Daniel C. Tosteson

46th APS President (1973-1974)
Daniel C. Tosteson

Born in Milwaukee, Wisconsin, Tosteson's professional career has been identified mainly with two eastern institutions, Harvard and Duke Universities. He graduated from Harvard College (1944) and from its medical school (1949) and then undertook the postdoctoral training described below. On his return from England (1958) he was appointed associate professor in the Department of Physiology of Washington University in St. Louis, but he remained there for only three years. In 1961 he became professor and chairman of the Department of Physiology and Pharmacology at Duke. Ten years later he was made also a James B. Duke Distinguished Professor and remained so until 1975 when he moved for two years to the University of Chicago. There he was simultaneously dean of the Division of Biological Sciences and of the Pritzker School of Medicine, vice-president for the Medical Center, and Lowell T. Coggeshall Professor of Medical Sciences. In 1977 he assumed similar positions at Harvard as dean of the faculty of medicine, president of the Harvard Medical Center, and Caroline Shields Walker Professor of Physiology. Throughout this sequence of top-level administrative positions, Tosteson has retained his identity as a physiologist and his reputation as an investigator at the forefront of membrane phenomena.

In both his pre- and postdoctoral training, Tosteson encountered a remarkably distinguished succession of mentors. He wrote of these years:
"My research interests are in general physiology. As a medical student and resident, I was attracted by the thinking of C. Bernard, L. J. Henderson, J. Loeb, and others who created this discipline by connecting and integrating biology with chemistry and physics. More specifically, I am interested in cellular functions and molecular mechanisms of ion transport across biological membranes. My fascination with the roles of water and salt in living systems began when I studied inorganic chemistry in Harvard College. It was strengthened during my first years at Harvard Medical School when I had the opportunity to learn under the tutelage of Professors E. M. Landis, H. Davenport, A. B. Hastings, J. Gamble, and others. This developing interest prompted me to do research with Eugene Landis for a year between my third and fourth years in medical school. During that year, I encountered J. R. Pappenheimer who had just joined the Department of Physiology at Harvard Medical School and whose analytical mind and enthusiastic commitment to the search for truth made a lasting impression on me."

"It was during my two years as a medical resident at the Presbyterian Hospital in New York that I first began working with ion movements across red cell membranes. I feel a strong sense of respect and gratitude to Robert F. Loeb who was my chief mentor during those years and to Bert Mudge and Bob Darling who permitted me to work in their laboratories. My postdoctoral years at Brookhaven National Laboratory, when I had the opportunity to talk frequently with D. D. Van Slyke, increased my understanding of and interest in the physiology of red cells. I was further encouraged in conversations with E. Ponder, A. Parpart, and M. Jacobs, among others. It was during that time that I first met J. F. Hoffman with whom I have worked closely, though intermittently, ever since."

"From 1955 to 1957, I spent two wonderful years in Europe, first in Copenhagen with H. H. Ussing and later in Cambridge with A. L. Hodgkin. I continued to work with red cell membranes, even though they were not the main line of work either in Ussing's or Hodgkin's laboratories. I spent many educational hours brainstorming with Hans Ussing during the time when he was first developing a picture of the differences in transport properties of the inward- and outward-facing membranes of the epithelial cells in frog skin. At the laboratories on Downing Street in Cambridge, I not only had the privilege of encountering Alan Hodgkin, but also many other outstanding scientists such as A. F. Huxley, R. Keynes, W. Rushton, I. M. Glynn, B. Matthews, and the Adrians, father and son. The final part of my lengthy (7 years) postdoctoral research training was at NIH in the Laboratory of Kidney and Electrolyte Metabolism of the National Heart Institute, then under the direction of Bob Berliner. Through the efforts of Bob, Jim Shannon, and others, NIH was then, as now, a superb environment for the growth and maturation of young investigators. Many of the associations and acquaintances that I made then have persisted throughout my career."

Three papers (e.g., ref. 1) describe the first experiments Tosteson conceived and carried out independently---ion transport in red blood cells from patients with sickle cell anemia. The relation between physicochemical properties of hemoglobin and transport of ions across red cell membranes still occupies his attention, with current work on cation transport in red cells from individuals homozygous for hemoglobin C. Three later papers (e.g., ref. 2) helped open a fruitful line of investigation that eventually led to understanding how the co-transport of Na and K in avian red cells is hormone and volume regulated. Similar transport systems seem to be present in many types of mammalian cells.

In his paper published in 1959 (3), Tosteson wrote of his long-term interest in transport of Cl- and other monovalent anions across red cell membranes. "I did most of the work during my happy visit to Copenhagen in 1955-56." Two papers (4, 7) were done with colleagues named Hoffman, the former with J. F. Hoffman when he and Tosteson were together at NIH, the latter with an M.D.-Ph.D. student at Duke, P. G. Hoffman. They represent a number of studies from Tosteson's laboratory on high-K+ and low-K+ sheep red cells. Tosteson said he began the study hoping to learn how membrane transport regulates the Na and K composition of cells. The theoretical basis of experiments he and J. F. Hoffman described (4) was done "in Cambridge on those cold, dark mornings in the winter and spring of 1957." The second of the papers (7) made two important points about cation transport in high-K+ and low-K+ sheep red cells: 1) the difference between the two genotypes is due not only to a greater membrane surface concentration of Na-K pumps in high-K+ cells, but also to a difference in kinetic properties of the pumps in the two types of cells, and 2) the inside-facing and outside-facing sides of the pump are kinetically isolated from one another. A paper published in 1975 (10) is the first report of the most important pathway regulating distribution of lithium between inside and outside of human red cells. The maximum rate of transport through this system varies from one person to another, and these interindividual differences can be correlated with syndromes such as mania and hypertension.

