Microcosm

by Carl Zimmer

  Nirenberg would share a Nobel Prize for Medicine the following year. Delbrück got his the year after. Lederberg, Tatum, and many others who worked on E. coli were also summoned to Stockholm. A humble resident of the gut had led them to glory and to a new kind of science, known as molecular biology, that unified all of life. Jacques Monod, another of E. coli’s Nobelists, gave Albert Kluyver’s old claim a new twist, one that many scientists still repeat today.

  “What is true for E. coli is true for the elephant.”

  THE SHAPE OF LIFE

  With the birth of molecular biology, genes came to define what it means to be alive. In 2000, President Bill Clinton announced that scientists had completed a rough draft of the human genome—the entire sequence of humans’ DNA. He declared, “Today, we are learning the language in which God created life.”

  But on their own, genes are dead, their instructions meaningless. If you coax the chromosome out of E. coli, it cannot build proteins by itself. It will not feed. It will not reproduce. The fragile loop of DNA will simply fall apart. Understanding an organism’s genes is only the first step in understanding what it means for the organism to be alive.

  Many biologists have spent their careers understanding what it means for E. coli in particular to be alive. Rather than starting from scratch with another species, they have built on the work of earlier generations. Success has bred more success. In 1997, scientists published a map of E. coli’s K-12’s entire genome, including the location of 4,288 genes. The collective knowledge about E. coli makes it relatively simple for a scientist to create a mutant missing any one of those genes and then to learn from its behavior what that gene is for. Scientists now have a good idea of what all but about 600 genes in E. coli are for. From the hundreds of thousands of papers scientists have published on E. coli comes a portrait of a living thing governed by rules that often apply, in one form or another, to all life. When Jacques Monod boasted of E. coli and the elephant, he was speaking only of genes and proteins. But E. coli turns out to be far more complex—and far more like us—than Monod’s generation of scientists realized.

  The most obvious thing one notices about E. coli is that one can notice E. coli at all. It is not a hazy cloud of molecules. It is a densely stuffed package with an inside and an outside. Life’s boundaries take many forms. Humans are wrapped in soft skin, crabs in a hard exoskeleton. Redwoods grow bark, squid a rubbery sheet. E. coli’s boundary is just a few hundred atoms thick, but it is by no means simple. It is actually a series of layers within layers, each with its own subtle structure and complicated jobs to carry out.

  E. coli’s outermost layer is a capsule of sugar teased like threads of cotton candy. Scientists suspect it serves to frustrate viruses trying to latch on and perhaps to ward off attacks from our immune system. Below the sugar lies a pair of membranes, one nested in the other. The membranes block big molecules from entering E. coli and keep the microbe’s molecules from getting out. E. coli depends on those molecules reacting with one another in a constant flurry. Keeping its 60 million molecules packed together lets those reactions take place quickly. Without a barrier, the molecules would wander away from one another, and E. coli would no longer exist.

  At the same time, though, life needs a connection to the outside world. An organism must draw in new raw materials to grow, and it must flush out its poisonous waste. If it can’t, it becomes a coffin. E. coli’s solution is to build hundreds of thousands of pores, channels, and pumps on the outer membrane. Each opening has a shape that allows only certain molecules through. Some swing open for their particular molecule, as if by password.

  Once a molecule makes its way through the outer membrane, it is only half done with its journey. Between the outer and inner membranes of E. coli is a thin cushion of fluid, called the periplasm. The periplasm is loaded with enzymes that can disable dangerous molecules before they are able to pass through the inner membrane. They can also break down valuable molecules so that they can fit in channels embedded in the inner membrane. Meanwhile, E. coli can truck its waste out through other channels. Matter flows in and out of E. coli, but rather than making a random, lethal surge, it flows in a selective stream.

  E. coli has a clever solution to one of the universal problems of life. Yet solutions have a way of creating problems of their own. E. coli’s barriers leave the microbe forever on the verge of exploding. Water molecules are small enough to slip in and out of its membranes. But there’s not much room for water molecules inside E. coli, thanks to all the proteins and other big molecules. So at any moment more water molecules are trying to get into the microbe than are trying to get out. The force of this incoming water creates an enormous pressure inside E. coli, several times higher than the pressure of the atmosphere. Even a small hole is big enough to make E. coli explode. If you prick us, we bleed, but if you prick E. coli, it blasts.

