SiS Review
Dr. Mae-Wan Ho reviews: Cells, Gels and the Engines of Life: A New, Unifying Approach to Cell Function
Don't, don't read this book, if you've built your life around the notion that cell biology consists of nothing more than enormously complicated networks of interacting proteins and genes for carrying out a list of vital functions; like moving the cell around, digesting food, receiving and transmitting signals from the environment, making the cell grow bigger, and eventually dividing it into two.
Don't even think of touching this book if you believe that everything about the cell will be understood when the function of every gene and every protein has been worked out ad infinitum, and life itself could then be simulated by the fastest supercomputer. For that's what we are told by the molecular geneticists who have sequenced the human and other genomes, and are now desperate to find some meaning in it all. Don't touch this book, because it will destroy your life and puncture your illusions; or at least throw you into a terrible state of self-doubt.
If, however, you have been bored out of your mind with the proliferation of lists upon lists of molecular nuts and bolts that simply don't add up to a whole, and secretly wondering how the cell might really work, then beg, borrow, steal or buy a copy of this book right now. You are in for a big treat. This book will sweep you off your feet.
It is like having a thorough spring-cleaning done on your mind. The layers of intellectual cobwebs accumulating ever since you decided to read biology - and never really been encouraged to think your way to any modicum of understanding - all cleared away, one by one, until you see sunlight sparkling in your mind's eye. You've regained the innocence of first gazing into life's wonders, and ready for more. Not a gel in sight, and no equations either.
With disarming lightness and charm, Gerald Pollack sweeps aside the big myths out of which the entire subject has been spun, thus disposing of perhaps 99 percent of what one might have learned from cell biology textbooks. Well, perhaps I should explain that the molecular 'hardware' does exist, but the explanatory mechanisms may all be wrong. The most important message in this book is that life cannot be understood without understanding some elementary physics and chemistry. There needs to be a complete overhaul of the typical life-science curriculum in universities and lower down.
The first to go is the myth that the cell is enclosed by a cell membrane that forms a barrier to substances going in and out of the cell. And hence, an endless list of specific channel proteins are necessary to allow various substances such as inorganic ions, sugars, amino-acids, hormones, etc. etc. to pass in and out, all guarded by specific receptors that make the channel proteins 'open'; not to mention the specific protein 'pumps' supposedly operating to transport ions uphill against their concentration gradients.
All that is rather like a house that has a dog-flip, a cat-flip and a mouse-flip, when it is obvious to men and beast alike that anything smaller than the dog will be able to use the dog-flip. The artwork in this book is wonderful, by the way.
Pollack reviews evidence dating from the early part of the last century that practically all the properties attributed to the cell membrane are there even when the membrane has been dissolved away, or great holes and tears made in it, or even when a whole chunk of the cell has been cut away.
These membrane-specific properties include the so-called membrane potential, the negative electrical potential inside the cell relative to the outside, as well as the action potential, an electrical spike discharge generated when the cell membrane (presumably) is electrically or otherwise stimulated. Furthermore, these cells, denuded of membranes, or full of gaping holes in their membrane, nevertheless keep hold of their ions and small molecules for a long time after there are no barriers to prevent them from diffusing away.
The next to go are stories on how cells secrete substances that make other cells do specific things by vesicles filled with neural transmitter, what have you, inside the cell migrating outwards, and fusing with the cell membrane, thus discharging their 'payload'.
Or how cells can transport large cargoes by molecular machines with molecular 'feet' walking along molecular monorails; how cells themselves are supposed to move and divide by 'contractile fibres', and how our muscles are supposed to contract by tiny 'cross-bridges' walking or sliding along fixed, filaments.
Goodness me. How many hours have I wasted trying to make sense of it all? And all, quite probably, to no avail, if Pollack is to be believed.
So, what's the grand unifying principle that could explain all that, which is nothing short of life itself?
It could be no more than phase transition involving gels, for that's what most proteins are, according to Pollack.
One is reminded of the supercomputer in Adam Douglas' Hitch-hikers Guide to the Galaxies, finally answering the question that's it has been deliberating for ages, "What is the meaning of life?"
"Forty-two!"
First thing first, why doesn't the cell need a membrane? Because, rather than being a bag of enzymes and other proteins enclosed in a membrane, the cell is a highly organised state of matter, more like a poly-electrolyte gel akin to egg white, or gelatin. This poly-electrolyte gel, with a lot of negative charges, accommodates smaller ions such as potassium (K+) and exclude the much larger sodium (Na+). That's why the cell is predominantly filled with potassium, while the extracellular fluid like our blood, lymph, tears and the sea, are rich in sodium. There aren't enough potassium ions adsorbed to neutralise all the negative charges, so the cell invariably ends up with a negative electrical potential relative to the outside. That gel potential has been mistaken for 'membrane' potential. And the orthodoxy is sticking to its story.
But surely, the potassium atom is much bigger than the sodium. Yes, so the positively charged potassium exerts a weaker force on the surrounding water than the sodium and ends up with a much smaller hydration shell. So water is the key, isn't it?
