Wetware: A Computer in Every Living Cell

Wetware: A Computer in Every Living Cell

by Dennis Bray

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In the tradition of as Erwin Schrödinger’s What Is Life? and Richard Dawkins’s The Selfish Gene, a distinguished cell biologist explains how living cells perform computations

How does a single-cell creature, such as an amoeba, lead such a sophisticated life? How does it hunt living prey, respond to lights, sounds, and smells, and display complex sequences of movements without the benefit of a nervous system? This book offers a startling and original answer.

In clear, jargon-free language, Dennis Bray taps the findings of the new discipline of systems biology to show that the internal chemistry of living cells is a form of computation. Cells are built out of molecular circuits that perform logical operations, as electronic devices do, but with unique properties. Bray argues that the computational juice of cells provides the basis of all the distinctive properties of living systems: it allows organisms to embody in their internal structure an image of the world, and this accounts for their adaptability, responsiveness, and intelligence.

In Wetware, Bray offers imaginative, wide-ranging and perceptive critiques of robotics and complexity theory, as well as many entertaining and telling anecdotes. For the general reader, the practicing scientist, and all others with an interest in the nature of life, the book is an exciting portal to some of biology’s latest discoveries and ideas.

Product Details

ISBN-13: 9780300167849
Publisher: Yale University Press
Publication date: 03/01/2011
Edition description: New Edition
Pages: 280
Sales rank: 959,295
Product dimensions: 6.10(w) x 9.10(h) x 0.70(d)

About the Author

Dennis Bray is professor emeritus, University of Cambridge, and coauthor of several influential texts on molecular and cell biology. In 2007, he was awarded the prestigious European Science Prize in Computational Biology.

Read an Excerpt


Clever Cells

It was a rainy November Cambridge afternoon when Bill Grimstone appeared at my office in the Zoology Department and said he had something to show me. It was rare, even during the term, to sight him, and most unusual for him to be in such an animated state. Bill was an archetypal imperturbable Cambridge don: suave, phlegmatic, with graying hair, spectacles and a slight cast in one eye, and given to wearing a tweed jacket and a tie. As I followed him down the corridor to his room, I speculated that there could be only one reason for this excitement — his research. Sure enough, as he ushered me into his small office, he gestured toward a wooden chair in front of a microscope. Even before he flicked the switch to activate the light, I knew I would be looking at termite guts.

Termites live by eating and digesting wood. In the tropics they build huge colonies like pillars, and, I gather, they can be serious pests if they settle into your home. I've also learned that termites, to gain nourishment from wood, have to degrade wood's primary component, cellulose, and that this requirement presents a biochemical challenge. Cellulose is just a chain of glucose subunits. But animals cannot digest this potentially rich source of food, for reasons that have always been a mystery to me. You might have thought that an evolving organism would easily acquire the single enzyme (a protein performing a specific reaction) needed to tap into such a potentially rich source of energy. But the fact is that any animal, including an insect, that wants to digest wood must recruit bacteria. Termites do so by turning the gut into an oxygen-free chamber full of special bacteria that degrade cellulose: a mutually beneficial ménage because the termite provides the bacteria with a constant supply of well-chewed wood fragments to digest. In return the bacteria turn the wood into sugars and other easily digestible molecules. They take some of the nutrients for their own use and leave the rest for their insect host.

So as I looked down Bill's microscope I saw, as expected, a jumble of wood fragments surrounded by the dark forms of bacteria, rounded or rod-shaped. But as I fumbled with the unfamiliar controls, something altogether more formidable slid into view. It was a single cell, but as unlike the textbook fried-egg image of a cell as one could imagine. This was a huge Wurlitzer of a cell, covered from head to foot with writhing snakelike flagella — protrusions cells use to drive them through water. Every portion of its body, which seemed immense under the powerful magnification of the microscope, moved with its own rhythm, as though driven by cogs and machines beneath the carapace. As I passed the eyepiece to Bill, the writhing circular motion continued, unfazed by our observation. "Trichonympha," Bill explained in his cultured baritone. "And here," as he searched with the microscope stage, "is Streblomastix, with a background of Spirochaetes." He had left the microscope focused on a large serpentine body that bristled with surface hairs surrounded by darting helical structures. As I watched, the Streblomastix gave a sudden convulsive twist that carried it out of the field of view.

