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46th APS President (1973-1974)
Daniel C. Tosteson
(b. 1925)
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.
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