Microcosm (8 page)

These noisy bursts can produce long-term differences between genetically identical bacteria. They turn out to be responsible for making some
E. coli
eager for lactose and others reluctant. If you could peer inside a reluctant
E. coli,
you would find a repressor clamped tightly to the
lac
operon. Lactose can sometimes seep through the microbe’s membrane, and it can even sometimes pry away the repressor. Once the
lac
operon is exposed,
E. coli’
s gene-reading enzymes can get to work very quickly. They make an RNA copy of the operon’s genes, which is taken up by a ribosome and turned into proteins, including a beta-galactosidase enzyme.

But each
E. coli
usually contains about three repressors. They spend most of their time sliding up and down the microbe’s DNA, searching for the
lac
operon. It takes only a few minutes for one of them to find it and shut down the production of beta-galactosidase. Only a tiny amount of beta-galactosidase gets made in those brief moments of liberty. And what few enzymes do get made are soon ripped apart by
E. coli
’s army of protein destroyers. Adding a little more lactose does not change the state of affairs. Too little of the sugar gets into the microbe to keep the repressors away from the
lac
operon for long. The microbe remains reluctant.

Keep increasing the lactose, however, and this reluctant microbe will suddenly turn eager. There’s a threshold beyond which it produces lots of beta-galactosidase. The secret to this reversal is one of the other genes in the
lac
operon. Along with beta-galactosidase,
E. coli
makes the protein permease, which sucks lactose molecules into the microbe. When a reluctant
E. coli’
s
lac
operon switches on briefly, some of these permeases get produced. They begin pumping more lactose into the microbe, and that extra lactose can pull away more repressors. The
lac
operon can turn on for longer periods before a repressor can shut it down again, and so it makes more proteins—both beta-galactosidase for digesting lactose and permease for pumping in more lactose. A positive feedback sets in: more permease leads to more lactose, which leads to more permease, which leads to more lactose. The feedback drives
E. coli
into a new state, in which it produces beta-galactosidase and digests lactose as fast as it can.

Once it becomes eager,
E. coli
will resist changing back. If the concentration of lactose drops, the microbe will still pump in lactose at a high rate, thanks to all the permease channels it has built. It can supply itself with enough lactose to keep the repressors away from the operon so that it can continue making beta-galactosidase and permease. Only if the lactose concentrations drop below a critical level do the repressors suddenly get the upper hand. Then they shut the operon down, and the microbe turns off.

This sticky switch helps to make sense of Novick and Weiner’s strange experiments. Two genetically identical
E. coli
can respond differently to the same level of lactose because they have different histories. The reluctant one resists being switched on while the eager one resists being switched off. And both kinds can pass on their state to their offspring. They don’t bequeath different genes to their descendants. Some give their offspring a lot of permeases on their membranes and a lot of lactose molecules floating through their interiors. Others give their offspring neither.

Combine this peculiar switch with
E. coli
’s unpredictable bursts and you have a recipe for individuality. If a colony of
E. coli
encounters some lactose, some of the bacteria will respond with a huge burst of proteins from their
lac
operon. They will push themselves over the threshold from reluctant to eager, and they will stay that way even if the lactose drops. Other
E. coli
will respond to the lactose with no proteins at all. They will remain reluctant. These clones take on different personalities thanks to chance alone.

E. coli
also gets some of its personality from an extra layer of heredity. Some of its DNA is covered with caps made of hydrogen and carbon atoms. These caps, known as methyl groups, change the response of
E. coli’
s genes to incoming signals. They can, in effect, shut a gene down for a microbe’s entire life without harming the gene itself. When
E. coli
divides in two, it bequeaths its pattern of methyl groups to its offspring. But under certain conditions,
E. coli
will pull methyl groups off its DNA and put new groups on—for reasons scientists don’t yet understand.

Some of the factors that spin the wheel for
E. coli
spin it for us as well. To smell, for example, we depend on hundreds of different receptors on the nerve endings in our noses. Each neuron makes only one type of receptor. Which receptor it makes seems to be a matter of chance, determined by the unpredictable bursts of proteins within each neuron. Our DNA carries methyl groups as well, and over our lifetime their pattern can change. Pure chance may be responsible for some changes; nutrients and toxins may trigger others. Identical twins may have identical genes, but their methyl groups are distinctive by the time they are born and become increasingly different as the years pass. As the patterns change, people become more or less vulnerable to cancer or other diseases. This experience may be the reason why identical twins often die many years apart. They are not identical after all.