We watched for perhaps twenty minutes until the preparation eventually died, probably through the seepage of poisonous oxygen. Bill described and named one after another of the strange creatures we saw. It was his research project, a.k.a. hobby, to classify and describe the inhabitants of the dark recesses of the termite. Every now and then in the past, he had selected a species with an especially intriguing anatomy for further investigation. Fixed and embedded in resin, the creature would be cut into ultrathin slices. Sections of its anatomy would be viewed in an electron microscope — a procedure for which Bill was justifiably famous. Many of these pictures revealed new microanatomical structures, especially those associated with flagella. But what impressed me most deeply — the lasting memory I have of this visit — was the sudden view it gave me of this hidden world, teeming with life. Why were these strange creatures living in such an unlikely place? Why were they moving? Where was there to go? Who was eating whom, and why?

A few years later Bill retired from the Zoology Department and bequeathed to me a pile of videotapes he had made of the organisms in termite guts. As I watched these tiny animals writhing and crawling through their hidden world, it occurred to me that I was seeing them through a screen of science. I knew (sort of) what was occurring in each waving flagellum. I knew (in broad terms) of which chemicals the beast was made, how it generated energy, and how it sensed its environment. But this information, acquired from books and research papers, gave me no clues to the motive forces and internal states of these living forms. What if these same images were shown to someone who knew nothing of microscopes or modern biology — perhaps from an Amazonian tribe with no knowledge of modern civilization? What would he or she make of these strange wriggling forms? Surely they would seem monsters from a nightmare world, moving with a purpose driven by dark motives. Even a sophisticated Victorian microscopist, meticulously noting the morphology and classification of protozoan species, might speculate (as indeed many did) about the psychic properties of these "infusoria": whether their behavior was in any sense "conscious." But of course we, in this molecule-besotted, fact-filled twenty-first century, know better ... or do we?

The kind of naïve natural history observation that so fascinated Bill is deeply unfashionable today. You would find it difficult to get a research grant to study the morphology and behavior of protozoa for its own sake. But a century ago it was cutting-edge science. Eager biologists equipped with shiny new microscopes of unprecedented power devoted their careers to observations of the miniature living world. Thanks to them we know that every corner of our Earth is fertile, full of life. In a charming passage in Manual of the Infusoria, William Saville-Kent, formerly assistant to the famous English biologist T. H. Huxley, revealed his enthusiasm:

On Saturday, October the 10th, 1879, a day of intense fog, the author gathered grass, saturated with dew, from the Regent's Park Gardens, the Regent's Park, and the lawn of the Zoological Gardens, and submitted it to microscopical examination, without the addition of any supplementary liquid medium. In every drop of water examined, squeezed from the grass or obtained by its simple application to the glass slide, animalcules in their most active condition were found to be literally swarming, the material derived from each of the several named localities yielding, notwithstanding their close proximity, a conspicuous diversity of types.

This diversity Saville-Kent then proceeded to enumerate in painstaking detail. No surprise, because we now know that living forms are everywhere — meters down in soil, suspended in the surface waters of the oceans or in their muddy sediments, embedded in Arctic ice, even floating in clouds. Every crack and cranny of our urban environment is a universe where forms visible only under a microscope crawl, swim, compete, and struggle for existence. We are aware of this fact; it conditions our daily hygiene. But what do we really know about the life of these organisms? What do they sense? How do they respond? What is important to them?

