Preface ......................................................... i
Answers to Readers's Queries (Read First!) ................... viii
Introduction .................................................... 1
1 How It Began on the Wrong Foot—Perhaps Inescapably ........... 5
2 The Same Mistake Repeated in Cell Physiology ................. 8
3 How the Membrane Theory Began ............................... 10
4 Evidence for a Cell Membrane Covering All Living Cells ...... 14
4.1 From studies of cel-volume changes and solute
permeability ........................................... 14
(1) A semipermeable diffusion barrier at the cell
surface ........................................... 14
(2) Plasmolysis ....................................... 14
(3) Transient and sustained volume changes ............ 16
(4) Membrane regeneration ............................. 18
4.2 From Bernstein's membrane theory of cellular electric
potentials ............................................. 21
4.3 From Donnan's theory of ionic distribution and
membrane potential ..................................... 23
5 Evidence for the Cell Content as a Dilute Solution .......... 26
5.1 Early evidence for free cell water ..................... 26
5.2 Early evidence for free cell K+ ........................ 26
6 Colloid, the Brain Child of a Chemist ....................... 29
6.1 Colloid, the namesake of gelatin and a cogent model
for protoplasm ......................................... 29
6.2 Coacervates ............................................ 31
(1) History ........................................... 31
(2) Bungenberg de Jong's two views .................... 31
(3) Coacervate and protoplasm ......................... 33
(4) Coacervate and the living cell .................... 34
7 Legacy of the Nearly Forgotten Pioneers ..................... 35
8 Aftermath of the Rout ....................................... 40
8.1 The tiny Hungarian enclave under E. Ernst .............. 40
8.2 The Leningrad school led by Nasonov and Troshin ........ 41
9 Troshin's Sorption Theory for Solute Distribution ........... 43
10 Ling's Fixed Charge Hypothesis .............................. 47
10.1 A theory of selective accumulation of K+ over Na+ ...... 48
(1) Enhancement of counter-ion (or neutral
molecules) association with site fixation ......... 48
(2) The salt-linkage hypothesis and a critical role
for ATP ........................................... 50
(3) The 1952 electrostatic model for the selective
accumulation of K+ over Na+ ....................... 50
10.2 Experimental verifications of the LFCH (and parts
of AIH) ................................................ 52
(1) Cytoplasm rather than the cell membrane as the
seat of selective K+ accumulation (and Na+
exclusion) ........................................ 53
(2) Confirming the salt-linkage hypothesis for past
failures to demonstrate selective adsorption
of K+ on isolated proteins ........................ 55
(3) The great majority of cell K+ is not free ......... 56
(3.1) Mobility of intracellular K+ ................ 56
(3.2) From X-ray absorption-edge fine
structure .................................. 60
(3.3) K+ activity measured in living cells with
a K+-specific ion-sensitive
microelectrode ............................. 60
(4) Cell K+ adsorbed on β- and γ-carboxyl groups
one-on-one and in close contact ................... 62
(4.1) K+ adsorption follows the characteristics
of a Langmuir adsorption isotherm .......... 62
(4.2) K+ adsorption on β- and γ-carboxyl
groups .................................... 64
(5) In striated muscle cells, the K+-adsorbing β-
and γ-carboxyl groups belong mostly to myosin ..... 66
(6) Quantitative relationship between adsorbed K+
and ATP ........................................... 69
(7) A summary of Section 10.2 ......................... 71
11 The Polarized Multilayer Theory of Cell Water ............... 74
11.1 Background ............................................. 74
11.2 Polarized multilayer theory of cell water and its
world-wide confirmation ................................ 75
11.3 Theoretical and practical extensions of the PM theory
(and confirmations) .................................... 81
(1) The invention of MRI .............................. 81
(2) What makes gelatin unique leads to a new
definition of colloid ............................. 84
(3) A new hypothesis of coacervate based on the PM
theory ............................................ 85
(4) A quantitative theory of solute distribution
(exclusion) in cell water and model system and
its experimental verification ..................... 90
(5) A possible cause for the lower q-value for Na+
(salts) in cell water than in extrovert models .... 99
(6) Answer to A.V. Hill's once-widely-accepted proof
of free cell water and of free cell K+ ........... 100
(7) Osmotic cell volume control ...................... 101
(7.1) What reduces the intracellular water
activity to match that of a Ringer's
solution? ................................. 102
(7.2) Reversible osmotic shrinkage of
solutions of an extrovert model in
dialysis sacs immersed in concentrated
solutions of substances to which the sac
membrane is fully permeable ............... 105
12 The Membrane-Pump Theory and Grave Contradictions .......... 109
13 The Physico-chemical Makeup of the Cell Membrane ........... 115
13.1 Background ............................................ 115
(1) The membrane theory .............................. 115
(2) LFCH (and AI Hypothesis) ......................... 118
13.2 Ionic permeation ...................................... 119
13.3 Water traffic into and out of living cells is bulk-
phase limited ......................................... 123
13.4 Permeability of living cells to water is orders of
