One of the surprises in this splendid, fascinating book arises from Hille's thumbnail history of the very idea of individual ion channels.

It is a much more recent idea than I realized. Not until the mid-1960s did neurophysiologists finally arrive at the now commonplace image of an ion channel as an individual structure - an ion-specific porthole or passageway through the cell membrane.

Hille emphatically characterizes the individual channel as "a discrete entity," and as "a distinct molecule." By 1965 this concept had been in the air for a while, but it did not prevail or become the dominant picture until binding studies were conducted with tetrodotoxin and saxitoxin. Largely thanks to this work, by the late 1960s, the author recounts, the names "Na Channel" and "K Channel" began to be used consistently.

The familiar picture of individual channels embedded in the cell membrane was brought to us by the magic of long division. For example, "Dividing specific binding by membrane area yields an average saxitoxin receptor density of 110 sites per square micrometer on the axon membranes of the vagus. We now know that the tetrodotoxin-saxitoxin receptor is a single site on the Na channel, so this experiment tells us how many Na channels there are in the membrane. Surface densities of 100 to 400 channels per square micron are typical ..."

The picture you get is one of barrel like protein ports floating like buoys in the membrane, nicely regimented into rows and columns, neatly anchored at the intersection points of an imaginary grid. It is, of course, an image made ideal by the arithmetic which originally produced it.

Hille concludes: "Now that we can record from single channels - and even purify the chemically, and sequence and modify their genes - there remains no question of their molecular individuality.

Well, it is in some sense just a semantic matter, but a few observers, of whom I am one, think there remains after all a colossal, towering, staggeringly important question about the molecular "individuality" of these passages. This is because they can be structurally and functionally linked.

Linked receptors are a commonplace of biochemistry. Extensive linkage between ion channels in nerves would open up some very nice possibilities, explain many mysteries, etc.

Is there any evidence for linked or complex ion receptors? At the end of Chapter 5, in a literature summary, the author remarks on the then newly discovered double barreled anionic channels, and notes some Cl channel electrophysiological data that seem to make it look "as though the channel were a cluster of pores - like a sieve or an aggregate of straws. An alternative would be that the pore fluctuates through frequent rearrangements of many constituent parts."

This is precisely the type of liberated thinking that could get us somewhere fast. If you put two pulls on an ordinary zipper, you can create a pore that travels. It is easier, not harder, to come up with this kind of mechanism by assembling protein subunits. You can also make starbursts, "cootie catchers", "Jacob's ladders" sliding anagram toys, and many other plaything analogs using protein repetitive units, links, foldings and conformational changes.

To what end? Why should linked or continuous pore structures be more interesting that discrete and isolated pores?

Imagine a nerve in which finely graded input information can be conveyed, by all-or-nothing impulses, all the way from input to output using, let's say, 100 distinct information channels that extend longitudinally from one end of the nerve to the other. The longitudinal channels are created by linking transverse channels. A corduroy membrane. Possibly linear, possibly helical.

In a nerve of this type, an increment of graded information is inherent in the longitudinal channel number: 1, 2, 3, etc. An impulse traveling down the axon would appear, to conventional instruments used to study nerves, as the blank, familiar, all-or-nothing impulse so confidently presented to us on page 1 of every neurophysiology text. But such an impulse would not be blank. It would be freighted with meaning. With this single impulse, the intensity of the original input stimulus could be conserved and communicated all the way to the brain.

The idea is reasonable because it points to a type of neuron that would enable us to think as fast as we do.

It is also reasonable in light of evidence accumulated since 1993 (See Spikes, Rieke et al) that a single impulse does in fact convey information to the brain. Adrian was wrong. The long familiar rate code isn't one. Somehow, a single nerve impulse carries information. How? The secret seems inherent in the neuron - and the neuron is a mechanism built up using ion gates.

Ion channel research is becoming one the most fruitful and fashionable fields in biological science. There are more recent books on the subject, (Frances Ashcroft's for example) but perhaps because they must cover more ground, they seem a lot less careful about pointing out the assumptions and reiterating the history of the ideas on which the field is grounded.

This book is bedrock. Bertil Hille identifies in precise language each significant underlying assumption, and details the experimental tools that were used to develop the (still pretty fuzzy) picture we hold in our minds' eyes of the nerve membrane. As the field evolves, some of the basic assumptions are going to have to be re-examined. This book will help you understand exactly what they were and, thus, where to push for fresh possibilities.

The author has received the Lasker award, and this one quite often foreshadows the Nobel. You can sense, in reading this book, the extreme quality of his science and of his intelligence.

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