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Classics in clinical science: James L. Gamble and “gamblegrams”
MEDICINE,
SCIENCE AND SOCIETY
Classics in Clinical Science: James L. Gamble and “Gamblegrams” A. McGEHEE
James Lawder Gamble (1883-1959) one of the most important contributors to the advance of clinical science in this country, graduated from the Harvard Medical School in 1910. Following a two-year medical internship at the Massachusetts General Hospital and a year on the staff at the Children’s Hospital in Boston, he visited various European clinics. His sojourn in Europe represented a turning point in his career, as he developed an interest in the study of disease by the quantitative methods of biochemistry, cumbersome as they were at that time [l-3]. On his return to Boston, Gamble worked for a brief period in the laboratory of Otto Folin, professor of biochemistry at Harvard, where simple chemical procedures applicable to the study of metabolic processes in man were being developed. He then returned to the Massachusetts General Hospital as an investigator in the small chemical laboratory under the direction of Fritz Talbot. While there, he formed an enduring friendship with his Harvard classmate Walter W. Palmer, who later became Professor of Medicine at Columbia’s College of Physicians and Surgeons in New York. Gamble fell under the spell of Professor Lawrence J. Henderson, with whom Palmer was working; he was fascinated by Henderson’s physicochemical approach to physiologic processes. In accepting the Kober Medal of the Association of American Physicians in 1951, Gamble [4] spoke as follows regarding the importance of these early influences on his career: “In 1913 the gentle and kindly Folin gave me headspace . . . and I found it an exciting experience to learn these new technics which made quantitative information so easy to come by. . . I had a great affection for Van Slyke’s first CO2 burette. It was not the large machine of nowadays
HARVEY,
M.D.
with the noisy mechanical shaker. One rocked it gently by hand as a little girl does her doll. . . “On leaving Folin’s laboratory my luck continued. In a small chemistry laboratory at the MGH my classmate Bill Palmer was measuring pH in the urine for the first time and carrying out under Lawrence Henderson’s guidance their classic description of the process of acid excretion . . . Henderson appeared about twice a week to see how Bill was getting along. It was evident that he did not like the clatter that I made dashing about the Laboratory tending my various analyses and one day he came over, placed his hand on my shoulder and said: ‘Young man, you will never get anywhere in this game until you learn an attitude of leisure.’ From then on he took the kindliest interest in my endeavor in a direction for which I was so ill prepared. Although I never worked directly with Henderson I learned from him to admire the beauty of the physico-chemical systems which sustain the body fluids, the marvel of their automaticity and their remarkable resiliency in the presence of obstacles imposed by disease, and ever since I have been content to work in this field as a humble artisan applying the simple tool of quantitative description to the pattern provided by this great architect of concept. Lawrence Henderson’s friendliness, which came to me by sheer accident, I count as one of fortune’s largest gifts.” In 1915, Gamble was invited to become a staff member in the new full-time department of pediatrics under John Howland at the Johns Hopkins University School of Medicine. He remained in Baltimore until 1922 when he was recruited by Oscar Schloss to join him in the establishment of a full-time staff in the department of pediatrics at the Harvard Medical School. Schloss left Boston within a year to return to New York, but fortu-
From the Department of Medicine, The lohns Hopkins University School of Medicine ond Hospital, Baltimore, Maryland. Requests for reprints should be addressed to Dr. A. McCehee Harvey, E. Kennerly Marshall, ]r., Professor of Medicine, Department of Medicine, The lohns Hopkins University School of Medicine and Hospital, Baltimore, Maryland 21205.