These different patterns are also one reason why clones of humans and animals can never be perfect replicas. In 2002, scientists in Texas reported that they had used DNA from a calico cat named Rainbow to create the first cloned kitten, which they named Cc. But Cc is not a carbon copy of Rainbow. Rainbow is white with splotches of brown, tan, and gold. Cc has gray stripes. Rainbow is shy. Cc is outgoing. Rainbow is heavy, and Cc is sleek. New methylation patterns probably account for some of those differences. Clones may also get hit by a unique series of protein bursts. The very molecules that make them up turn them into individuals in their own right.

At the very least,
E. coli’
s individuality should be a warning to those who would put human nature down to any sort of simple genetic determinism. Living things are more than just programs run by genetic software. Even in minuscule microbes, the same genes and the same genetic network can lead to different fates.

Four

THE
E. COLI
WATCHER’S FIELD GUIDE

A HUMAN KRAKATAU

         
ON AUGUST
26, 1883,
a little world was born. An island volcano called Krakatau, located between Java and Sumatra in the Sunda Strait, hurled a column of ash twenty miles into the air. Rock turned to vapor and roared across the strait at 300 miles an hour. The eruption left a submerged pit where the cone of the volcano had been, along with a few lifeless islands. Nine months later, a naturalist who visited the scene reported that the only living thing he could find was a single small spider.

The new islands of Krakatau lay twenty-seven miles from the nearest land. It took years for life to make its way across the water and take hold again. A film of blue-green algae grew over the ash. Ferns and mosses sprouted. By the 1890s a savanna had emerged. Along with the spiders came beetles, butterflies, and even a monitor lizard. Some of the arriving species swam to the islands, some flew, and some simply drifted on the wind.

These species did not take hold on Krakatau in a random scramble. Rugged pioneers came first and later gave way to other species. The savanna surrendered to forests. Coconut and fig trees grew. Orchids, fig wasps, and other delicate species could now move onto the islands. Early settlers such as zebra doves could no longer find a place in the food web and vanished. Even now, more than 120 years after the eruption, Krakatau is not finished with its transformation. In the future it may be ready to receive bamboo, which will revolutionize its ecosystem yet again.

The history of Krakatau followed ecological rules that guide life wherever new habitats appear. Volcanic eruptions wipe islands clean. Landslides clear mountainsides. As glaciers melt, shorelines bounce out of the sea.

And babies are born. To microbes, a newborn child is a Krakatau ready to be colonized. Its body starts out almost completely germ free, and in its first few days
E. coli
and other species of bacteria infect it. They establish a new ecosystem, which will mature and survive within the child through its entire life. And it will develop over time according to its own ecological rules.

There is much more to
E. coli’
s life than can be seen in a petri dish. Its pampered existence in the laboratory makes very few demands on it. Out of the 4,288 genes scientists have identified in
E. coli
K-12, only 303 appear to be essential for its growth in a laboratory. That does not mean the other 3,985 genes are all useless. Many help
E. coli
survive in the crowded ecosystem of the human gut, where a thousand species of microbes compete for food.

A scientist studying
E. coli
in a flask may completely overlook some of its essential strategies for surviving in the real world. For all the work that has gone into
E. coli
over the past century, for example, microbiologists often fail to acknowledge just how social a creature it is. To survive,
E. coli
work together. The bacteria communicate and cooperate. Billions of them join together to build microbial cities. They wage wars together against their enemies.

In the real world there is no single way of being an
E. coli. E. coli
K-12 is just one of many strains that live in warm-blooded animals and have many strategies for surviving. Some are harmless gut grazers. Others shield us from infections. And still others kill millions of people a year. To know
E. coli
by K-12 alone is a bit like knowing the family
Canidae
from a Pomeranian dozing on a silk pillow. Outside there are dingoes and bat-eared foxes, red wolves and black-backed jackals.

FINDING A HOME

E. coli
is a pioneer. Long before most other microbes have moved into a human host, it has established a healthy colony.
E. coli
may infect a baby during the messy business of childbirth, hitch along on the fingertips of a doctor, or make its leap as mother nurses child. It rides waves of peristalsis into the stomach, where it must survive an acid bath. As the swarms of protons in hydrochloric acid seep into it,
E. coli
builds extra pumps that can flush most of them out. It does not try to behave like a normal microbe in the stomach; instead, it enters what one scientist has called “a Zen-like physiology.” Except for the proteins it needs to defend against stomach acid,
E. coli
simply stops making proteins altogether.

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.