In 1967 Tosteson and Andreoli and their colleagues began a continuing effort to use lipid bilayers to analyze molecular events in transport of ions across biological membranes and to connect the primary, secondary, and tertiary structure of molecules with their capacity to promote transport of ions across membranes (5, 6). Most of this work has been done in collaboration with his wife, Magdalena T. Tosteson. Examples of molecules studied in this manner include valinomycin (6) and some of its analogues (e.g., ref. 12), cholera toxin (11), and mellittin (13). Finally, Tosteson wrote that another theme of his research on bilayers is work done with J. Gutknecht (8) on the role of unstirred layers in regulating transport across membranes.

Tosteson was elected to membership in the Institute of Medicine of NAS in 1975 and to fellowship in AAAS (Boston) in 1979 and also in the Danish Royal Society. He has held senior offices in the Society of General Physiologists (president, 1968-69), AAMC (1960-70; chairman, 1973-74), and the Biophysical Society (Council, 1970-73). He is a member of the Association of American Physicians. The honorary degree doctor of science has been awarded to him by the Universities of Copenhagen (1979) and Liege (1983), as well as by the Medical College of Wisconsin (1984).

Most of the major national and federal scientific organizations have called on Tosteson for counsel from time to time. These include several committees and boards of NAS and the NRC, NIH, the National Science Foundation (NSF), the National Board of Medical Examiners, the Universities of Texas and of California, and the National Kidney Disease Foundation. He is a founding member of the National Foundation for Depression. For APS, Tosteson was elected councillor in 1968 and president elect in 1972. He served also as a member of the Education Committee as a representative of the general physiologists (1961-67), of the Finance Committee (1977-79), and of the Editorial Board of Physiological Reviews (1976-78).

During his term as president, Tosteson was particularly concerned about the relationship of the Society to the rapidly expanding fields of molecular, cellular, and general physiology. He attempted to increase the representation of these specialties in annual and fall meetings and also in affairs of APS. One method for attaining this goal was to organize a three-day intersociety colloquium at the 1974 Spring Meeting of FASEB on the topic "Membranes, ions and impulses," in collaboration with representatives of the Biophysical Society and the Societies for Neuroscience and of General Physiology. In his past president's address (9), Tosteson summarized his conclusions about these problems and spoke to the changing concepts and definitions that effect physiology and physiologists. In a more recent appraisal he has written:

"At present, the epistemology of the biological sciences is arcane and confused. . . . One might ask whether the word, physiology, has served its purpose and should be gracefully retired to the archives. Aside from the obvious practical, sound, economic, and even political problems that such action would encounter, there is a deeper philosophical reason for sustaining and strengthening the discipline. . . . Because of new and exciting discoveries in recent decades, the conceptual and practical pathway toward complete characterization of every molecule that comprises a human being or any other living entity is now open. It is no longer a question of whether but of when such information will be available. But it is a serious, nontrivial question as to how we can best use this vast body of information. . . . It seems to me that this difficult theoretical and integrative work is at the center of our discipline. Physiology as long attracted individuals with a frame of mind to seek out such labors.

Selected Publications

1. Tosteson, D. C., E. Shea, and E. C. Darling. Potassium and sodium of red blood cells in sickle cell anemia. J. Clin. Invest. 31: 406, 1952.

2. Tosteson, D. C., and J. S. Robertson. Potassium transport in duck red cells. J. Cell. Comp. Physiol. 47: 147, 1956.

3. Tosteson, D. C. Halide transport in red blood cells. Acta Physiol. Scand. 46: 19, 1959.

4. Tosteson, D. C., and J. F. Hoffman. Regulation of cell volume by active cation transport in high and low potassium sheep red cells. J. Gen. Physiol. 44: 169, 1960.

5. Andreoli, T. E., J. A. Bangham, and D. C. Tosteson. The formation and properties of thin lipid membranes from HK and LK sheep red cell lipids. J. Gen. Physiol. 50: 1729, 1967.

6. Andreoli, T. E , M. Tieffenberg, and D. C. Tosteson. The effect of valinomycin on the ionic permeability of thin lipid membranes. J. Gen. Physiol. 50: 2527, 1967.

7. Hoffman, P. G., and D. C. Tosteson. Active sodium and potassium transport in high potassium and low potassium sheep red cells. J. Gen. Physiol. 58: 438, 1971.

8. Gutknecht, J., L. Brunner, and D. C. Tosteson. The permeability of thin lipid membranes to bromide and bromine. J. Gen. Physiol. 59: 486, 1972.

9. Tosteson, D. C. Physiology and the future, past-president's address. Physiologist 17: 423-430, 1974.

10. Haas, M., J. Schooler, and D. C. Tosteson. Coupling of lithium to sodium transport in human red cells. Nature Lond. 258: 428, 1975.

11. Tosteson, M. T., and D. C. Tosteson. Bilayers containing gangliosides develop channels when exposed to cholera toxin. Nature Lond. 275: 142-144, 1978.

12. Latorre, R., J. J. Donovan, W. Koroshetz, D. C. Tosteson, and B. F. Gisin. Ion transport mediated by the valinomycin analog cyclo (L-Lac-L-Val-D-Pro-D-Val) (PV-Lac). J. Gen. Physiol. 77: 387-417, 1981.

13. Tosteson, M. T., and D. C. Tosteson. The sting: mellittin forms channels in lipid bilayers. Biophys. J. 36: 109-116, 1981.