  One way E. coli defends against its self-imposed pressure is with a corset. It creates an interlocking set of molecules that form a mesh that floats between the inner and outer membranes. The corset (known as the peptidoglycan layer) has the strength to withstand the force of the incoming water. E. coli also dispatches a small army of enzymes to the membranes to repair any molecules damaged by acid, radiation, or other abuse. In order to grow, it must continually rebuild its membranes and peptidoglycan layer, carefully inserting new molecules without ever leaving a gap for even a moment.

  E. coli’s quandary is one we face as well. Our own cells carefully regulate the flow of matter through their walls. Our bodies use skin as a barrier, which must also be pierced with holes—for sweat glands, ear canals, and so on. Damaged old skin cells slough off as the underlying ones grow and divide. So do the cells of the lining of our digestive tract, which is essentially just an interior skin. This quick turnover allows our barriers to heal quickly and fend off infection. But it also creates its own danger. Each time a cell divides, it runs a small risk of mutating and turning cancerous. It’s not surprising, then, that skin cancer and colon cancer are among the most common forms of the disease. Humans and E. coli alike must pay a price to avoid becoming a blur.

  THE RIVER THAT RUNS UPHILL

  Barriers and genes are essential to life, but life cannot survive with barriers and genes alone. Put DNA in a membrane, and you create nothing more than a dead bubble. Life also needs a way to draw in molecules and energy, to transform them into more of itself. It needs a metabolism.

  Metabolisms are made up of hundreds of chemical reactions. Each reaction may be relatively simple: an enzyme may do nothing more than pull a hydrogen atom off a molecule, for instance. But that molecule is then ready to be grabbed by another enzyme that will rework it in another way, and so on through a chain of reactions that can become hideously intricate—merging with other chains, branching in two, or looping back in a circle. The first species whose metabolism scientists mapped in fine detail was E. coli.

  It took them the better part of the twentieth century. To uncover its pathways, they manipulated it in many ways, such as feeding it radioactive food so that they could trace atoms as E. coli passed them from molecule to molecule. It was slow, tough, unglamorous work. After James Watson and Francis Crick discovered the structure of DNA, their photograph appeared in Life magazine: two scientists flanking a tall, bare sculpture. There was no picture of the scientists who collectively mapped E. coli’s metabolism. It would have been a bad photograph anyway: hundreds of people packed around a diagram crisscrossed with so many arrows that it looked vaguely like a cat’s hairball. But for those who know how to read that diagram, E. coli’s metabolism has a hidden elegance.

  The chemical reactions that make up E. coli’s metabolism don’t happen spontaneously, just as an egg does not boil itself. It takes energy to join atoms together, as well as to break them apart. E. coli gets its energy in two ways. One is by turning its membranes into a battery. The other is by capturing the energy in its food.

  Among the channels that decorate E. coli’s membran
es are pumps that hurl positively charged protons out of the microbe. E. coli gives itself a negative charge in the process, attracting positively charged atoms that happen to be in its neighborhood. It draws some of them into special channels that can capture energy from their movement, like an electric version of a waterwheel. E. coli stores that energy in the atomic bonds of a molecule called adenosine triphosphate, or ATP.

  ATP molecules float through E. coli like portable energy packs. When E. coli’s enzymes need extra energy to drive a reaction, they grab ATP and draw out the energy stored in the bonds between its atoms. E. coli uses the energy it gets from its membrane battery to get more energy from its food. With the help of ATP, its enzymes can break down sugar, cutting its bonds and storing the energy in still more ATP. It does not unleash all the energy in a sugar molecule at once. If it did, most of that energy would be lost in heat. Rather than burning up a bonfire of sugar, E. coli makes surgical nicks, step by step, in order to release manageable bursts of energy.