These are difficult questions and, like the subject of protozoa behavior itself, extremely unfashionable. Indeed, there seems to be an unwritten convention or law that one should not even raise these issues in a scientific context. Contemporary biologists have an amazing ability to visualize and record what happens in cells. They not only follow single free-living cells but also identify cells moving in the depths of an embryo or in adult tissues. They can pick out specific structures or even single molecules, watch as they move from one location in a cell to another, probe them with microelectrodes or laser tweezers. You can find videos of moving cells on the Internet. But you will be hard put to discover, in all this amazingly rich resource, anyone prepared to ask, as Barbara McClintock did in her Nobel acceptance speech, what knowledge a cell has of itself.

And that, surely, is to be regretted. We have such an abundance of knowledge about living organisms, certainly compared with what the Victorians knew, that we should surely be able to tackle this fundamental question. Like manic pathologists at an autopsy competition, we have littered our workbenches with the dissected viscera of cells. Functional parts (organelles) and molecules of all kinds are set out in display, minutely described and labeled. But where in this museum of parts do we find sensation, volition, or awareness? Which insensate substances come together, and in what sequence, to produce sentient behavior?

Addressing these issues in this book will take us on a voyage that visits most corners of contemporary biology, from protein chemistry to psychology and beyond. But let us start by defining exactly what it is that single cells can do and by tracking the simplest animate wanderings.

Most bacteria are simple rod-shaped cylinders, a few microns long. One micron is a millionth of a meter, a thousandth of a millimeter; a human hair is about eighty microns in diameter. It would take thousands of bacteria to cover a period on this page. They have a tough outer wall and a cytoplasm containing a jumble of protein, DNA, and other molecules. Despite their small size and rudimentary construction, bacteria are capable of independent locomotion, by swimming or gliding over surfaces. In 1854 the German biologist Wolfgang Pfeffer showed that if he introduced a capillary pipette filled with nutrient mixtures such as yeast or meat extract into a solution containing swimming bacteria, the bacteria would collect around the pipette and eventually enter into its tip. Capillaries filled with acid, alkali, or alcohol had the opposite effect, causing the bacteria to swim away. Other investigators at the time observed bacteria responding to light, temperature, or the concentrations of salts. Interest in this simple and accessible system then lapsed for many years. It was not revived until the 1970s, when Julius Adler at the University of Wisconsin in Madison began to systematically analyze food seeking in the common gut bacterium Escherichia coli. Today, thanks to the discoveries of a generation of microbiologists, biochemists, geneticists, and biophysicists, we have a detailed knowledge of the molecular machinery of E. coli chemotaxis (that is, movement toward chemicals). No other form of animal behavior is understood at anything like this level of detail.

Bacteria swim by means of thin helical flagella, like curly hairs on their surface. Driven by tiny molecular machines — literally motors — embedded in the bacterial membrane, the flagella rotate at speeds of more than one hundred cycles per second. The motors sporadically stop and start, change their direction of rotation, and in this way steer the bacteria according to their surroundings. In the case of E. coli, the motors spend most of their time spinning in a counterclockwise direction. When they all turn the same way, the four to six flagella collect into a tight helical bundle, like a pigtail, that drives the cell in one direction through the water. But every now and again, at a frequency that depends on the local environment, one or more of the motors switches to a clockwise direction. This brief reversal breaks up the flagella bundle, and the cell performs a brief chaotic dance called a tumble. Coming out of a tumble, the cell heads off in a new direction. Which way it goes is uncontrolled, random: what is important is not where it goes when it tumbles, but when.

Escherichia coli can detect something like fifty distinct chemicals. The list includes sugars and amino acids that act as attractants (the bacterium swims toward them) and a motley mixture of heavy metals, acids, and toxic substances that are repellents. E. coli's sensitivity is legendary. Even the slightest whiff of the attractant amino acid aspartate (a concentration of less than one part in ten million) is enough to change its swimming. A cell detects a substance that sticks specifically to its surface — the stronger the binding the greater the sensitivity. In the case of aspartate, just a few molecules are enough to turn the cell.

