidney in relation to diuresis and urinary secretion. I to V, inclusive. Am. J. Physiol., 49:302-43. Mustard gas. }. Am. Med. Assoc., 73:684-86. 1920 The influence of diuresis on the elimination of urea, creatinine and chlorides. }. Pharmacol. Exp. Ther., 16: 141-54. With John W. Williams. The toxicity and skin irritant effect of cer- tain derivatives of dichloroethyl sulfide. }. Pharmacol. Exp. Ther., 16:259-72. 1921 With Marian M. Crane. A separation of substances eliminated by the kidney into groups on the basis of the effects of changes in blood flow and temporary anemia. Am. }. Physiol., 55:278-79. 1922 The effect of loss of carbon dioxide on the hydrogen ion concen- tration of urine. I. Biol. Chem., 51:3-10.

344 BIOGRAPHICAL MEMOIRS With B. S. Neuhausen. An electrochemical study of the condition of several electrolytes in the blood. }. Biol. Chem., 53:365-72. With Marian M. Crane. Studies on the nervous control of the kid- ney in relation to diuresis and urinary secretion. VI. The effect of unilateral section of the splanchnic nerve on the elimination of certain substances by the kidney. Am. J. Physiol., 62:330-40. 1923 With I. L. Vickers. The mechanism of the elimination of phenol- sulphonephthalein by the kidney. A proof of secretion by the convoluted tubules. The Johns Hopkins Hosp. Bull., 34: 1-7. With Marian M. Crane. The influence of temporary closure of the renal artery on the amount and composition of urine. Am. I. Physiol., 64:387-403. With Joseph Barcroft. The effect of external temperatures on the minute volume in man. Q. J. Exp. Physiol., Suppl.: 180-81. With Joseph Barcroft. Note on the effect of external temperature on the circulation in man. l. Physiol., 58:145-56. 1924 With Marian M. Crane. The secretory function of the renal tu- bules. Am. I. Physiol., 70:465-88. With i. G. Edwards. Microscopic observations of the living kidney after the injection of phenolsulphonephthalein. Am. I. Physiol., 70:489-95. With }. Leonard Vickers. Permeability of the urinary bladder to urea and sodium chloride. Am. i. Physiol., 70:607-12. 1925 Cardiac output. Am. I. Physiol., 72:192. 1926 Studies on the cardiac output of the dog. Am. I. Physiol., 76:178- 79. Studies on the cardiac output of the dog. I. The cardiac output of the normal unanesthetized dog. Am. J. Physiol., 77:459-73. The secretion of urine. Physiol. Rev., 6:440-84. American contemporaries. John Jacob Abel. Ind. Eng. Chem., 18:984.

ELI KENNERLY MARSHALL, JR. 345 Studies on the cardiac output of the dog. II. The influence of atro- pine and carbon dioxide on the circulation of the unanesthe- tized dog. I. Pharmacol. Exp. Ther., 29:167-75. 1928 With Geo. A. Harrop, Jr., and Arthur Grollman. The use of nitro- gen for determining the circulatory minute volume. Am. }. Physiol., 86:99-109. With Arthur Grollman. The time necessary for rebreathing in a lung-bag system to attain homogeneous mixture. Am. I. Phys- iol., 86:110-16. With Arthur Grollman. A method for the determination of the circulatory minute volume in man. Am. I. Physiol., 86:117-37. With Allan L. Grafflin. Structure and function of kidney in Lophius piscatorius. Am. I. Physiol., 85:391. With Allan L. Grafflin. The structure and function of the kidney of Lophius p~scatorius. Bull. Johns Hopkins Hosp., 43:205 -35. 1929 The secretion of urine by the aglomerular kidney. Am. }. Physiol., 90:446-47. The aglomerular kidney of the toadfish (Opsanus taut. Bull. Johns Hopkins Hosp., 45:95 - 101. 1930 The cardiac output of man. Medicine, 9:175-94. A comparison of the function of the glomerular and aglomerular kidney. Am. J. Physiol., 94:1-10. With Homer W. Smith. The glomerular development of the ver- tebrate kidney in relation to habitat. Biol. Bull., 59:135-53. 1931 Physiology of today. In: Biology in Human Affairs, ed. Edward M. East, pp. 272-91. New York: Whittlesey House-McGraw-Hill. The secretion of phenol red by the mammalian kidney. Am. I. Physiol., 99:77-86. 1932 With Allan Lyle Grafflin. The function of the proximal convoluted segment of the renal tubule. I. Cell. Comp. Physiol., 1: 161-76.

