Whole Organ Approaches to Cellular Metabolism: Permeation, Cellular Uptake, and Product Formation

576 Pages·1998·26.12 MB·English

by  James B. Bassingthwaighte, Carl A. Goresky, John H. Linehan (auth.), John H. Linehan, Carl A. Goresky (eds.)

Whole Organ Approaches to Cellular Metabolism
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Authors and discussants in the planning conference, Whole Organ Approaches to
Cellular Metabolism, held at the Montreal General Hospital, July 14-16, 1995.
Left to right, using informal names: Back row, standing: Nicole Siauve, Hans van
Beek, Sasha Popel, Andi Deussen, Moise Bendayan, Jan Schnitzer, Eugenio
Rasio, Tom Harris, Mel Silverman, Rick Haselton, Said Audi, Chris Dawson,
Colin Rose, and Dick Effros. Front row, sitting: Fernando Vargas, Sandy Pang,
Jim Bassingthwaighte, Francis Chinard, Carl Goresky, Jack Linehan, Andreas
Schwab, Dick Weisiger, Harry Goldsmith. (Absent: Keith Kroll.)
James B. Bassingthwaighte
Carl A. Goresky
John H. Linehan
Editors
Whole Organ Approaches
to Cellular Metabolism
Permeation, Cellular Uptake, and
Product Formation
With 190 Illustrations
, Springer
James B. Bassingthwaighte Carl A. Goresky (deceased)
Department of Bioengineering formerly, Division of Gastroenterology
University of Washington Department of Medicine
Seattle, WA 98195, USA McGill University School of Medicine
Montreal, Quebec H3G
John H. Linehan Canada
Biomedical Engineering Department
Marquette University
Milwaukee, WI 53233-1881,USA
Library of Congress Cataloging-in-Publication Data
Bassingthwaighte, James.
Whole organ approaches to cellular metabolism : permeation, cellular uptake, and product
formation / James B. Bassingthwaighte, Carl A. Goresky, John H. Linehan.
p. cm.
Includes bibliographical references and index.
I. Metabolism. 2. Cell metabolism. 3. Endothelium. 4. Capillaries. 1. Goresky,
Carl A., 1932-1996. II. Linehan, John H. III. Title.
QPI7l.B37 1998
572',4-dc21 97-19015
Printed on acid-free paper.
© 1998 Springer-Verlag New York Inc.
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Carl Arthur Goresky
August 25th, 1932 to March 21st, 1996
Carl Goresky was the epitome of the physician-scientist, and even more. Two
dozen scientists gathered at the Montreal General Hospital in July 1995 to give
tribute to Carl's scientific contributions; they met in admiration, respect, and love
for the man, rather than the symbol of science. They met to plan this book on the
methods and approaches to making discoveries about cellular metabolism in the
intact organ. This is part of the issue of carrying forward the information from
genomics, proteomics, and molecular and cellular biology into physiological
phenotyping and an understanding of the behavior of an intact organ and organ-
ism. Such research can be undertaken only by studying intact systems, an ap-
proach Carl pioneered and promoted.
Carl grew up in CastIegar, in the mountains of British Columbia, where his
father was the town physician. Carl played the piano so well that he could have
made a career of it; he climbed mountains, hunted, collected minerals, and worked
as a stevedore on the Columbia River barges. At 16 he went to McGill, and by 22
had completed a B.Sc. and his M.D. As a part of a medical residency at Johns
Hopkins Medical School he spent 2 years with Dr. Francis Chinard. Francis had
pioneered the multiple indicator dilution technique for estimating solute transport
and volumes of distribution (Chinard et aI., 1955). Carl brought the technology,
v
VI Carl Arthur Goresky
including a sample collecting system and many ideas, back to McGill, where he
completed a Ph.D. His advisor was an encouraging, brilliant man, Arnold Burgen,
whose policy was to give free reign to such a "student," which was just as well
because Dr. Burgen left for Oxford before the thesis was complete.