904
June 1979 The American Journal of Medicine
Volume 66
MEDICINE, SCIENCE AND SOCIETY--HARVEY
nately Gamble’s close friend, Kenneth Blackfan, succeeded Schloss as head of the department. Gamble and Blackfan made a dramatically successful team at Harvard until Blackfan’s death 18 years later. Gamble, who was made Professor of Pediatrics at Harvard in 1930, continued to work at the Children’s Hospital in Boston until his death in 1959. Gamble’s career blossomed while he was in Baltimore and he never forgot the debt that he owed to John Howland, who gave “a young, ill-trained, would-be investigator a place in his fine new chemistry laboratory and sustained his courage by a kindly disregard of his first fumbling efforts” [4]. Recalling these days, Gamble [4] remarked: “This laboratory was the first one in this country for the study of disease in the clinic by quantitative methods of chemistry. It was the consummation of John Howland’s clear vision of the value of such equipment in a university department. He brought a brilliant young biochemist from St. Louis to set it in motion, The ebullient McKim Marriott lost no time in doing this. We were all expected to make our choice of features of disease to assail by approaches of our own devising so there was in his (Howland’s) laboratory a happy lack of program and a delightful spirit of free adventure. The establishment of the laboratory came opportunely at the beginning of the era of micromethods of measurement which greatly facilitated examination of biochemical events in patients. Clinical medicine was being given a large new armament and it was exciting to find that these methods, which were being developed by Folin, Van Slyke and others, made the information we were after easy to come by.” When Gamble returned to Baltimore in 1919 after a short absence during World War I, Howland had developed a deep interest in the treatment of epilepsy by the ketosis of starvation. Gamble tackled this problem with two Canadian collaborators, Graham Ross and F. F. Tisdall. Rarely have data been subjected to more original deductive reasoning than they were in the classic metabolic experiments which were published in 1922. The results are best summarized in Gamble’s own words [5]: “One, the data display, in operation, the two adjustable components of the acid-base construction of urine (titrable acidity and ammonia production) which Henderson and Palmer described and which permit the removal of anion excess within the prescribed limit for urine acidity without expenditure of fixed base beyond the quantity which probably presents for removal. Two, they show the determining role of fixed base in sustaining the osmolar value of the body fluids because of the adjustability of the total cationanion equality. Three, they show the relation of volume of the body fluids to fixed base content on the premise of preservation of the normal osmolar value with the corollary that, so long as the kidney is operating accurately, loss [or gain) of water and electrolyte will be parallel. On this basis the data were used to allocate losses of water from the body compartments from
measurements of outgo of intracellular and of extracellular base.” Perhaps more significant than the specific contribution which these experiments made to the knowledge of electrolyte physiology was their influence on clinical investigation. At a time when clinical investigation consisted of using some new method to record endless observations, Gamble planned a crucial experiment to elucidate basic problems of function and applied chemical means to this end. In the words of Robert F. Loeb [6]: “These experiments constituted a pioneer approach to the interpretation of quantitative description in terms of the mechanisms involved. Meaning received the primary emphasis. The general design of the experiments devised by Gamble continues to be the pattern for most studies dealing with electrolyte and water metabolism today. The expression of data by simple graphic means, now known as ‘gambelian diagrams’ or ‘gamblegrams,’ has been generally adopted and is a blessing for students, teachers and investigators alike.” The principal feature of Gamble’s numerous studies was the remarkably clear demonstration that the total electrolyte concentration of the body fluids was maintained constant in the face of a great variety of drastic attacks: a constancy he was able to show to be closely dependent upon the acid-base construction of the urine. From these observations he deduced the fundamental role of the concentration of electrolyte in extracellular fluid for determining the distribution of water between the body fluid compartments. The constancy of electrolyte concentration shown by Gamble, although not absolute, is a remarkably good one as biologic constants go. In 1931 Peters and Van Slyke [7] epitomized these investigations as follows: “A corollary of the generalization (Gamble’s), that the total base concentration per unit of water in all tissues of the organism remains constant, is that changes in the base and water content of the organism parallel one another. Gamble and his co-workers had demonstrated that measures which reduce the water content of the organism lead to the excretion of an equivalent amount of base and, conversely, measures which deplete base are attended by equivalent losses of water. Retention of base entails retention of water and accumulation of water is associated with storage of base. When the water changes affect chiefly the extracellular fluid, the base simultaneously retained or lost is chiefly sodium; when the cellular fluids are involved the base which accompanies them is chiefly potassium.” These ideas of Gamble’s form the basis of our understanding of dehydration and edema, and for rational technics of therapy. They also form the central premise for the theoretic formulations and experimental verification of much of our knowledge of the renal mechanisms concerned with electrolyte regulation. As pointed out by William M. Wallace [8], a student
June 1979
The American Journal of Medicine
Volume 66
905
MEDICINE, SCIENCE AND SOCIETY-HARVEY
of Gamble’s, “biochemists and physiologists might write their stories differently and center their evaluation around the work of A. R. Cushney, L. J. Henderson, A. N. Richards, D. D. Van Slyke, A. B. Hastings, H. W. Smith, W. 0. Fenn, and E. F. Adolph. Those from internal medicine would remember that A. W. Sellards described the acidosis of cholera five years before Howland and Marriott published their similar observations and they would construct their history about the contributions of W. W. Palmer, J. H. Austin, W. C. Stadie, J. P. Peters, D. W. Atchley, and R. F. Loeb. There were other pediatricians who made important contributions including Kramer and Shohl and, in addition, D. C. Darrow, A. M. Butler, A. F. Hartman, and G. M. Guest. But whatever point of view is taken in describing the events James Lawder Gamble must remain one of the important pioneers.” After Gamble’s return to Harvard his studies moved forward from the mechanism of acidosis to investigations of the effect of various lesions of the gastrointestinal tract upon the volume and composition of body fluids. In 1933, with Allen Butler and Charles F. McKhann, he published a paper entitled “Intracellular Fluid Loss in Diarrhea1 Dtsease” in which he pointed out the potassium deficits which Daniel Darrow and Gamble’s pupil, Edward Pratt, showed the importance of in their studies carried out,a decade later.
