Table Of ContentA PHYSICAL THEORY OF THE LIVING STATE:
the Association-Induction Hypothesis
A BLAISDELL BOOK IN THE PURE AND APPLIED SCIENCES
Consulting Editor
P A U L R . G R 0 S S , Brown University
A PHY ICAL THEORY
OF THE
LIVING STATE:
the Association-Induction Hypothesis
with Considerations of the Mechanisms Involved
in Ionic Specificity, Behavior of Proteins, Selective
Accumulation of Ions and Nonelectrolytes, Cellular
Electrical Potentials, Ionic Permeability and Diffu-
sion, Excitation and Inhibition, Contractile Mech-
anism, Enzyme Action, Drug and Hormone Action,
Antibody-Antigen Reaction, Fertilization, Chemical
Embryology, Growth, Differentiation, and Cancer
GILBERT NING LING
BLAISDELL PUBLISHING COMPANY
A Division of Random House, Inc.
NEW YORK· LONDON
First Edition, 1962
Copyright @ 1962, by Blaisdell Publishing Company,
a Division of Random House, Inc.
All rights reserved under International and Pan-American
Copyright Conventions.
Library of Congress Catalog Card Number: 62-11835
Manufactured in the United States of America
Dedicated to
my father, Yen-tseLing ;k_ ~ 7J. fu j_
my mother, Chi-Ian Ling ; t. );.j -- rfj ~ A
and
my wife, Shirley W. Ling
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PREFACE
Over a dozen years ago, Gilbert Ling arrived at my laboratory at the University
of Chicago as a Boxer Fellow from China to start his graduate studies. At that
time, the capillary electrode was being developed and he entered vigorously into
its improvement and use in measuring membrane potentials. Extensive experi-
ments directed toward analysis of the metabolic events maintaining these poten-
tials led to the conclusion that the frog sartorius muscle fiber retains a considerable
membrane potential despite the blocking or suppression of all known metabolic
processes. The potential and the asymmetric concentrations of ions inside and
outside the muscle fiber with which the potential is associated must then be a
static rather than a dynamic or flux type of equilibrium.
Ions, Ling reasoned, distribute themselves between the protoplasm and the
intercellular phases in accordance with a pre-existing standard free-energy differ-
ence established by the architecturally maiutained pattern of fixed charges. The
protein skeleton of the cytoplasm, with its ionic sites, would bind free ions; on
thermodynamic grounds, potassium would be the more firmly associated cation.
This was the heart of Ling's "Fixed-Charge Hypothesis." It led to many experi-
ments, successfully performed, which indeed indicated that no pump or semi-
permeable membrane is required to maintain the ionic inequalities inside and
outside the cell. I attempted to summarize this phase of the theory for Ling at
the Wisconsin Conference on "Metabolic Aspects of Transport Across Cell Mem-
branes." In the intervening years, this relatively simple and static picture has
been enriched in many directions. It has been applied in this monograph to the
most varied phenomena of living systems.
The performance of living systems depends on their organized and dynamic
heterogeneity, itself produced by the system's own early activity at the level of
subordinate units in response to continuing environmental stimuli. The parallel-
cylinder organization of muscle fibers, fibrils, and protein threads makes possible
the functional shortening and thickening of contraction and the resultant forces
vii
viii PREFACE
and movements of larger structures; but the organization of these fibers and
fibrils is the result of previous activity of macromolecules, molecules, and ions,
and demands the existence of an organized heterogeneity also in this micro
domain. Biologists have advanced the understanding of structures in organisms,
through organs, cells, and organelles, to the resolution limits of electron micros-
copy. Chemists have revealed the scaffolding from electron-shelled atoms,
through simple complex molecules, to the great polymeric macromolecules.
It is in the realm between macromolecule and protoplasm that Ling's con-
tribution falls. His formulation attempts to bring order into the confusion of
phases within and without organized protoplasmic structures, much as W. Gibbs
succeeded in bringing order out of the confusion of the behavior of solutes in
multiphased simpler systems.
Life is, indeed, "a thing of watery salt," enmeshed in a macromolecular frame-
work. Its rich play of behavior emerges from the inhomogeneities of its simplest
components as these become magnified through interaction and combination,
just as the full richness of language depends on the component letters and pho-
nemes and their ordering. If the stuff of life is built from water, simple ions,
molecules, and macromolecules, then particularities which seem trivial at the
molecular level must magnify into singularities of great moment at higher levels
of organization.
The courageous insight of Arrhenius gave us ions and the explanation of con-
ductivity, of the reactions of acids and bases, of colligative properties, and of
much more in physical chemistry. But "concentration" had to be corrected to
"activity"; ions became hydrated; charges were no longer randomly distributed
in a volume but achieved an electrostatic organization; the spatial distribution
of charges within ionized or ionizable molecules became important; actual dis-
tances and shapes came to control interaction possibilities; and so on through
the distinguished contributions of Bjerrum, Debye, Hlickel, Linderstr¢m-Lang,
Kirkwood, and many others. Ling has taken a further step in examining the
details of organization of the proteins and their binding sites and of the simple
ions and their adsorption energies. His work builds on that of the physical
chemists and lays a foundation for that of the biological morphologists. As ions
determine collagen fiber pattern periods and these periods allow calcium pre-
cipitation only when of certain values, so do the fiber patterns determine cell
growth and architecture and, indeed, also feed back to control ionic partition
and action.
Ling derives such a wealth of biological phenomena from the interaction of
proteins and ions that the question inevitably arises as to whether his theories are
so general and unspecific that they would fit anything and are therefore of little
value. That this is not the case is, however, obvious to the student of his pres-
entation. In the great majority of cases, he has worked out the consequences of
his formulation in a theoretically rigorous and numerically sharp manner and