The first part of the thesis was the hallmark 1963 paper (Goresky. 1963). It
demonstrated that a set of solutes passing through the liver following simultane-
ous bolus injection into the portal vein emerged into the hepatic vein in a charac-
teristic way. The shapes of their outflow dilution curves were identical, relative to
their mean transit time, and could be superimposed upon each other by scaling the
time axis by their individual mean transit times. The observation that the curves
superimposed defined all the solutes to be flow-limited in their exchange between
blood and tissue: RBC, plasma protein, sucrose, sodium, and water. This concep-
tual step was based on the deeper idea that the capillary-tissue exchange unit was
axially distributed, not a lumped compartment or mixing chamber. These two
ideas, coupled with Christian Crone's demonstration that the bolus injection tech-
nique could be used to measure capillary permeability (Crone, 1963), set the stage
for the use of the multiple indicator dilution technique to elucidate substrate
transmembrane transport and intracellular metabolism. Carl's paper on sul-
fobromophthalein published in 1964, the remainder of the thesis, did exactly that.
A refinement of the analysis to correct for catheter delay was published the same
year with Carl's first student Mel Silverman, who worked later with Francis
Chinard.
Kenneth Zierler. Chinard's compatriot as an undergraduate and colleague as a
faculty member at Hopkins, had watched Carl's development in Francis' labora-
tory in 1958-59, and his excellent performance as chief medical resident the next
year. As a reviewer of the 1964 papers for Circulation Research he saw the
brilliance of these: "There was so much meat in it, so creative." Of the 1963 work
he said, "Carl made at least three very important points in this paper, which was
obviously technically meticulous." The first point concerned the axially dis-
tributed geometry of the capillary, which Carl called a "linear two-compartment
system," but which Ken preferred to call a linear two-component system to dis-
tinguish it from the mixing chamber idea associated with the word compartment.
His second point was Carl's simple diagram of the system of partial. rather than
ordinary, differential equations. The third was the flow-limited behavior de-
scribed above.
By "technically meticulous" I think Ken was referring not only to the experi-
mental methods but also the methods of analysis. From his first paper onward,
Carl used mathematical phrasing, and characterized the biology in terms of the
parameters of a precisely hypothesized physiological system. The wealth of pa-
pers that followed over 34 years had his mathematical mark upon them. Each
advanced the field another step. The flow-limited transport idea applied to gasses
carried by erythrocytes, the "red cell carriage effect" (Gore sky et al., 1975). The
use of Michaelis-Menten expressions for saturable transformation appeared in
the 1964 papers. Crone demonstrated this for transport across the brain capillary
membrane barrier for glucose a year later (Crone, 1965).
Carl Arthur Goresky vii
The general, model-free mass balance expressions were laid out by Zierler
(Meier and Zierler, 1954; Zierler, 1962a, 1962b), but Carl had developed the next
stages through model-dependent analyses of the observations: (1) passive barrier
limitation (Goresky et aI., 1970); (2) concentrative transport (Goresky et aI.,
1973); (3) carrier-mediated transport (Silverman and Goresky, 1965); (4) intra-
tissue diffusion (Goresky and Goldsmith, 1973); (5) intraorgan flow heterogeneity
(Rose and Goresky, 1976); (6) transport limitations by two barriers in series (Rose
et aI., 1977; Rose and Goresky, 1977); (7) reaction via intracellular enzymes
(Gore sky et aI., 1983); (8) receptor binding (Cousineau et aI., 1986); and (9)
oxygen transport (Rose and Goresky, 1985).
As Carl unraveled the mysteries of increasingly complex systems, he main-
tained the purity, even if not the simplicity, of the mathematics he used. He
believed in finding the analytical solutions to the partial differential equations,
and while getting advice from Glen Bach of the Department of Mechanical
Engineering, fought his way through each new method of solution. He didn't
really trust the accuracy of numerical methods, I suspect, or didn't feel that they
offered so much benefit that mathematical elegance could be sacrificed. I like
numerical methods for the freedom of concept that they offer, and for speed of
solution, but these were secondary issues for him. Carl was strongly principled.