magnitudes faster than that of phospholipid
bilayers .............................................. 126
13.5 Interfacial tension of living cell is too low to
match that of a phospholipid layer .................... 126
13.6 Ionophores strongly enhance K+ permeability through
authentic continuous phospholipid bilayer but no
impact on the K+ permeability of cell membrane of
virtually all living cells investigated ............... 129
13.7 Strongly polarized-and-oriented water in lieu of
phospholipid bilayer .................................. 131
14 The Living State: Electronic Mechanisms for its
Maintenance and Control .................................... 135
14.1 The launching of the association-induction
hypothesis ............................................ 136
(1) Prelude .......................................... 136
(2) The c-value and a quantitative theory for the
control of the rank order of ionic adsorption .... 140
(3) The c-value analogue and its control of protein
folding vs water polarization .................... 143
(3.1) The control of the secondary structure
of proteins ............................... 144
(3.2) The control of the physical state of the
bulk-phase water .......................... 147
14.2 What distinguishes life from death at the cell and
below-cell level? The new concept of the living
state ................................................. 148
(1) The living state ................................. 148
(2) The elemental living machine ..................... 152
(3) What distinguishes the dead state from the
active living state? ............................. 154
(4) What does food provide: energy or negative
entropy? ......................................... 155
14.3 Electronic mechanisms of remote, one-on-many
control ............................................... 156
(1) Electronic induction in proteins ................. 158
(2) Cooperative interaction as the basis for abrupt
and coherent transitions between stable states ... 164
(3) The classification of drugs and other cardinal
adsorbents: EWC, EDC and EIC ..................... 167
(4) ATP, the Queen of cardinal adsorbents, as an
EWC .............................................. 168
(5) What do drugs and other cardinal adsorbents
do? .............................................. 170
(6) How cardinal adsorbents produce across-the-
board uniform electron-density change of many
proximal functional groups ....................... 171
(7) Multiple control of single enzyme sites and
"gangs" of pharmacological "effector sites" ...... 175
15 Physiological Activities: Electronic Mechanisms and Their
Control by ATP, Drugs, Hormones and Other Cardinal
Adsorbents ................................................. 179
15.1 Selective solute distribution in living cells:
cooperativity and control ............................. 180
(1) K+, Na+ and Mg2+ accumulation in living cells ..... 180
(2) Control of the solvency of cell water by ATP ..... 183
(3) The control of the rank order in alkali-metal
ion adsorption by ouabain ........................ 186
(4) Control of D-glucose and glycine distribution
by insulin ....................................... 192
15.2 The control of ion permeability ....................... 194
(1) Na+ efflux in normal and in IAA-poisoned muscle
cells ............................................ 195
(2) The influence of ouabain on the rank order of
the strengths of alkali-metal ion adsorption on
cell surface anionic sites ....................... 198
15.3 Salt-ion-induced swelling of normal and injured
cells ................................................. 200
(1) Cell swelling in isotonic KCl .................... 200
(2) Injury-induced cell swelling in isotonic NaCl .... 201
15.4 True active transport across bifacial epithelial
cell layers and other bifacial systems ................ 203
(1) Active Na+ transport across frog skin ............ 205
(2) Active Rb+ transport into Nitella cell sap ....... 207
15.5 The resting potential ................................. 209
(1) Historic background .............................. 209
(1.1) The membrane potential theory and
modifications ............................. 209
(1.1.1) The ionic theory ................. 210
(1.1.2) The electrogenic pump theory ..... 212
(1.2) Phase-boundary potential theories ......... 213
(1.2.1) Baur's ion adsorption potential
theory ........................... 213
(1.2.2) Beutner's phase boundary
potential theory ................. 214
(1.2.3) Horovitz's (and Nicolsky's)
theories of glass electrode
potentials ....................... 215
(2) The close-contact surface adsorption (CSA)
theory of cellular electrical potentials ......... 216
(2.1) The importance of close-contact once
more ...................................... 217
(2.2) Out of the union of two failed models
for the the membrane potential, a
super-model for the close-contact
surface adsorption potential .............. 218
(2.2.1) Both model and living cell show
similar rank order of
sensitivity to alkali-metal
ions ............................. 218
(2.2.2) Both model and living cell are
indifferent to external CI ....... 219
(2.2.3) Both model and living cell
demonstrate an approximately
150 times greater sensitivity
to H+ than to K+ ................. 219
(2.2.4) Both model and living cell are
indifferent to external Mg++ ..... 219
(2.3) The original equation for the resting
potential ................................. 220
(2.4) Edelmann's deciding experiment ............ 221
(2.5) Control of the resting potential .......... 221
(2.5.1) Control by ouabain and other
EDC's by raising the c-value of
surface β- and γ-carboxyl
groups ............................ 222
(2.5.2) Control by adrenaline as an EWC
by lowering the c-value of
surface β- and γ-carboxyl