906
June 1979
The American Journal of Medicine
By 1939, Gambfe [9] had assembled his observations and experiments in a looseleaf syllabus, first privately printed and subsequently published by the Harvard University Press, entitled “Chemical Anatomy, Physiology and Pathology of Extracellular Fluid.” This volume is a medical classic which has had an enormous impact upon a whole generation of medical students and physicians. REFERENCES I. Butler AM: Presentation
of the John Howland Medal and Award of the Amercan Pediatric Society to James L. Gamble. Am J Dis Child 90: 483,1959. 2. Janeway C: Pediatric profile-James Lawder Gamble (1883-1959). J Pediatr 56: 701, 1960. 3. Loeb RF: James Lawder Gamble [July 18,1883-May 28.1959) Biog Mem Nat1 Acad Sci 36: 146,1962. (Contains Gamble’s complete bibliography.] 4. Gamble JL: Acceptance of the Kober Medal Award. Trans Assoc Am Physicians 64: 36,195l. 5. Gamble IL, Ross G, Tisdall FF: A study of acidosis due to ketone acids. Trans Am Pediatr Sot 34: 289,1922. 6. Loeb RF: Presentation of the Kober Medal Award to lames Lawder Gamble. Trans Assoc Am Physicians 64: 29,.1951. 7. Peters JP, Van Slyke DD: Quantitative Clinical Chemistry, vol 1. Interpretation. Baltimore, Williams & Wilkins, 1931. 8. Wallace WM: An account of the origins of the investigations of James L. Gamble and an analysis of his contributions to physiology and medicine. Pediatrics 26: 898, 1960. 9. Gamble JL: ChemicaI Anatomy, Physiology and Pathology of Extracellular Fluid: A Lecture Syllabus. Cambridge, Harvard University Press, 1939.
Volume 66
SCIENCE AND SOCIETY
Classics in Clinical Science: James L. Gamble and “Gamblegrams” A. McGEHEE
James Lawder Gamble (1883-1959) one of the most important contributors to the advance of clinical science in this country, graduated from the Harvard Medical School in 1910. Following a two-year medical internship at the Massachusetts General Hospital and a year on the staff at the Children’s Hospital in Boston, he visited various European clinics. His sojourn in Europe represented a turning point in his career, as he developed an interest in the study of disease by the quantitative methods of biochemistry, cumbersome as they were at that time [l-3]. On his return to Boston, Gamble worked for a brief period in the laboratory of Otto Folin, professor of biochemistry at Harvard, where simple chemical procedures applicable to the study of metabolic processes in man were being developed. He then returned to the Massachusetts General Hospital as an investigator in the small chemical laboratory under the direction of Fritz Talbot. While there, he formed an enduring friendship with his Harvard classmate Walter W. Palmer, who later became Professor of Medicine at Columbia’s College of Physicians and Surgeons in New York. Gamble fell under the spell of Professor Lawrence J. Henderson, with whom Palmer was working; he was fascinated by Henderson’s physicochemical approach to physiologic processes. In accepting the Kober Medal of the Association of American Physicians in 1951, Gamble [4] spoke as follows regarding the importance of these early influences on his career: “In 1913 the gentle and kindly Folin gave me headspace . . . and I found it an exciting experience to learn these new technics which made quantitative information so easy to come by. . . I had a great affection for Van Slyke’s first CO2 burette. It was not the large machine of nowadays
HARVEY,
M.D.
