Microcosm (7 page)

Left unchecked, however, a sudden rush of sigma 32 would be too much of a good thing. The microbe would churn out heat-shock proteins far beyond its needs. In fact,
E. coli
makes just the right number of heat-shock proteins to cope with a particular temperature. It makes more proteins for higher temperatures, fewer for cooler ones. It exerts this fine control with a series of feedback loops.

E. coli’
s heat-shock proteins don’t just protect against heat. They also control the thermometer protein itself, sigma 32. Some of them grab sigma 32 and tuck it away in a pocket. Others cut it to pieces. In the first few moments of dangerous heat, heat-shock proteins are too busy helping unfolded proteins to attack sigma 32. But once they get the crisis under control, more and more heat-shock proteins become free to grab sigma 32. As the level of sigma 32 drops,
E. coli
makes fewer new heat-shock proteins.

This feedback helps keep
E. coli
from exploding with heat-shock proteins. It also controls the level of heat-shock proteins. If
E. coli
is merely warm rather than scorching, the heat-shock proteins quickly reduce the level of sigma 32. But as the temperature increases, they have to cope with more unfolded proteins, and thus they allow sigma 32 to remain high so that
E. coli
will produce more heat-shock proteins. And once
E. coli
cools down to a comfortable temperature, its thermostat shuts down the heat-shock proteins almost completely.

E. coli’
s robust self-control comes from the feedback loops built into its network. To engineers this principle is second nature. The autopilot in a Boeing 777 uses the same kinds of feedback to keep the plane level as it is buffeted by wind shears and downdrafts. In neither case does robustness come from some all-knowing consciousness. It emerges from the network itself.

THE BIG PICTURE

Put genes together into circuits and they can do much more than they could on their own. Put circuits together and you create a living thing.

In the 1940s, Edward Tatum and other scientists got the first hints of what certain genes in
E. coli
were for. As of 2007, researchers had a pretty good idea of what about 85 percent of its genes do, making
E. coli
the gold standard of genetic familiarity. Scientists have created online databases for
E. coli’
s genes, its operons, its metabolic pathways. Mysteries remain—there are forty-one enzymes drifting around inside
E. coli
for which scientists have yet to find genes, for example—but a rough portrait of
E. coli’
s entire system is emerging, the closest thing biologists have to a complete solution to any living organism.

Bernhard Palsson, a biologist at the University of California, San Diego, has overseen the construction of a model of
E. coli’
s metabolism. As of 2007, he and his colleagues had programmed a computer with information on 1,260 genes and 2,077 reactions. The computer can use this information to calculate how much carbon flows through
E. coli’
s pathways, depending on the sort of food it eats. Palsson’s model does a good job of predicting how quickly
E. coli
will grow on a diet of glucose and how much carbon dioxide it will release. If Palsson switches off the oxygen, the model shunts carbon into an oxygen-free metabolic pathway, just as
E. coli
does. If Palsson leaves out a particular protein, the model metabolism rearranges itself just as the metabolism of a real mutant
E. coli
would. It predicts
E. coli’
s behavior in thousands of conditions. The model and
E. coli
alike make the best of whatever situation they face, adjusting their metabolism in order to grow as fast as they can.

How does
E. coli’
s metabolism manage to stay so supple when it is made up of hundreds of chemical reactions? With thousands of possible pathways it could choose from, why does it choose among the best few? Why doesn’t the whole system simply crash? Part of the solution lies in the shape of the network itself, the very layout of its labyrinth.

When scientists map the pathways that a carbon atom can take through
E. coli’
s metabolism, the picture they see looks like a bow tie. On one side of the bow tie are the chemical reactions that draw in food and break it down. These reactions follow each other along simple pathways, a fan of incoming arrows. Eventually the arrows all converge on the bow tie’s knot. There the pathways get much more complicated. The product of a reaction may get pulled into many different reactions, depending on the conditions at that moment. It is there, in the knot, that
E. coli
creates the building blocks for all its molecules. The building blocks enter the other side of the bow tie—an outgoing fan of pathways. Each pathway produces a very different sort of molecule—this one a membrane molecule, that one a piece of RNA, another one a protein. The pathways on the far side of the bow tie fan out without crossing over. A molecule on its way to becoming a protein does not become a piece of DNA.

The bow tie architecture in
E. coli
makes good engineering sense. Man-made networks, such as a telephone network or a power grid, are often laid out in a bow tie as well. A bow tie architecture lets networks run efficiently and robustly. The Internet, for example, has an incoming fan made up of signals from e-mail programs, Web browsers, and all sorts of other software, each with its own peculiar sorts of information processing. In order for this stream of data to get onto the Internet, it must first be turned into a code that obeys the Internet’s protocols. These data streams move from personal computers to servers and then into a small core of routers. The signals can then flow into an outgoing fan of pathways, toward another computer, where the standard stream of data can be converted into a picture, a document, or some other peculiar form.

In both the Internet and
E. coli,
the bow tie knot allows each network to function even when parts of it fail. A mutation that destroys one metabolic reaction will not kill
E. coli
because in the knot there are other pathways onto which it can still shunt carbon. The Internet can continue sending messages even after one of the servers shuts down because it can move the messages through another pathway.

The bow tie architecture also saves energy in both systems. If
E. coli
did not have a bow tie, it would have to create a dedicated pathway of enzymes to make every molecule it needed. Each of those enzymes would require its own gene. Instead,
E. coli’
s pathways all dump their products into the same network in the knot of the bow tie. Likewise, the Internet does not have to link every computer directly to every other one, or use special codes for every kind of file it carries. In both cases this arrangement is possible only because the entire network obeys certain rules. On the Internet every message must be converted into the same data packets. In
E. coli
all energy transfers must use the same currency: ATP.