  E. coli uses some of this energy to build new molecules. Along with the sugar it breaks down, it also needs a few minerals. But it has to work hard to get even the trace amounts it requires. E. coli needs iron to live, for example, but iron is exquisitely scarce. In a living host most iron is tucked away inside cells. What little there is outside the cells is usually bound up in other molecules, which will not surrender it easily. E. coli has to fight for iron by building iron-stealing molecules, called siderophores, and pumping them out into its surroundings. As the siderophores drift along, they sometimes bump into iron-bearing molecules. When they do, they pry away the iron atom and then slide back into E. coli. Once inside, the siderophores unfold to release their treasure.

  While iron is essential to E. coli, it’s also a poison. Once inside the microbe, a free iron atom can seize oxygen atoms from water molecules, turning them into hydrogen peroxide, which in turn will attack E. coli’s DNA. E. coli defends itself with proteins that scoop up iron as soon as it arrives and store it away in deep pockets. A single one of these proteins can safely hold 5,000 iron atoms, which it carefully dispenses, one atom at a time, as the microbe needs them.

  Iron is not the only danger E. coli’s metabolism poses to itself. Even the proteins it builds can become poisonous. Acid, radiation, and other sorts of damage can deform proteins, causing them to stop working as they should. The mangled proteins wreak havoc, jamming the smooth assembly line of chemistry E. coli depends on for survival. They can even attack other proteins. E. coli protects itself from itself by building a team of assassins—proteins whose sole function is to destroy old proteins. Once an old protein has been minced into amino acids, it becomes a supply of raw ingredients for new proteins. Life and death, food and poison—all teeter together on a delicate fulcrum inside E. coli.

  As E. coli juggles iron, captures energy, and transforms sugar into complex molecules, it seems to defy the universe. There’s a powerful drive throughout the universe, known as entropy, that pushes order toward disorder. Elegant snowflakes melt into drops of water. Teacups shatter. E. coli seems to push against the universe, assembling atoms into intricate proteins and genes and preserving that orderliness from one generation to the next. It’s like a river that flows uphill.

  E. coli is not really so defiant. It is not sealed off from the rest of the universe. It does indeed reduce its own entropy, but only by consuming energy it gets from outside. And while E. coli increases its own internal order, it adds to the entropy of the universe with its heat and waste. On balance, E. coli actually increases entropy, but it manages to bob on the rising tide.

  E. coli’s metabolism is something of a microcosm of life as a whole. Most living things ultimately get their energy from the sun. Plants and photosynthetic microbes capture light and use its energy to grow. Other species eat the photosynthesizers, and still other species eat them in turn. E. coli sits relatively high up in this food web, feeding on the sugars made by mammals and birds. It gets eaten in turn, its molecules transformed into predatory bacteria or viruses, which get eaten as well. This flow of energy gives rise to forests and other ecosystems, all of which unload their entropy on the rest of the universe. Sunlight strikes the planet, heat rises from it, and a planet full of life—an E. coli for the Earth—sustains itself on the flow.

  A SENSE OF WHERE YOU ARE

  Life’s list grows longer. It stores information in genes. It needs barriers to stay alive. It captures energy and food to build new living matter. But if life cannot find that food, it will not survive for long. Living things need to move—to fly, squirm, drift, send tendrils up gutter spouts. And to make sure they’re going in the right direction, most living things have to decide where to go.

  We humans use 100 billion neurons bundled in our heads to make that decision. Our senses funnel rivers of information to the brain, and it responds with signals that control the movements of our bodies. E. coli, on the other hand, has no brain. It has no nervous system. It is, in fact, thousands of times smaller than a single human nerve cell. And yet it is not oblivious to its world. It can harvest information and manufacture decisions, such as where it should go next.

  E. coli swims like a spastic submarine. Along the sides of its cigar-shaped body it sprouts about half a dozen propellers. They’re shaped like whips, trailing far behind the microbe. Each tail (or, as microbiologists call it, flagellum) has a flexible hook at its base, which is anchored to a motor. The motor, a wheel-shaped cluster of proteins, can spin 250 times a second, powered by protons that flow through its pores into the microbe’s interior.