346 BIOGRAPHICAL MEMOIRS Kidney secretion in reptiles. Proc. Soc. Exp. Biol. Med., 29:971- 73. The secretion of urea in the frog. }. Cell. Comp. Physiol., 2:349- 53. 1933 With Allan L. Grafflin. Excretion of inorganic phosphate by the aglomerular kidney. Proc. Soc. Exp. Biol. Med., 31:44-46. With W. hi. Burgess and A. M. Harvey. The site of the antidiuretic action of pituitary extract. }. Pharmacol. Exp. Ther., 49:237- 49. 1934 The comparative physiology of the kidney in relation to theories of renal secretion. Physiol. Rev., 14: 133-59. With Morris Rosenfeld. Control of cyanide action: Cyanohydrin equilibria in vivo and in vitro. i. Pharmacol. Exp. Ther., 51: 134. With Morris Rosenfeld. Control of cyanide action: Cyanohydrin equilibria in viva and in vitro. }. Pharmacol. Exp. Ther., 52:445-61. 1935 With Morris Rosenfeld. Depression of respiration by oxygen. ,. Pharmacol. Exp. Ther., 54:155. 1936 With Morris Rosenfeld. Depression of respiration by oxygen. }. Pharmacol. Exp. Ther., 57:437-57. 1937 With Morris Rosenfeld. Pyruvic acid cyanohydrin as a respiratory stimulant. A study of cyanide action. i. Pharmacol. Exp. Ther., 59:222-40. With W. C. Cutting and Kendall Emerson, fir. Acetylation of para- aminobenzenesulfonamide in the animal organism. Science, 85: 202~3. With Kendall Emerson, fir., and W. C. Cutting. Para-amino- benzenesulfonamide. Absorption and excretion: Method of de- termination in urine and blood. }. Am. Med. Assoc., 103:953- 57.

ELI KENNERLY MARSHALL, JR. 347 Determination of sulfanilamide in blood and urine. Proc. Soc. Exp. Biol. Med., 36:422-24. With Edward M. Walzl and D. H. LeMessurier. Picrotoxin as a res- piratory stimulant. I. Pharmacol. Exp. Ther., 60:472-86. With E. M. Walzl. On the cyanosis from sulfanilamide. Bull. Johns Hopkins Hosp., 61:140 - 44. With Kendall Emerson, Jr., and W. C. Cutting. The renal excretion of sulfanilamide. }. Pharmacol. Exp. Ther., 61: 191-95. With Kendall Emerson, tr., and W. C. Cutting. The distribution of sulfanilamide in the organism. }. Pharmacol. Exp. Ther., 61:196-204. Determination of sulfanilamide in blood and urine. I. Biol. Chem.. 122:263-73. 1938 Certain phases of the pharmacologic properties of sulfanilamide. Med. Ann. D.C., 7:5-7. With W. C. Cutting and Kendall Emerson, Jr. The toxicity of sul- fanilamide. I. Am. Med. Assoc., 110:252-57. John Jacob Abel. Science, 87:566-69. With I. T. Litchfield, Jr. The determination of sulfanilamide. Sci- ence, 88:85-86. With W. C. Cutting and W. L. Cover. The absorption and excretion of certain sulfanilamide derivatives. Bull. Johns Hopkins Hosp., 63:318-27. With W. C. Cutting. Absorption and excretion of sulfanilamide in the mouse and rat. Bull. Johns Hopkins Hosp., 63:328-36. With A. C. Bratton and I T. Litchfield, Jr. The toxicity and ab- sorption of 2-sulfanilamidopyridine and its soluble sodium salt. Science, 88: 597-99. 1939 Pharmacology of sulfanilamide. I. Urol., 4 1: 8-1 3. An unfortunate situation in the field of bacterial chemotherapy. l. Am. Med. Assoc., 112: 352-53. Bacterial chemotherapy. The pharmacology of sulfanilamide. Physiol. Rev., 19:240-69. With Perrin H. Long. The intravenous use of sodium sulfapyri- dine. }. Am. Med. Assoc., 112: 1671-75. With A. C. Bratton. A new coupling component for sulfanilamide determination. l. Pharmacol. Exp. Ther., 66:4.

