by Carl Zimmer
After two hours in this acid Zen, E. coli is driven out of the stomach and into the intestines. Its pumps continue driving out its extra protons until its interior gets back its negative charge. Its biological batteries power up once more, and it can now begin to make new proteins and repair old ones. It returns to the everyday business of living. E. coli has not yet reached its new home, though—it must first travel through the small intestine and into the large one. The distance may be only thirty feet, but it’s about 7 million times the length of E. coli. If you dived into the ocean in Los Angeles and swam 7 million body lengths, you could cross the Pacific.
As E. coli drifts through the human gut, its hook-tipped hairs snag on the intestinal walls. A gentle flow of food is enough to detach the hooks, allowing the microbe to roll along. But if the flow becomes strong, the hairs begin to grip stubbornly to the wall. It just so happens that the hairs bring E. coli to a halt exactly in the place in the large intestine that suits it best, where food flows by at top speed. The warmth of the gut triggers it to make proteins it can use to harvest iron, to break down sugar, and to weld together amino acids. It begins to feed and thrive, at least for a few days.
As E. coli grows and multiplies, it prepares the way for its own downfall. It uses up much of the oxygen in the intestines and alters their chemistry by releasing carbon dioxide and other wastes. It creates a new habitat that other species of microbes can invade and dominate. This ecosystem E. coli helps to build in our bodies is spectacular. It can reach a population of 100 trillion, outnumbering the cells of our body ten to one. Scientists estimate that a thousand species of microbes can coexist in a single human gut, which means that if you were to make a list of all the genes in your body, the vast majority of them would not be human.
As other species prosper, E. coli dwindles away until it makes up just one-tenth of 1 percent of the population of gut microbes. It becomes prey to viruses and predatory protozoans. It must compete with other microbes for food. But it also comes to depend on other species of microbes for food. As its host grows older and gives up milk, the gut starts to fill with starches and other complex sugars that E. coli can’t break down. It’s like going to a restaurant and having your waiter suddenly switch your chocolate mousse with a bowl of hay. E. coli must now wait for other species of bacteria to break down complex sugars so it can feed on their waste.
Yet even as a minor scavenger, E. coli may be able to repay the other microbes for their services. Some research suggests that by clearing away simple sugars, scavengers like E. coli may allow other microbes to break down complex sugars more quickly. E. coli also continues to snatch up what little oxygen accumulates in the gut from time to time. By keeping the level of oxygen at a steady low, E. coli makes the gut reliably comfortable for the vast majority of resident microbes. Cradled in this ecological web, E. coli colonies will grow in the human gut for the host’s entire lifetime. As many as thirty different strains may live there at any moment. It is a very rare person who is ever E. coli free.
Here is another way in which we are like E. coli: we, too, depend on our microbial jungle. We need bacteria to break down many of the carbohydrates in our food. Our microbial passengers synthesize some of the vitamins and amino acids we need. They help control the calories that flow from our food to our bodies. A change in the bacteria in your gut may change your weight. Intestinal microbes also ward off diseases, a fact that has led doctors to feed premature infants protective strains of E. coli. The bacteria protect the gut by releasing chemicals that repel pathogens and by creating a tightly knit community that the pathogens simply can’t invade.
It is difficult, in fact, to say exactly where these bacteria stop and our own immune systems begin. They help our immune systems manage a delicate balance between killing pathogens and not destroying our own tissues. Studies show that some strains of E. coli can cool down battle-frenzied immune cells. A healthy supply of E. coli may help ward off not just pathogens but autoimmune diseases such as colitis. Some scientists argue that our immune systems return the favor by stimulating the bacteria to form thick protective clusters that coat the intestines. The clusters not only block invaders but also prevent individual microbes from penetrating the lining of the gut. All this biochemical goodwill makes sense—after all, we and E. coli are members of the same collective.