Carl maintained close relationships with many colleagues inside and outside of
McGill over his career. Foremost among these were Francis Chinard, his early
mentor, and Ken Zierler, Mel Silverman, Arnold Burgen, and others. My relation-
ship with Carl began in 1960 when Carl came to the Mayo Clinic to see his
classmate Andy Engel; Carl and I were both beginning our independent studies
using indicator dilution methods. Thereafter we met regularly not only at scien-
tific meetings but also at each other's homes and institutions, sharing our efforts to
sort out what we didn't understand. Carl made everyone feel a partner in these
explorations; while the average guru tells one how it is, Carl helped everyone to
reason their way toward an answer.
Carl's qualities as a teacher were seldom equalled. He was patient, careful, and
kind, and led the residents and fellows through a topic. The GI residents loved
him; when he died in the Montreal General, they all came as a group to his bedside
to pay their respects. But when presenting a new topic at a scientific meeting he
didn't always think of himself as a teacher but as the presenter of the information,
in all its glory. Some presentations were difficult for the general aUdience, though
great for the cogniscenti; Carl was modest to a fault, in the sense that he seemed to
think that everyone was as smart and quick as he was. At McGill and on many
occasions elsewhere he was a magnificent teacher. One of the best lectures I have
ever heard, Carl gave out of the blue; he was asked to explain indicator dilution
methods to an evening meeting of the National Academy of Engineering in
Washington, D.C. Knowing that the biology was unknown to his audience, but
that quantitative approaches were known, he gave a most erudite comprehensive
review of the concepts and applications in a half hour, with just chalk and
blackboard.
Carl provided leadership in the medical sciences. He edited the journal Clinical
viii Carl Arthur Goresky
and Investigative Medicine throughout his last 12 years. He headed the Division
of Gastroenterology at the two McGill hospitals, the Royal Victoria and the
Montreal General, having brought their two gastroenterology divisions into the
first merger between the two hospitals. His efforts in science and medicine were
recognized for the impact he had on both. He received the Landis Award of the
Microcirculatory Society, the Gold Medal of the Canadian Liver Foundation, the
Distinguished Achievement Award of the American Association for the Study of
Liver Diseases, and many others. In 1995 he was named officer of the Order of
Canada, equivalent to a knighthood in the United Kingdom.
Behind him he leaves many colleagues who will carry on his efforts. Harry
Goldsmith and Andreas Schwab, his close friends and colleagues in the research
unit, Colin Rose in Cardiology, Phil Gold and Doug Kinnear in Medicine, all at
the Montreal General, Eugenio Rasio and Moise Bendayan at the University of
Montreal, Jocelyn Dupuis at the Montreal Heart Institute, Mel Silverman and
Sandy Pang at the University of Toronto, and others scattered around the globe,
continue, like myself, to learn from him and to build upon his ideas. Gone he may
be, but never to be forgotten.
James B. Bassingthwaighte
References
Chinard, F. P., G. J. Vosburgh, and T. Enns. Transcapillary exchange of water and of other
substances in certain organs of the dog. Am. J. Physiol. 183:221-234, 1955.
Crone, C. The permeability of capillaries in various organs as determined by the use of the
"indicator diffusion" method. Acta Physiol. Scand. 58:292-305, 1963.
Crone, C. Facilitated transfer of glucose from blood into brain tissue. J. Physiol. 181: 103-
113,1965.
Meier, P., and K. L. Zierler. On the theory of the indicator-dilution method for measurement
of blood flow and volume. J. Appl. Physiol. 6:731-744, 1954.
Zierler, K. L. Circulation times and the theory of indicator-dilution methods for determin-
ing blood flow and volume. In: Handbook of Physiology, Sect. 2: Circulation, Wash-
ington, D.C.: American Physiological Society, 1962, pp. 585-615.