The molecular mechanism of E. coli chemotaxis is a superb illustration of cellular information processing. But the most salient point to mention here is that the movements of the bacteria are highly unpredictable, or "noisy." These tiny cells are continually buffeted by water molecules and easily knocked off course, a universal aspect of all small particles suspended in water. So to pursue any direction for more than a second or so, bacteria have to continually reassess their situation. How do they do this? The answer is that they have a sort of short-term memory that tells them whether conditions are better at this instant of time than a few seconds ago. By "better" I mean richer in food molecules, more suitable in acidity and salt concentration, closer to an optimum temperature, and so on. If on average conditions have improved, or at least are not any worse, then the bacteria will continue to swim in the same direction. But if conditions are deteriorating, then the bacteria tumble; they swim off in a new direction, selected more or less at random. The repeated execution of this pragmatic routine carries them over long distances and complicated terrains toward favorable locations.

But what do I mean by saying that bacteria have a short-term memory? Doesn't this phrase assign to bacteria a capacity that is really found only in higher organisms? Words like memory, awareness, and information are easy to use but require careful definition to avoid misunderstanding. I'm using short-term memory here in a colloquial, nonspecialist way, referring to how a swimming bacterium carries with it an impression of selected features of its surroundings encountered in the past few seconds. This continually updated record is crucial for chemotaxis, because without it the bacterium would not be able to tell whether it was moving toward or away from a more favorable environment.

And how do I know bacteria have a memory? You can demonstrate it in the following way. Take a population of bacteria in a small drop of water and measure the fraction of cells that are tumbling at any instant. For a typical strain of E. coli this fraction will be perhaps 20 percent. Now add a minute quantity of aspartate. The cells will immediately suppress their tumbles, and the fraction of tumbling cells will fall to close to zero. In other words, the cells have experienced an improvement in their environment (a taste of food) and consequently persist in their current direction of swimming. Adding the food substance uniformly to the solution makes every direction equally advantageous.

But now observe what happens to the swimming bacteria. Over the next minute or so, you will see first one then another bacterium start to tumble. Eventually (after a time that depends in part on how much aspartate you added), every one of the bacteria will be swimming and tumbling just as though nothing had changed. Once again, approximately 20 percent will be tumbling at any moment. So if this were your first view of the cells, you would not know that they were now immersed in aspartate. (If you're worried about the fact that the bacteria eat aspartate, then the same experiment can be performed with substances that are not devoured by the bacteria.) But the bacteria are indeed changed by their experience, as can be shown simply by removing the attractant. Immediately, all of the bacteria (or almost all, since these responses are highly variable and no two bacteria are exactly the same) begin to tumble, frenetically and without interruption. Evidently they have sensed that conditions have now deteriorated. They have changed their swimming pattern to move to a different location rather as you or I might move away to avoid an unpleasant smell.

So I can state that when the bacteria came in contact with aspartate, they became subtly changed. They acquired an internal trace or record that remained even after the visible effects on swimming caused by the aspartate disappeared. This trace or record corresponds to what is termed adaptation in behavioral experiments, and it represents a sort of knowledge acquired by a cell. Note, however, that it is not the same thing as learning. The bacteria always do the same thing given the same set of environmental stimuli. A biologist would say that their responses are "programmed by their genes," or, more simply, "hard-wired."


Excerpted from "Wetware"
by .
Copyright © 2009 Dennis Bray.
Excerpted by permission of Yale UNIVERSITY PRESS.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Table of Contents

ONE Clever Cells,
TWO Simulated Life,
THREE Protein Switches,
FOUR Protein Signals,
FIVE Cell Wiring,
SIX Neural Nets,
SEVEN Cell Awareness,
EIGHT Molecular Morphing,
NINE Cells Together,
TEN Genetic Circuits,
ELEVEN Robots,
TWELVE The Juice,
THIRTEEN Amoeba Redux,
Sources and Further Reading,

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