with the noisy mechanical shaker. One rocked it gently by hand as a little girl does her doll. . . “On leaving Folin’s laboratory my luck continued. In a small chemistry laboratory at the MGH my classmate Bill Palmer was measuring pH in the urine for the first time and carrying out under Lawrence Henderson’s guidance their classic description of the process of acid excretion . . . Henderson appeared about twice a week to see how Bill was getting along. It was evident that he did not like the clatter that I made dashing about the Laboratory tending my various analyses and one day he came over, placed his hand on my shoulder and said: ‘Young man, you will never get anywhere in this game until you learn an attitude of leisure.’ From then on he took the kindliest interest in my endeavor in a direction for which I was so ill prepared. Although I never worked directly with Henderson I learned from him to admire the beauty of the physico-chemical systems which sustain the body fluids, the marvel of their automaticity and their remarkable resiliency in the presence of obstacles imposed by disease, and ever since I have been content to work in this field as a humble artisan applying the simple tool of quantitative description to the pattern provided by this great architect of concept. Lawrence Henderson’s friendliness, which came to me by sheer accident, I count as one of fortune’s largest gifts.” In 1915, Gamble was invited to become a staff member in the new full-time department of pediatrics under John Howland at the Johns Hopkins University School of Medicine. He remained in Baltimore until 1922 when he was recruited by Oscar Schloss to join him in the establishment of a full-time staff in the department of pediatrics at the Harvard Medical School. Schloss left Boston within a year to return to New York, but fortu-
From the Department of Medicine, The lohns Hopkins University School of Medicine ond Hospital, Baltimore, Maryland. Requests for reprints should be addressed to Dr. A. McCehee Harvey, E. Kennerly Marshall, ]r., Professor of Medicine, Department of Medicine, The lohns Hopkins University School of Medicine and Hospital, Baltimore, Maryland 21205.
904
June 1979 The American Journal of Medicine
Volume 66
MEDICINE, SCIENCE AND SOCIETY--HARVEY
nately Gamble’s close friend, Kenneth Blackfan, succeeded Schloss as head of the department. Gamble and Blackfan made a dramatically successful team at Harvard until Blackfan’s death 18 years later. Gamble, who was made Professor of Pediatrics at Harvard in 1930, continued to work at the Children’s Hospital in Boston until his death in 1959. Gamble’s career blossomed while he was in Baltimore and he never forgot the debt that he owed to John Howland, who gave “a young, ill-trained, would-be investigator a place in his fine new chemistry laboratory and sustained his courage by a kindly disregard of his first fumbling efforts” [4]. Recalling these days, Gamble [4] remarked: “This laboratory was the first one in this country for the study of disease in the clinic by quantitative methods of chemistry. It was the consummation of John Howland’s clear vision of the value of such equipment in a university department. He brought a brilliant young biochemist from St. Louis to set it in motion, The ebullient McKim Marriott lost no time in doing this. We were all expected to make our choice of features of disease to assail by approaches of our own devising so there was in his (Howland’s) laboratory a happy lack of program and a delightful spirit of free adventure. The establishment of the laboratory came opportunely at the beginning of the era of micromethods of measurement which greatly facilitated examination of biochemical events in patients. Clinical medicine was being given a large new armament and it was exciting to find that these methods, which were being developed by Folin, Van Slyke and others, made the information we were after easy to come by.” When Gamble returned to Baltimore in 1919 after a short absence during World War I, Howland had developed a deep interest in the treatment of epilepsy by the ketosis of starvation. Gamble tackled this problem with two Canadian collaborators, Graham Ross and F. F. Tisdall. Rarely have data been subjected to more original deductive reasoning than they were in the classic metabolic experiments which were published in 1922. The results are best summarized in Gamble’s own words [5]: “One, the data display, in operation, the two adjustable components of the acid-base construction of urine (titrable acidity and ammonia production) which Henderson and Palmer described and which permit the removal of anion excess within the prescribed limit for urine acidity without expenditure of fixed base beyond the quantity which probably presents for removal. Two, they show the determining role of fixed base in sustaining the osmolar value of the body fluids because of the adjustability of the total cationanion equality. Three, they show the relation of volume of the body fluids to fixed base content on the premise of preservation of the normal osmolar value with the corollary that, so long as the kidney is operating accurately, loss [or gain) of water and electrolyte will be parallel. On this basis the data were used to allocate losses of water from the body compartments from