TOGETHERNESS
In 2003, Jeffry Stock and his colleagues at Princeton University put E. coli in a maze. The maze, which measured less than a hundredth of an inch on each side, had walls of plastic and a roof of glass. The scientists submerged it in water and then injected E. coli into the entrance. The bacteria began to spin their flagella and swim. Stock’s team had added a gene for a glowing protein to each E. coli so they could follow their trail as the microbes wandered through the labyrinth.
At first the bacteria seemed to move randomly. But they gradually gathered together and began to swim in schools. Some of the schools got trapped in a dead end, where the bacteria were content to stay with one another. The other bacteria swam after them, and after two hours the dead end was filled with a huddled mass of glowing microbes.
To figure out how the bacteria were finding one another, the Princeton scientists set mutants loose in the maze. They found that E. coli can congregate as long as their microbial tongues taste the amino acid serine. It just so happens that in the normal course of its metabolism, E. coli casts off serine in its waste. Scientists had known of the microbe’s attraction to serine since the 1960s, but they had generally assumed that it had something to do with the microbe’s search for food. E. coli’s sociable flocking in the maze raised another possibility: its tongue may be tuned to find other E. coli.
Not long ago E. coli and most other bacteria were considered loners. After all, they seemed to lack the sort of glue that holds societies together: a way to communicate. They cannot write e-mail; they cannot shake their tail feathers; they cannot sing across a desert at dawn. But E. coli does have a kind of language of its own and its own kind of society.
E. coli’s social life has been overlooked for decades because most biologists have been more interested in the bare basics of its existence: how it feeds, grows, and reproduces. They’ve perfected the recipe for getting E. coli to do all three things as fast as possible. The warm, oxygen-rich, overfed life E. coli enjoys in the lab favors individual microbes that can breed quickly. But it bears little resemblance to E. coli’s normal existence. Although each person eats about sixty tons of food in a lifetime, E. coli may starve for hours or days. When it does get the chance to eat, it may be presented with a low-energy sugar barely worth the effort it takes to break down. E. coli may have to compete with other microbes for every molecule. At the same time, it must withstand assaults from viruses, predators, and man-made dangers such as antibiotics. Its host may become ill, devastating its entire habitat. One of the best ways to withstand all these catastrophes is to join forces with other E. coli.
Once they gather, the bacteria may do a number of things. Under some conditions a group of E. coli will sprout a new kind of flagellum, one that’s far longer than its ordinary tail. The new flagella join together, tethering millions of bacteria into a single seething mass. Instead of swimming, they swarm across a surface, squirting out molecules that soak up water and create a carpet of slime. Swarming allows E. coli to glide across a petri dish or, scientists suspect, across an intestinal wall.
E. coli can also settle down and build a microbial city. Scientists have long been aware that bacteria can form a cloudy layer of scum on their flasks, known as a biofilm. Biofilms simply annoyed biologists at first. But a closer look revealed biofilms to be marvelously intricate structures. All microbes can make biofilms, and scientists suspect that the vast majority of microbes spend most of their lives in one. Biofilms form slimy coats on river bottoms, on the ocean floor, at the bottom of acid-drenched mine shafts, and on the inner walls of our intestines.
Biofilms may be everywhere, but studying them is not a simple
matter. Scientists have had to ditch their flasks and petri dishes and think of new kinds of experiments. Some have built special chambers with warm flowing water to mimic the human gut. Under the right conditions, E. coli will settle down inside them and begin to build its biofilm. As the bacteria drift through the chamber, some alight on the bottom. Normally the microbes immediately let go and swim on, but sometimes they settle down instead. Some experiments suggest that E. coli make this decision if they detect other E. coli nearby. They sense their fellow microbes by the chemicals they release—not just serine and other sorts of waste but special molecules that serve as signals and can change the way other E. coli behave.