Our readers will be familiar with water and water in living organisms, specially featured in "Water, water everywhere" series in SiS 15, where we said that the water in the cell, as well as outside the cell in connective tissues, is in a liquid crystalline state bound to proteins and other macromolecules.
Liquid crystals and gels are the same with regard to the large amount of water adsorbed, except that liquid crystals are molecularly 'aligned', or ordered, and gels are not. Thus collagen is liquid crystalline with all the molecules aligned. If you cook collagen for a long time, it turns into gelatin, a gel with the molecules randomly dispersed. So, the properties of gel apply to liquid crystals, perhaps even more so.
It is the layers of adsorbed water on the surfaces of proteins and other macromolecules in the cell cytoplasm that exclude the larger sodium ions, except when a phase transition occurs, and the bound water comes off the surfaces.
Many physical measurements support the idea that most if not all of the cell water are in this bound, ordered state, in which nothing will dissolve in it, and it is restricted in its motion. What binds and orders the water molecules are surface charges attracting the water molecule. The water molecule is special as it can undergo extensive hydrogen bonds with one another and with other molecules. Surfaces with a lot of charges will be able to capture many layers of water molecules all lined up; whereas surfaces with few charges will be unable to retain bound water. It is estimated that the layers of water thus adsorbed in the cell are between 5 to10.
And, practically all the vital functions of the cell may be explained in terms of phase transition of gels from a hydrated state, in which the water is adsorbed to the enormous surfaces available, to a condensed state, in which the water is displaced and literally squeezed out. It happens very quickly indeed. This could well explain how 'secretary' vesicles can actually forcibly eject their 'pay-load', when they change from a condensed state explosively to an expanded state on reaching the outside, rather like a compressed spring is suddenly released. No 'membrane fusion' necessary.
Now, this phase transition is quite dramatic, the difference in total volume between a fully hydrated gel and a condensed state could be as much as a thousand fold. This surely can't be happening all the time, because we don't normally shrink and expand like Alice in Wonderland.
The phase transitions could be much more localised, probably because the cells never has extensive patches of purely one kind of molecules, and more importantly, there is organisation in the cytoplasm, with diverse molecules aligned and arrayed next to one another in what biochemist Ricky Welch, not mentioned in this book, referred to as a distinct and varied 'cytosocial environment'.
Localised phase transitions could account for the sudden electrical discharges typical of action potentials, for example, when potassium ions are released with bound water, and sodium ions coming in to dissolve in the liberated water. What could trigger phase transition? Anything that changes surface charge distribution, adding a phosphate group in the ubiquitous phosphorylation reaction that appears to be involved in every 'signal transduction' cascade, for example; or binding divalent cations like calcium (Ca2+) with two positive charges that could link up two protein surfaces, thus literally squeezing the bound water out.
These simple phase transitions propagating along a long fibre could automatically make 'molecular motors' stream along the tracts, in what has come to be known as 'cytoplasmic streaming', most prominent in the long fibres or axons of nerve cells, but can also be seen in giant alga. Basically, it is the tiny local turbulences of water being released from the surface and the rebinding, coupled with the local wave-like contraction and expansion of the molecular tract undergoing phase transition that propels the cargoes along, with the greatest of ease.
And how might muscles work? By phase transition of course. All the fibres, actin, myosin and the newly discovered connecting filaments, contribute to the contraction of muscle by propagated phase transition, and you can see this in sections of muscle quick frozen in the midst of a contraction.
I leave you to discover how cells really divide.
Pollack may be wrong on many details, and it is a moot point whether one should call all movements of bound water onto and off protein surfaces 'phase transition', and, I am slightly disappointed that he hasn't gone on to talk about liquid crystalline phases at all.
Pollack refers to the important work of many early pioneers, such as Professor Gilbert Ling who went from China to the United States on a Boxer Fellowship, and soon found himself at odds with the orthodoxy over the existence of the cell membrane and the membrane potential. Another is Albert Szent-Gyorgyi, a founding father of biochemistry who got a Nobel prize, but had very unorthodox ideas nonetheless that inspired many including me. Pollack could have mentioned Joseph Needham's remarkable little book, Order and Life, published in 1936, which has anticipated a lot of the new cell biology that Pollack so skilfully compels us to think about.
It is clear to me, especially after reading this book, that molecular biologists have been thinking themselves into a right muddle of molecular cogs and wheels, cross-bridges, membrane receptors, channels, switches, signal transducers, nuts and bolts galore that guzzle energy like our own mechanical devices, and wondering where all that energy could come from. That, by the way, is why a lot of nano-machines that nano-technologists intend to build will go nowhere. They should first learn about phase transitions, and there are already some marvellous applications described in this book developed by scientists who take the physics and chemistry seriously.
The cell is not assembled from a nano-Meccanno set, nor endless nano-Lego pieces that depends on many so isolated push-pull, drive-driven, lock and key mechanical actions. Not, the cell has been engaged in molecular Kungfu instead, performing all its vital functions with the greatest of ease and the least of bother. Just imagine that.
Article first published 29/04/03
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