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' 3 E 9 2 i € .2v 7 t n = .i --: 'a :: a. . = * -i - )t !; €;+ 3t -.2 a+ == X;! iP 28 o- ) s: :+. >; , . 3=zE1=aYa1q,-y7.Z3i=;L^-3==-:.-i1asz2=+i=! r:= --a =;:: 6v i:r -- - --.-=:.-E^=2zZi:3ez'!:;;; aee=4: =i=2? !,2== o'- i 7 -i a; a i = iz :: ?Z aViaj, Y, :.;7? = i?-s n,: >'-E=-.\ia>t/zXn ip'AE:i ='-_ eif ie.,ri=_V,F :: *i:1i a!iZlt/.-'1.-, :":; t: i .- "r-:iE2'"i;iir = iZ:>: 2!, --Y-=ElEEliZ.)_=..-.-a=t'=t-J==:-,!:1- -= =t=1==-2 - ..= -=zzz=::, ; . z i i z , = - = s s = P- -C 3.t P r-: t E1 f;6 '(cid:0) 9. i: E' r,€ i = i==-:T::-.:-F:: z'=_- *Tnj;i!!:4- r { =;-<='; I J &ir";-= S =:' q+.n..2r- r t =,41€- J<!'^ii l.+"lE 4Lde 4- a+ 7',i - '(cid:0)2-: ! :;::-::: ; n-rG = ^ . 3 FH:1j- :b-5: Ei FA+5 99;3anl- -C.< =: t ; e:Ei. + +g-!3:.I- : 5d = : 9 : : 1 e. = ^ - t :9 :=- _; -.: 3I i+X ! 3 ^A c = i*= H 4: = =I3 = ='={ =-= Z':; B r ! ;::": r -y6'-6:. \ *z n * o i= 3-€ . z ra Z ? -6 1 s t € ( = 3 F 2 : q ; E q . : o ; 3 ; - a r . = d ; : C CONTENTS ACKNOWLEDGEMENTS vi PREFACE x SECTION I. TOWARD GROUND TRUTH 1 This section deals with generally accepted views of cell biology. By peel- ing back layers of assumption, it attempts to get at the core of truth. In the end, an unorthodox conclusion is drawn about the nature of the cell. 1. Debunking Myths 3 2. The Croak of the Dying Cell 25 3. Cytoplasmic Discomfort 39 SECTION II. BUILDING FROM BASICS 51 This section pursues elementary cell function, with emphasis on water and protein surfaces. We see how the interaction of these two elements gives rise to ion partitioning, cell potential, and several other of the most basic features of cell physiology in ways that differ from current views. 4. Water 53 5. Solutes 77 6. Ions 87 7. Cell Potentials 99 viii SECTION III. AN HYPOTHESIS FOR CELL FUNCTION 111 Building on previous chapters, this section advances the hypothesis that cell function resembles gel function. It examines the role of the phase- transition in gels, and considers the potential for a similar role in cells. 8. Phase Transition: A Mechanism for Action 113 SECTION IV. APPROACHING CELL DYNAMICS 131 This section pursues details of active cell function. Building on previous chapters, it explores the possibility that diverse cellular actions are mediated by a common mechanism—the phase-transition. 9. Secretion 133 10. The Action Potential 145 11. Transport 163 12. Transport with Flair 185 13. Cell Division 207 14. Muscle Contraction 225 SECTION V. TYING LOOSE ENDS 249 This section considers issues common to the preceding chapters. It be- gins with cellular evolution and energetics, and then moves on to ex- plore the underlying themes that integrate the material of the book. 15. Energy 251 16. A New Paradigm for Cell Function 267 REFERENCES 285 INDEX 299 ix P P REFACE This book is about the cell and how it functions. Books about cell func- tion have become commonplace, but the approach taken here is not at all common. It builds on fundamental principles of physics and chemis- try rather than on accepted higher-level constructs. The premise is that nature’s functional paradigms are elegant, simple, and probably far less convoluted than current wisdom purports them to be. The book’s goal is to identify these simple paradigms from physical chemical basics. The story begins with a curious scene described in the standard cell- biology textbook by Alberts et al. (first edition, p. 604). A crawling cell somehow manages to get stuck onto the underlying surface. The leading edge continues to press on, tears free, and continues its journey onward as though oblivious to the loss of its rear end. Something about this scenario does not seem right. We have been taught that cell function depends on the integrity of the cell membrane; yet the membrane of this cell has been ripped asunder and the cell continues to function as though none of this matters. It’s business as usual—even though the cell has effectively been decapitated. When first exposed to this scenario, I reacted the way you may be react- ing—the cell must somehow reseal. The membrane must spread over the jagged surfaces, covering the wound and restoring the cell’s integrity. I was inclined to accept this seemingly flimsy account even though I could not understand how a bilayer membrane built of molecules with fixed lateral packing could spread over half again as much area. Nevertheless, it seemed expedient to shelve this anomaly and press on with more im- mediate matters; someone else could figure out what might be going on. x With time, it became clear that the survival of the decapitated cell was but one example of a set of related anomalies. Cells survive sundry in- sults equivalent to being guillotined, drawn and quartered, and shot full of holes with electrical bullets (Chapter 2). If the ruptured membrane does not reseal—and no evidence I’ve seen convinces me that “resealing” is any more than a conveniently invoked expedient—the implication is that membrane integrity may be less consequential than presumed. From this realization springs the early material of this book. If mem- brane integrity is not essential, then what holds the contents inside the cell? If you are willing to consider the cytoplasm as a gel instead of an ordinary aqueous solution, then an answer may be at hand, for gels don’t necessarily disintegrate when sliced; the contents will not spill out. The gel-like nature of the cytoplasm forms the foundation of this book. Biologists acknowledge the cytoplasm’s gel-like character, but textbooks nevertheless build on aqueous solution behavior. A gel is quite different from an aqueous solution—it is a matrix of polymers to which water and ions cling. That’s why gelatin desserts retain water, and why a cracked egg feels gooey. The concept of a gel-like cytoplasm turns out to be replete with power. It accounts for the characteristic partitioning of ions between the inside and outside of the cell (Chapter 6). It also explains the cell’s electrical potential: potentials of substantial magnitude can be measured in gels as well as in demembranated cells (Chapter 7). Thus, the gel-like character of the cytoplasm accounts for the basic features of cell biophysics. The focus then shifts from statics to dynamics. Here again the question is whether adequate explanations can emerge from the cell’s gel-like char- acter. Contrary to the common perception, gels are not inert. With modest prompting, polymer gels undergo structural transitions that can be as profound as the change from ice to water, which is why they are classified as phase-transitions. Polymer-gel phase-transitions are com- monly exploited in everyday products ranging from time-release pills to disposable diapers. They have immense functional potential. xi