Once a group of E. coli has committed itself to forming a biofilm, the microbes start to build sticky fibers to snag one another and pull together into a tight cluster. They’re joined by more floating E. coli, and the cluster grows. They begin to squirt a rubbery slime from their pores, entombing themselves in a matrix. As the biofilm takes shape, it does not form a flat sheet. It grows looming towers, broad pedestals, and a network of crisscrossing avenues. All of these changes require each microbe to switch hundreds of genes on and off in a complicated, coordinated fashion. E. coli biofilms are in some ways like our bodies. A biofilm may not get up and walk around on two legs. But, like our cells, it forms collectives in which different cells take on different jobs and work together to promote their shared survival.
A biofilm of E. coli
Scientists are still trying to figure out exactly why E. coli bothers to build biofilms. An individual microbe must make a great sacrifice to join the effort, spending a lot of its precious energy to build the glue that will join it to other microbes. If an individual E. coli should happen to get stuck deep inside the biofilm, it will have a harder time getting food than it would have if it remained floating free. These costs may be outweighed by benefits. Biofilms may provide E. coli with sustenance and protection. Biofilms can withstand harsh swings of the environment. Viruses may have a harder time penetrating biofilms than infecting single cells. Antibiotics are a thousand times weaker against biofilms than against individual microbes.
Biofilms may also allow bacteria to work together to catch food. Nutrients may get caught in the rubbery slime of biofilms and flow down canals to reach out-of-the-way microbes. Bacteria can also work cooperatively in biofilms by dividing their labors. The ones near the surface can get more food and oxygen than the ones buried deep inside. But they also face more stress. The E. coli nestled at the base of a biofilm may slip into a state of suspended animation, a kind of microbial seed bank. From time to time they may break off from the biofilm and drift away, becoming free-floating individuals or settling back down on the gut to build a new biofilm.
Humans, the supremely social species, don’t cooperate just to build cities and help their fellow humans. They also cooperate to wage war. And here again E. coli mirrors our social life. We build missiles and bombs. E. coli builds chemical weapons. Known as colicins, these deadly molecules kill in many ways. Some pierce the microbe’s membrane like a spear, forcing its innards to spill out. Others block E. coli from building new proteins. Others destroy DNA.
In order to launch a colicin attack, some E. coli must make the ultimate sacrifice. A few microbes in a population will build hundreds of thousands of colicin molecules in a matter of seconds, until they swell with weaponry. The microbes do not have channels through which they can neatly pump out their colicins. Instead, they make suicide enzymes that cut open their membranes. As they explode, the colicins blast out and hit neighboring E. coli. Their close relatives are spared the attack, however, because they carry genes that produce a colicin-disabling antidote. The sacrifice of a few E. coli clears away the competition, and their fellow clones prosper. The social life of E. coli, it seems, extends beyond life itself.
FAREWELL, MY HOST
Once a strain of E. coli establishes itself in our guts, it can remain there for decades. But the bacteria also escape their hosts, by a route that’s so obvious there’s no need to dwell on it. Suffice it to say that every day the world’s human population releases more than a billion trillion E. coli into the environment. Countless more escape from other mammals and from birds. They are swept down sewer pipes and streams, sowed upon the ground and sea. They must withstand summers and winters, droughts and floods. They must eke out an existence without a luxurious diet of half-digested sugar. For long stretches they may have to survive with no food at all. In soil and water there are many predators waiting to devour E. coli, including nematode worms and creeping amoebas. Some predators overpower E. coli by sheer size. Others, such as the bacteria Bdellovibrio, push their way into E. coli’s periplasm and destroy it from within. The bacteria Myxococcus xanthus release molecules that smell to E. coli like the whiff of food. The unlucky microbe swims to its own destruction.