348 BIOGRAPHICAL MEMOIRS With l. T. Litchfield, fir., and H. }. White. The effect of sulfanil- amide on streptococcus infection in mice. Ther., 66:23. i. Pharmacol. Exp. With A. Calvin Bratton. A new coupling component for sulfanil- amide determination. T Biol. Chem., 128: 537-50. John Jacob Abel (1857-19381. Trans. Assoc. Am. Phys., 54:7-8. With I. T. Litchfield, Jr., and H. I. White. The experimental basis for a method for the quantitative evaluation of the effectiveness of chemotherapeutic agents against streptococcus infection in mice. I. Pharmacol. Exp. Ther., 67:437-53. With l. T. Litchfield, Jr. Some aspects of the pharmacology of sul- fapyridine. J. Pharmacol. Exp. Ther., 67:454-75. With A. Calvin Bratton and H. I. White. Comparison of certain pharmacological and antibacterial properties of p-hydrox- aminobenzenesulfonamide and sulfanilamide. Proc. Soc. Exp. Biol. Med., 42: 847-48. With J. T. Litchfield, Jr. Some aspects of the pharmacology of sul- fapyridine. Trans. Assoc. Am. Physicians, 54:154-56. The present status and problems of bacterial chemotherapy. I. Bac- teriol., 39:25(A). 1940 Dr. John I. Abel. Washington Coll. Bull., 18: 17-19. Medical research: The story of sulfanilamide. N.C. Med. }.,1: 1-14. The present status and problems of bacterial chemotherapy. Sci- ence, 91:345-50. With J. T. Litchfield, Tr., and H. l. White. The comparative thera- peutic activity of sulfanilamide, sulfapyridine, and diaminosul- fone in streptococcus infections in mice. I. Pharmacol. Exp. Ther., 69:89-102. With I. T. Litchfield, Jr., and H. I. White. The comparative thera- peutic activity of sulfanilamide, sulfapyridine, sulfathiazole and diaminosulfone in type I pneumococcus infections in mice. }. Pharmacol. Exp. Ther., 69:166-70. Experimental basis of chemotherapy in the treatment of bacterial infections. Bull. N.Y. Acad. Med., 16:723-31. With A. Calvin Bratton, H. J. White, and J. T. Litchfield, Jr. Sul- fanilylguanidine: A chemotherapeutic agent for intestinal in- fections. Bull. Johns Hopkins Hosp., 67:163-88. Sulfanilamide. Encyclopedia Americana, 25:817-18.