groups ............................ 223
15.6 The action potential .................................. 224
(1) Hodgkin-Huxley's theory of action potential ...... 225
(1.1) No standing Na+potential .................. 225
(1.2) Na channel not specific to Na+ ............ 226
(2) The close-contact surface adsorption (CSA)
theory of action potential ....................... 226
(2.1) The identification of the anionic groups
mediating ionic permeation and
generating the resting potential as β-
and γ-carboxyl groups carried on cell
surface proteins .......................... 229
(2.2) The selective preference for ions of the
cell surface β- and γ-carboxyl groups is
mutable, rather than fixed as in the
ionic theory .............................. 229
(2.3) The anionic groups mediating the entry
of Na+ into squid axons during an action
potential are the same β- and γ-carboxyl
groups but with a much higher c-value ..... 230
(2.4) Swelling of nerve fiber accompanying an
action potential .......................... 230
(2.5) The propagated c-value increase at the
surface β- and γ-carboxyl groups goes
pari passu with the depolarization of
cell surface water molecules .............. 231
16 Summary Plus ............................................... 233
16.1 Early history ......................................... 233
16.2 The membrane (pump) theory ............................ 235
16.3 Early protoplasm-oriented cell physiologists and
their contributions ................................... 236
16.4 Ling's fixed charge hypothesis (LFCH) ................. 237
16.5 The polarized multilayer (PM) theory of cell water .... 239
16.6 The association-induction hypothesis proper ........... 242
(1) The resting living state ......................... 242
(1.1) The resting living state as a
(metastable) equilibrium state ............ 242
(1.2) The resting living state as a
low-entropy state ......................... 243
(1.3) Do the major components of the living
cell exist in a different physical state
or conformation? .......................... 243
(1.3.1) Conformation of hemoglobin in
red blood cells from K+, Na+
distribution ..................... 243
(1.3.2) Conformation of myosin in frog
muscle cells from
nonelectrolyte distribution ...... 245
(1.3.3) Conformation of myosin and
actin in frog muscle cells from
vapor sorption ................... 245
(1.4) In maintaining the resting living state
ATP is indispensable ...................... 246
(1.5) Where does the excess (cell) water-to-
(cell) water interaction energy in the
resting living cell originate? ............ 246
(2) Global coherence and internal connectedness
in protoplasm .................................... 248
(2.1) Native hemoglobin in vitro ................ 248
(2.2) NaOH-denatured hemoglobin in vitro ........ 248
(2.3) Muscle proteins in vivo ................... 249
(3) Interpretation of the four classic
physiological manifestations ..................... 250
(3.1) Solute distribution ....................... 250
(3.2) Solute permeability ....................... 251
(3.3) Cell volume control ....................... 252
(3.4) Resting potential ......................... 253
(4) Physiological activities as reversible
cooperative transitions mediated by inductive
effects .......................................... 254
(4.1) c-value and c-value analogue:
the keyboard of life ...................... 255
(4.2) Changes in the partners of ionic and
hydrogen bonds as initiators as well as
targets of transmitted inductive effect ... 257
(4.3) Classification of drugs and other
cardinal adsorbents ....................... 258
(4.4) Maintenance and modulation of the
resting living state by various cardinal
adsorbents ................................ 258
(4.4.1) Maintenance of the living state
by ATP as EWC .................... 258
(4.4.2) Modulation of the resting
living state by ouabain as an
EDC .............................. 259
(4.5) Cyclic reversible physiological
activities ................................ 264
(4.5.1) True active transport ............ 264
(4.5.2) The action potential ............. 265
(5) The death state .................................. 266
(5.1) Life and death or protoplasm .............. 267
(5.2) How protoplasm dies ....................... 267
(5.3) The anatomy of dead protoplasm or cell .... 268
16.7 A sketch of the history of Mankind's search for
understanding of life ................................. 270
17 Epilogue ................................................... 272
Crossword puzzle and fox hunt: two models for scientific
research ................................................... 272
The secret of past success in major directional changes .... 273
Fragmentation and its impact on the future of science ...... 275
A verified unifying theory to put Humpty-Dumpty together
again ...................................................... 276
How a dedicated biology teacher holds the key to a better
future for basic life science .............................. 277
"Science, The Endless Frontier" can be as shining and
promising as ever .......................................... 279
Appendix 1 .................................................... 282
Super-Glossary ................................................ 288
List of Abbreviations ......................................... 330
List of Figures, Tables and Equations ......................... 333
References .................................................... 334
Author Index .................................................. 351
Subject Index ................................................. 356
Acknowledgments ............................................... 366
About the Author .............................................. 371
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