Leaving their hosts is probably a quick trip to death for most E. coli. But life can handle bad odds. Oaks shower the ground with acorns, almost none of which survive to become saplings. Our own bodies are made of trillions of cells, only a few of which may escape our own death by giving rise to children. Even if only a tiny fraction of E. coli in the wild survives and manages to find a new host, its life cycle will continue. And E. coli has several tricks for surviving on the outside. Its versatile metabolism lets it feed on many carbon-bearing molecules—even TNT. If a soil predator tries to eat it, the microbe can avoid being digested and instead thrive as a parasite. And if worse comes to worst, E. coli can fold down its DNA into a rugged crystal, slip into the stationary phase, and survive for years.
Or, just perhaps, E. coli can abandon hosts altogether. From time to time, scientists discover populations of E. coli that appear to be thriving as full-time outdoor microbes. In Australia, for example, researchers have discovered huge blooms of E. coli in lakes where none had been expected. The lakes are free of fecal matter, receiving no sewage or farm runoff. Yet on a warm day they are loaded with millions of billions of E. coli. The bacteria seem different from more familiar strains. For one thing they make an unusually tough capsule, which may act as a microbial wet suit, allowing them to survive year-round in the lakes. They no longer need hosts to avoid extinction. They have broken free.
A DAY AT THE FAIR
In central Connecticut, where I live, agricultural fairs are serious business. Every summer one town after another—Goshen, Durham, Haddam Neck—raises tents and Ferris wheels. Trailers arrive, rattling along the rocky paths, full of oxen ready to drag concrete blocks. Mayors and selectmen are summoned for cow-milking contests. The fairs have survived long after the agricultural communities that produced them wilted away. Yet they still swarm with thousands of people who come to see prize goats, delicately wrought pies, and flouncing roosters.
I go with my wife and two daughters to a few fairs each summer, and each time we go, I lose my sense of time. I feel as if I’m back in an age when a typical ten-year-old would know how to shear a sheep. But just when I’ve almost completely lost my moorings in a tent full of livestock, I notice a wooden post staked in the ground by the entrance, holding a box of soap. It snaps me back to the twenty-first century, and when we leave the tent I make very sure my daughters scrub their hands.
These tents are home to some exquisitely vicious bacteria. The microbes live in the animals winning the ribbons at the fairs, and they fall with the droppings into the hay, float off on motes of dust, hitchhike on the bristles of flies. They spread through the tents, sticking to floors and fences and wool and feathers. It takes a tiny dose of them—just a dozen entering the mouth—to make a person hideously ill. The intestines bleed; kidneys fail. Antibiotics only make the attack worse. All doctors can do is hook their patients to an intravenous line of saline solution and hope for the best. Most people do eventually recover, but some will suffer for the rest of their lives. A few will die.
When pathologists test the fatal bacteria, they meet up with a familiar friend: E. coli.
E. coli comes
in many strains. All of them share the same underlying biology, but they range enormously in how they make a living. Most are harmless, but outside laboratories, E. coli also comes in forms that can sicken or kill. To know E. coli, to know what it means for it to be alive, it’s not enough to study a tame strain such as K-12. The deadly strains are members of the species as well.
Scientists did not appreciate how dangerous E. coli could be for decades after Theodor Escherich discovered the bacteria. The first clear evidence that not all strains of E. coli were harmless bystanders came in 1945. John Bray, a British pathologist, had been searching for the cause of “summer diarrhea,” a deadly childhood disease that swept across Britain and many other industrialized countries every year. Bray hunted for bacteria that were common in sick children and missing from healthy ones.
Bray searched for the bacteria with antibodies, the best tools of his day. Antibodies are made by our immune cells when they encounter proteins from a pathogen. The antibodies can then attack the pathogen by recognizing its protein. Because antibodies are so exquisitely specific to their targets, they will ignore just about any other protein they encounter. Bray created antibodies to pathogens such as Salmonella by injecting the bacteria into a rabbit. Once the rabbit’s immune system had mounted an attack, Bray extracted the antibodies from its blood. He then added the antibodies to cultures of bacteria he reared from the diarrhea of sick children. He wanted to see if they would reveal any pathogens. They did not.