  Most of the time, E. coli’s motors turn counterclockwise, and when they do their flagella all bundle together into a cable. They behave so neatly because each flagellum is slightly twisted in the same direction, like the ribbons on a barber’s pole. The cable of flagella spin together, pushing against the surrounding fluid in the process, driving the microbe forward.

  E. coli can swim ten times its body length in a second. The fastest human swimmers can move only two body lengths in that time. And E. coli wins this race with a handicap, because the physics of water is different for microbes than for large animals like us. For E. coli, water is as viscous as mineral oil. When it stops swimming, it comes to a halt in a millionth of a second. E. coli does not stop on a dime. It stops on an atom.

  About every second or so, E. coli throws its motors in reverse and hurls itself into a tumble. When its motors spin clockwise, the flagella can no longer slide comfortably over one another. Now their twists cause them to push apart; their neat braid flies out in all directions. It now looks more like a fright wig than a barber’s pole. The tumble lasts only a tenth of a second as E. coli turns its motors counterclockwise once more. The flagella fold together again, and the microbe swims off.

  The first scientist to get a good look at how E. coli swims was Howard Berg, a Harvard biophysicist. In the early 1970s, Berg built a microscope that could follow a single E. coli as it traveled around a drop of water. Each tumble left E. coli pointing in a new random direction. Berg drew a single microbe’s path over the course of a few minutes and ended up with a tangle, like a ball of yarn in zero gravity. For all its busy swimming, Berg found, E. coli manages to wander only within a tiny space, getting nowhere fast.

  E. coli’s flagellum is driven by motorlike proteins that spin in its membrane.

  Offer E. coli a taste of something interesting, however, and it will give chase. E. coli’s ability to navigate is remarkable when you consider how little it has to work with. It cannot wheel and bank a pair of wings. All it can do is swim in a straight line or tumble. And it can get very little information about its surroundings. It cannot consult an atlas. It can only sense the molecules it happens to bump into in its wanderings. But E. coli makes good use of what little it has. With a few elegant rules, it gets where it needs to go.

  E. coli builds sensors and inserts them in its membranes so that their outer ends reach up like periscopes. Several thousand sensors cluster tog
ether at the microbe’s front tip, where they act like a microbial tongue. They come in five types, each able to grab certain kinds of molecules. Some types attract E. coli, and some repel it. An attractive molecule, such as the amino acid serine, sets in motion a series of chemical reactions inside the microbe with a simple result: E. coli swims longer between its tumbles. It will keep swimming in longer runs as long as it senses that the concentration of serine is rising. If its tumbles send it away from the source of serine, its swims become shorter. This bias is enough to direct E. coli slowly but reliably toward the serine. Once it gets to the source, it stays there by switching back to its aimless wandering.

  Scientists began piecing together E. coli’s system of sensing and swimming in the 1960s. They chose E. coli’s system because they thought it would be easy. They could take advantage of the long tradition of using mutant E. coli to study how proteins work. And once they had solved E. coli’s information processors, they would be able to take what they had learned and apply it to more complex processors, including our own brains. Forty years later they understand E. coli’s signaling system more thoroughly than that of any other species. Some parts of E. coli’s system turned out to be simple after all. E. coli does not have to compute barrel rolls or spiral dives. Its swim-and-tumble strategy works very well. Every E. coli may not get exactly where it needs to go, but many of them will. They will be able to survive and reproduce and pass the run-and-tumble strategy on to their offspring. That is all the success a microbe needs.

  Yet in some important ways, E. coli’s navigation defies understanding. Its microbial tongue can detect astonishingly tiny changes in the concentration of molecules it cares about, down to one part in a thousand. The microbe is able to amplify these faint signals in a way that scientists have not yet discovered. It’s possible that E. coli’s receptors are working together. As one receptor twists, it causes neighboring receptors to twist as well. E. coli may even be able to integrate different kinds of information at the same time—oxygen climbing, nickel falling, glucose wafting by. Its array of receptors may turn out to be far more than just a microbial tongue. It may be more like a brain.