ELI KENNERLY MARSHALL, JR. 1941 349 With A. Calvin Bratton, Lydia B. Edwards, and Ethel Walker. Sul- fanilylguanidine in the treatment of acute bacillary dysentery in children. Bull. Johns Hopkins Hosp., 68:94-111. Bacterial chemotherapy. Annul Rev. Physiol., 3:643-70. The pharmacology of sulfanilamide and its derivatives. In: Chemo- therapy. Philadelphia: University of Pennsylvania Press. With H. I. White, A. Calvin Bratton, and }. T. Litchfield, Jr. The relationship between the in vitro and the in vivo activity of sul- fonamide compounds. }. Pharmacol. Exp. Ther., 72: 112-22. With I. T. Litchfield, tr., and H. l. White. The mode of action of neoprontosil in streptococcus infections in mice. }. Pharmacol. Exp. Ther., 72:291-97. With H. I. White, and I. T. Litchfield, Jr. Quantitative comparisons of the activity of sulfanilamide, sulfapyridine, sulfathiazole and sulfadiazine against Escherichia cold in viva and in vitro. }. Phar- macol. Exp. Ther., 73: 104-18. 1942 Chemotherapy of avian malaria. Physiol. Rev., 22: 190-204. With }. T. Litchfield, Jr., and H. I. White. Sulfonamide therapy of malaria in ducks. I. Pharmacol. Exp. Ther., 75:89-104. Sulfaguanidine as a chemotherapeutic agent in intestinal infec- tions. Miss. Doctor, June:4-9. With I. T. Litchfield, Jr., H. i. White, A. C. Bratton, and R. G. Shepherd. The comparative therapeutic activity of sulfonam- ides against bacterial infections in mice. }. Pharmacol. Exp. Ther., 76:226-34. 1944 With Chester Keefer, Rene Dubos, and John S. Lockwood. Sym- posium on War Medicine. Chemotherapy. I. Pharmacology and Toxicology. Clinics, 2:1077-93. 1945 With W. Horsley Gantt. Toxicity of sulfanilamide on higher ner- vous activity. Bull. Johns Hopkins Hosp., 77: 104-15. With Earl H. Dearborn. The degradation of quinine in the duck, chicken, and dog. I. Pharmacol. Exp. Ther., 85:202-5.

350 BIOGRAPHICAL MEMOIRS 1946 With }. T. Litchfield, Jr., and H. J. White. The antimalarial action in ducks of certain sulfanilamide derivatives. }. Pharmacol. Exp. Ther., 86:273 - 79. Chemotherapy of malaria, 1941-45. Fed. Proc., 5: 298-304. With Earl H. Dearborn. The relation of the plasma concentration of quinacrine to its antimalarial activity. }. Pharmacol. Exp. Ther., 88:142-53. With Earl H. Dearborn. A comparison of drug-diet therapy with single daily oral dosage in avian malaria. J. Pharmacol. Exp. Ther., 88: 187-89. With Earl H. Dearborn. Curative action of drugs in lophurae ma- laria of the duck. Proc. Soc. Exp. Biol. Med., 63:46-48. Pharmacological investigations of potential antimalarial drugs. In: Survey of Antimalarial Drugs, 1941 - 45, ed. F. Y. Wiselogle, vol. 1, pp. 59-71. Ann Arbor: J. E. Edwards. 1947 With Earl H. Dearborn. The susceptibility of different species of avian malarial parasites to drugs. Am. }. Hyg., 45:25-28. Scientific principles, methods and results of chemotherapy, 1946. Medicine, 26:155-66. With K. C. Blanchard, and Emmett L. Buhle. Colorimetric meth- ods for determination of streptomycin. }. Pharmacol. Exp. Ther., 90:367-74. 1948 The absorption, distribution and excretion of streptomycin. I. Pharmacol. Exp. Ther., 92:43-48. The dosage schedule of penicillin in bacterial infections. Bull. Johns Hopkins Hosp., 82:403-7. Determination of para-aminosalicylic acid in blood. Proc. Soc. Exp. Biol. Med., 68:471-72. 1949 Distribution of 3,4-dimethyl-5-sulfanilamidoisoxazole in the body. Proc. Soc. Exp. Biol. Med., 68:472 - 73. With K. C. Blanchard. The antidiuretic effect of 3-hydroxy- cinchoninic acid derivatives. }. Pharmacol. Exp. Ther., 95:185- 90.