The inventors of the Internet did not realize they were creating this kind of network. They were only trying to balance cost and speed as they joined servers together. But unintentionally they created a model of
E. coli
that spans the Earth.

VIVE LA DIFFÉRENCE

We all have our own tastes. I don’t understand why some people eat snails. I can’t say for sure why I dislike them, but I can certainly think up a few stories. Maybe I have a certain kind of sensor on the cells of my tongue that goes into a spasm of dismay. Or maybe some network of neurons in my brain associates the taste of snails with some awful memory from my distant past. Or maybe I simply never had the opportunity to come to love snails because I grew up eating pizza and hamburgers and peanut butter. The gastronomic window has now closed.

I have no way of knowing whether any of those possibilities is true. I can’t go back in time, replay my life from the moment of conception, and see if a plate of escargots served at kindergarten lunch would have made a difference. I can’t clone myself a hundred times over and send my manufactured twins to foster homes in France. I am a single, useless snail-loathing datum.

My distaste for snails is a minor example of a major fact: life is full of differences. We humans differ from one another in ways too many to count. We are shy and bold, freckled and pale, truckers and hairdressers, Buddhists and Presbyterians. We get cancers in third grade and live for a century. We have fingerprints.

Scientists have only a rough understanding of how this diversity arises. We are not merely the output of software written in a programming code of DNA. As we develop in the womb, our genes interact with signals from our mothers. The environment continues to influence those genes in unpredictable ways after birth. The food we eat, the air we breathe, the traumas and joys and boredom of childhood, and all the rest have an influence on which genes become active. Our differences are not just hard to trace but a source of pride. We can produce greatness of all kinds: Babe Ruths and Frédéric Chopins, Mae Wests and Marie Curies. They are products of our complexity, of a species in which each individual carries 18,000 genes that can become 100,000 proteins, which give rise to creatures uniquely able to experience the world, to shape their lives by words, rituals, images. And this pride colors our image of
E. coli.

Surely
E. coli
must be all nature and no nurture. A colony descended from a single ancestor is just a billion genetically identical cousins, their behavior all run through the same genetic circuits.
E. coli
is just a single cell, after all, not a body made of a trillion cells that take years to develop.
E. coli
doesn’t grow up going to private school or searching for food on a garbage dump. It doesn’t wonder whether it might like snails for dinner. It’s just a bag of molecules. If it is genetically identical to another
E. coli,
then the two of them will live identical lives.

This may all sound plausible, but it is far from the truth. A colony of genetically identical
E. coli
is, in fact, a mob of individuals. Under identical conditions, they will behave in different ways. They have fingerprints of their own.

If you observe two genetically identical
E. coli
swimming side by side, for example, one may give up while the other keeps spinning its flagella. To gauge their stamina, Daniel Koshland, a scientist at the University of California, Berkeley, glued genetically identical
E. coli
to a glass cover slip. They floated in water, tethered by their flagella. Koshland offered them a taste of aspartate, an amino acid that attracts them and motivates them to swim. Stuck to the slide, the bacteria could only pirouette. Koshland found that some of the clones twirled twice as long as others.

E. coli
expresses its individuality in other ways. In a colony of genetically identical clones, some will produce sticky hairs on their surface, and some will not. In a rapidly breeding colony, a few individual microbes will stop growing, entering a peculiar state of suspended animation. In a colony of
E. coli,
some clones like milk sugar, and others don’t.

These differing tastes for lactose first came to light in 1957. Aaron Novick and Milton Weiner, two biologists at the University of Chicago, looked at how individual
E. coli,
respond to the presence of lactose. They fed
E. coli
a lactoselike molecule that could also trigger the bacteria to make beta-galactosidase. At low levels only a tiny fraction of the microbes responded by producing beta-galactosidase. Most did nothing.

Novick and Weiner added more of the lactose mimic. The eager individuals remained eager. The reluctant ones remained reluctant. Only after the lactose mimic rose above a threshold did the reluctant microbes change. Suddenly they produced beta-galactosidase as quickly as the eager microbes.

Somehow the bacteria were behaving in radically different ways even though they were all genetically identical. Novick and Weiner isolated eager and reluctant individuals and transferred them to fresh petri dishes, where they could breed new colonies of their own. Their descendants continued to behave in the same way. Eager begat eager; reluctant, reluctant. Novick and Weiner had found a legacy beyond heredity.

There’s much to be learned about
E. coli
by thinking of it as a machine with circuitry that follows the fundamental rules of engineering. But only up to a point. Two Boeing 777s that are in equally good working order should behave in precisely the same way. Yet if they were like
E. coli,
one might turn south when the other turned north.

The difference between
E. coli
and the planes lies in the stuff from which they are made. Unlike wires and transistors,
E. coli’
s molecules are floppy, twitchy, and unpredictable. They work in fits and starts. In a plane, electrons stream in a steady flow through its circuits, but the molecules in
E. coli
jostle and wander. When a gene switches on,
E. coli
does not produce a smoothly increasing supply of the corresponding protein. A single
E. coli
spurts out its proteins unpredictably. If its
lac
operon turns on, it may spit out six beta-galactosidase enzymes in the first hour, or none at all.

This burstiness helps turn genetically identical
E. coli
into a crowd of individuals. Michael Elowitz, a physicist at Cal Tech, made
E. coli
’s individuality visible in an elegant experiment. He and his colleagues added an extra gene to the
lac
operon, encoding a protein that gave off light. When he triggered the bacteria to turn on the operon, they began to make the glowing proteins. But instead of glowing steadily, they flickered. Each burst of fluorescent proteins gave off a pulse of light. Some bursts were big, and some were small. And when Elowitz took a snapshot of the colony, it was not a uniform sea of light. Some microbes were dark at that moment while others shone at full strength.