Zierler, K. L. Theoretical basis of indicator-dilution methods for measuring flow and
volume. Circ. Res. 10:393-407, 1962.
Preface
The field of capillary-tissue exchange physiology has been galvanized twice in
the past 25 years. A 1969 conference at the National Academy of Sciences in
Copenhagen resulted in the book Capillary Permeability: The Transfer of Mole-
cules and Ions Between the Capillary Blood and the Tissue (Crone and Lassen,
1970). It focused on the physiochemical aspects of transcapillary water and solute
transport. The field has matured considerably since. This volume was designed as
the successor to the 1970 book, and was created at a gathering of the authors at
McGill University. It too captures the breadth of a field that has been dramatically
enriched by numerous technical and conceptual advances. In 1970 it was already
known that the capillary wall was not merely a "cellophane bag" exerting steric
hindrances on solute particles. Instead, the endothelial surface was recognized as
the site of binding reactions and permeation by passive or carrier-mediated trans-
port. Furthermore, the cells of the blood could traverse evanescent wide openings
in the "zippered" clefts. Today, research priorities have turned more to cell-cell
interactions, toward understanding the utility of the gap junctional connections
between endothelial cells and neighboring smooth muscle cells, neuronal twigs,
and the parenchymal cells of organs. New discoveries in the past few years have
revealed the critical importance of the close relationships between the endothelial
cells and the parenchymal cells. Endothelial cell transporters, enzymes, and recep-
tors play critical roles in substrate transport to the parenchymal cells of the organ,
and in receptor-mediated responses related both to vasoregulation and to the
functions of the parenchymal cells of the organ. Thus the focus has shifted away
from permeation mechanisms and toward cellular metabolism.
This book brings together contributions from prominent researchers in the
kinetics of blood-tissue exchange processes, in endothelial biochemistry and
metabolism, and in cellular to whole body imaging, around the central theme of
endothelial and parenchymal cellular function. The planning meeting "Whole
Organ Approaches to Cellular Metabolism" was sponsored by the Commission on
Bioengineering in Physiology of the International Union of Physiological Sci-
ences, and supported generously by the Whitaker Foundation. Harry Goldsmith
organized a setting conducive to group discussion at the Montreal General Hospi-
tal. There was a focus on the interpretation of high-resolution data which provide
IX
x Preface
insight into cellular function using simulation analysis applied to physiological
systems. This is the only workable approach for whole animal and human studies
using nuclear magnetic resonance, positron emission tomography, and X-ray
computed tomography-imaging modes that are well suited for acquisition of
data in situations where modeling is essential to understanding of cellular func-
tion. Examples are studies of cancerous growth processes, myocardial and
cerebral ischemia, and the stages of recovery from injury. Positron emission
tomography is particularly useful for examining the distribution of receptors or
the dynamics of changing states of flow and metabolism. Noninvasive imaging
methods are the key to the identification of the local densities of receptors and the
assessment of their normal functions. The whole organ analytical approach pro-
vides the mechanism for integrating knowledge from all of these areas and relat-
ing them to a common set of underlying processes.
As this book was being brought together Carl Goresky died of renal adeno-
carcinoma. He worked strenuously to the end, and on his last day worked on
Chapter 1, the principles. The book is dedicated to his memory, to the many ideas
he pioneered, and to the leadership he provided in science and medicine.
Another colleague has been lost just as his career was blossoming. Keith Kroll,
who was born on December 9, 1948 and died on July 15, 1997, had the same spirit
of perseverance and dedication as did Carl as he struggled with a devastatingly
rapid progression of gastric adenocarcinoma. His last two years saw him emerge
as a leader in the understanding of cellular energy balance in the heart.
Carl Goresky and Keith Kroll were determined, brilliant scholars, kindly
teachers, and wonderful colleagues. While we try to follow in their footsteps, we
cannot do what they would have done.
James B. Bassingthwaighte
John H. Linehan