measurements of outgo of intracellular and of extracellular base.” Perhaps more significant than the specific contribution which these experiments made to the knowledge of electrolyte physiology was their influence on clinical investigation. At a time when clinical investigation consisted of using some new method to record endless observations, Gamble planned a crucial experiment to elucidate basic problems of function and applied chemical means to this end. In the words of Robert F. Loeb [6]: “These experiments constituted a pioneer approach to the interpretation of quantitative description in terms of the mechanisms involved. Meaning received the primary emphasis. The general design of the experiments devised by Gamble continues to be the pattern for most studies dealing with electrolyte and water metabolism today. The expression of data by simple graphic means, now known as ‘gambelian diagrams’ or ‘gamblegrams,’ has been generally adopted and is a blessing for students, teachers and investigators alike.” The principal feature of Gamble’s numerous studies was the remarkably clear demonstration that the total electrolyte concentration of the body fluids was maintained constant in the face of a great variety of drastic attacks: a constancy he was able to show to be closely dependent upon the acid-base construction of the urine. From these observations he deduced the fundamental role of the concentration of electrolyte in extracellular fluid for determining the distribution of water between the body fluid compartments. The constancy of electrolyte concentration shown by Gamble, although not absolute, is a remarkably good one as biologic constants go. In 1931 Peters and Van Slyke [7] epitomized these investigations as follows: “A corollary of the generalization (Gamble’s), that the total base concentration per unit of water in all tissues of the organism remains constant, is that changes in the base and water content of the organism parallel one another. Gamble and his co-workers had demonstrated that measures which reduce the water content of the organism lead to the excretion of an equivalent amount of base and, conversely, measures which deplete base are attended by equivalent losses of water. Retention of base entails retention of water and accumulation of water is associated with storage of base. When the water changes affect chiefly the extracellular fluid, the base simultaneously retained or lost is chiefly sodium; when the cellular fluids are involved the base which accompanies them is chiefly potassium.” These ideas of Gamble’s form the basis of our understanding of dehydration and edema, and for rational technics of therapy. They also form the central premise for the theoretic formulations and experimental verification of much of our knowledge of the renal mechanisms concerned with electrolyte regulation. As pointed out by William M. Wallace [8], a student
June 1979
The American Journal of Medicine
Volume 66
905
MEDICINE, SCIENCE AND SOCIETY-HARVEY
of Gamble’s, “biochemists and physiologists might write their stories differently and center their evaluation around the work of A. R. Cushney, L. J. Henderson, A. N. Richards, D. D. Van Slyke, A. B. Hastings, H. W. Smith, W. 0. Fenn, and E. F. Adolph. Those from internal medicine would remember that A. W. Sellards described the acidosis of cholera five years before Howland and Marriott published their similar observations and they would construct their history about the contributions of W. W. Palmer, J. H. Austin, W. C. Stadie, J. P. Peters, D. W. Atchley, and R. F. Loeb. There were other pediatricians who made important contributions including Kramer and Shohl and, in addition, D. C. Darrow, A. M. Butler, A. F. Hartman, and G. M. Guest. But whatever point of view is taken in describing the events James Lawder Gamble must remain one of the important pioneers.” After Gamble’s return to Harvard his studies moved forward from the mechanism of acidosis to investigations of the effect of various lesions of the gastrointestinal tract upon the volume and composition of body fluids. In 1933, with Allen Butler and Charles F. McKhann, he published a paper entitled “Intracellular Fluid Loss in Diarrhea1 Dtsease” in which he pointed out the potassium deficits which Daniel Darrow and Gamble’s pupil, Edward Pratt, showed the importance of in their studies carried out,a decade later.
906
June 1979
The American Journal of Medicine
By 1939, Gambfe [9] had assembled his observations and experiments in a looseleaf syllabus, first privately printed and subsequently published by the Harvard University Press, entitled “Chemical Anatomy, Physiology and Pathology of Extracellular Fluid.” This volume is a medical classic which has had an enormous impact upon a whole generation of medical students and physicians. REFERENCES I. Butler AM: Presentation
of the John Howland Medal and Award of the Amercan Pediatric Society to James L. Gamble. Am J Dis Child 90: 483,1959. 2. Janeway C: Pediatric profile-James Lawder Gamble (1883-1959). J Pediatr 56: 701, 1960. 3. Loeb RF: James Lawder Gamble [July 18,1883-May 28.1959) Biog Mem Nat1 Acad Sci 36: 146,1962. (Contains Gamble’s complete bibliography.] 4. Gamble JL: Acceptance of the Kober Medal Award. Trans Assoc Am Physicians 64: 36,195l. 5. Gamble IL, Ross G, Tisdall FF: A study of acidosis due to ketone acids. Trans Am Pediatr Sot 34: 289,1922. 6. Loeb RF: Presentation of the Kober Medal Award to lames Lawder Gamble. Trans Assoc Am Physicians 64: 29,.1951. 7. Peters JP, Van Slyke DD: Quantitative Clinical Chemistry, vol 1. Interpretation. Baltimore, Williams & Wilkins, 1931. 8. Wallace WM: An account of the origins of the investigations of James L. Gamble and an analysis of his contributions to physiology and medicine. Pediatrics 26: 898, 1960. 9. Gamble JL: ChemicaI Anatomy, Physiology and Pathology of Extracellular Fluid: A Lecture Syllabus. Cambridge, Harvard University Press, 1939.
Volume 66