ELI KENNERLY MARSHALL, JR. 351 The significance of drug concentration in the blood as applied to chemotherapy. In: Evaluation of Chemotherapeutic Agents, ed. Colin M. MacLeod, pp. 3-24. New York: Columbia University Press. Reid Hunt, 1870 - 1948. In: Biographical Memoirs of the National Academy of Sciences, vol.26, pp.25-44. Washington, D.C.: Na- tional Academy of Sciences. With Margaret Merrell. Clinical therapeutic trial of a new drug. Bull. Johns Hopkins Hosp., 85:221 - 30. 1950 With Kenneth C. Blanchard, Earl H. Dearborn, and Thomas H. Maren. Stimulation of the anterior pituitary by certain cinchon- inic acid derivatives. Bull. Johns Hopkins Hosp., 86:83-88. With Kenneth C. Blanchard and Earl H. Dearborn. Further obser- vations on the antidiuretic effect of cinchoninic acid derivatives. Bull. Johns Hopkins Hosp., 86: 89-101. The new science: The use of chemicals in the war on disease. In: Centennial Addresses of the City College of New York, ed. Samuel M. Middlebrook, pp. 33-41. New York: The City College Press. Abel the prophet. Johns Hopkins Mag., 1: 1 1-14. With Earl H. Dearborn. Certain aspects of the pharmacology of 3- hydroxy-2-phenylcinchoninic acid. Bull. Johns Hopkins Hosp., 87:36-49. With K. C. Blanchard, A. M. Harvey, J. E. Howard, A. Kattus, E. V. Newman, and C. G. Zubrod. The effect of 3-hydroxy-2- phenylcinchoninic acid upon rheumatic fever. Bull. Johns Hop- kins Hosp., 87:50-60 With C. Gordon Zubrod and Earl H. Dearborn. Effect of 3- hydroxy-2-phenylcinchoninic acid on renal secretion of phenol red and penicillin. Proc. Soc. Exp. Biol. Med., 74:671-74. With A. M. Harvey, and I. E. Howard, and (by invitation) K. E. Blanchard, C. Gordon Zubrod, Albert Kattus, and E. V. New- man. The effect of 3-hydroxy-2-phenylcinchoninic acid upon rheumatic fever. Trans. Assoc. Am. Phys., 63:108-11. 1951 With Kenneth C. Blanchard and Earl H. Dearborn. Certain aspects of the pharmacology of 3-hydroxycinchoninic acid. Bull. Johns Hopkins Hosp., 88:181-87.

352 BIOGRAPHICAL MEMOIRS 1952 The dosage schedule of chemotherapeutic agents. Pharmacol. Rev., 4:85-105. With Earl H. Dearborn and Louis Lasagna. On the mechanism of the antidiuretic action of cinchoninic acid derivatives. I. Phar- macol. Exp. Ther., 106: 103-21. 1953 With William F. Fritz. The metabolism of ethyl alcohol. T. Phar- macol. Exp. Ther., 109:431-43. 1954 With Albert H. Owens, in Absorption, excretion and metabolic fate of chloral hydrate and trichloroethanol. Bull. Johns Hop- kins Hosp., 95:1-8. Acetylation of sulfonamides in the dog. i. Biol. Chem., 211:499- 503. 1955 With Albert H. Owens, Jr. A comparative evaluation of the hyp- notic potency of chloral hydrate and trichloroethanol. l. Studies at the Johns Hopkins University School of Medicine. II. and III. Bull. Johns Hopkins Hosp., 96:71-83. With Albert H. Owens, Jr. Inhibition of the oxidation of trichlo- roethanol to tricholoracetic acid both in viva and in vitro by antabuse. I. Pharmacol. Exp. Ther., 113:42. The revolution in drug therapy. Johns Hopkins Mag., 6:2. With Albert H. Owens, Jr. Rate of metabolism of ethyl alcohol in the mouse. Proc. Soc. Exp. Biol. Med., 89:573-76. With Albert H. Owens, Jr. Further studies on the metabolic fate of chloral hydrate and trichloroethanol. Bull. Johns Hopkins Hosp., 97:320-26. With Albert H. Owens, Tr. The metabolism of ethyl alcohol in the rat. I. Pharmacol. Exp. Ther., 115:360-70. With Albert H. Owens, in A comparison of the metabolism of ethanol and trichloroethanol. Bull. Johns Hopkins Hosp., 97:359-404.

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Biographic Memoirs: Volume 56 contains the biographies of deceased members of the National Academy of Sciences and bibliographies of their published works. Each biographical essay was written by a member of the Academy familiar with the professional career of the deceased. For historical and bibliographical purposes, these volumes are worth returning to time and again.

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