Microcosm (6 page)

FlhDC is one of
E. coli’
s master switches. It can latch on to many spots along
E. coli’
s chromosome, where it can switch on a number of genes. These genes make many of the proteins that combine to make flagella.

In this simple form,
E. coli’
s flagella-building circuit has a major flaw. It can turn on flagella-building genes in response to stress, but it also has to shut them down as soon as the stress goes away. Once the microbe stops making new FlhDC, the old copies of FlhDC gradually disappear. As they do, the genes FlhDC controls can no longer make their proteins. The complex assembly of flagella comes screeching to a halt in response to the slightest improvement. When conditions turn bad again, this circuit has to fire up its flagella machine from scratch. In a crisis, those delays could be fatal.

E. coli
does not fall victim to false alarms, however, because it has extra loops in its genetic circuit. In addition to switching on flagella genes, FlhDC switches on a backup gene called FliA.

FliA can switch on the flagella genes as well.

But FliA is also controlled by another protein, called FlgM. It grabs new copies of FliA as soon as
E. coli
makes them, preventing them from switching on the flagella genes. Here is the circuit with FlgM added:

FlgM cannot keep FliA repressed for long, however, because
E. coli
can expel it through the same syringe it uses to build its flagella. As the number of FlgM proteins dwindles, more FliA genes become free to switch on the flagella-building genes.

Here, at last, is the full noise filter as reconstructed by Alon and his colleagues:

This elegant network gives
E. coli
the best of all worlds. When it starts building flagella, it remains very sensitive to any sign that stress is going away. That’s because FlhDC alone is keeping the flagella-building genes switched on. But once
E. coli
has built a syringe and begins to pump out FlgM, the noise filters kick in. If the stress drops, so does the level of FlhDC. But
E. coli
has created enough free FliA genes to keep its flagella-building genes switched on for more than an hour. If the respite is temporary,
E. coli
will start making new copies of FlhDC, and its construction of flagella will go on smoothly.

E. coli
can filter out noise, but it’s not deaf. If conditions get significantly better,
E. coli
can stop making flagella. Its extra supply of FliA cannot last forever. The proteins become damaged and are destroyed by
E. coli’
s molecular garbage crews. If the stress does not return in time, the microbe will run out of FliA, and the circuit will shut down. The good times have truly returned.

Scientists are now starting to map the circuitry of genes in other species as carefully as Alon and his colleagues have in
E. coli.
But it will take time. Scientists don’t yet know enough about how the genes and proteins in those circuits build good models. In many cases, scientists know only that gene A turns on gene B and gene C, without knowing what causes it to flip the switch or what happens when it does.

But Alon has discovered a remarkable lesson even in that tiny scrap of knowledge. He and his colleagues have surveyed the genes in
E. coli
and a few other well-studied organisms—yeast, vinegar worms, flies, mice, and humans. The arrows that link them tend to form certain patterns far more often than you’d expect if they were the result of chance.
E. coli’
s noise filter, for example, belongs to a class of circuits that engineers call feed-forward loops. (The loop in the noise filter goes from FlhDC to FliA to the flagella-building genes.) Feed-forward loops are unusually common in nature, Alon and his colleagues have shown. Nature has a preference for a few other patterns as well, which also seem to allow life to take advantage of engineering tricks like the noise filter.
E. coli
and the elephant, it seems, are built not only with the same genetic code. They’re also wired in much the same way.

LIFE ON AUTOPILOT

An orange winter dusk has settled in. Out my window I can see the webs of bare maple branches. Photons stream through the window and patter on the photoreceptors lining my retina. The photoreceptors produce electric signals, which they trade among themselves and then fire down the fibers of my optic nerves into the back of my brain. Signals move on through my brain, following a network made of billions of neurons linked by trillions of branches. An image emerges. I get up from my desk to turn on the lights. At first I can see nothing outside, but after a moment my eyes adjust. I can still see the trees, down to their twigs.

I must remind myself how remarkable it is that I can still see them. A moment earlier my vision was exquisitely tuned to perceiving the world at dusk. If it had stayed that way after I turned on the light, I would have been practically blinded. Fortunately my eyes and brain can retune themselves for the noonday sun or a crescent moon. If the light increases, my brain quickly tightens my irises to reduce the light coming in. When the lights go out, my pupils expand, and my retinal neurons boost the contrast between light and dark in my field of vision. An engineer would call my vision robust. In other words, it works steadily in an unsteady world.

Our bodies are robust in all sorts of ways. Our brains need a steady supply of glucose, but we don’t black out if we skip dinner. Instead, our bodies unload reserves of glucose as needed. A clump of cells develops into an embryo by trading a flurry of signals to coordinate their divisions. The signals are easily disrupted, but most embryos can still turn into perfectly healthy babies. Again and again life avoids catastrophic failure and remains on course.

Until recently, scientists had no solid evidence for where life’s robustness comes from. To trace robustness to its source, they needed to know living things with a deep intimacy—the same intimacy an engineer may have with an autopilot system, using its plans to carry out experiments. But the blueprints of most living things remain classified. Among the few exceptions is
E. coli.

E. coli
faces threats to its survival on a regular basis. Set a petri dish on a windowsill on a sunny day and you bring the microbes in it to the brink of disaster. In order to work properly, a protein needs to maintain its intricate origami-like folds. Overheated proteins shake themselves loose. They can no longer do the job on which
E. coli’
s survival depends.

Yet
E. coli
does not die from a few degrees of extra heat. As the temperature rises, the microbe makes molecules known as heat-shock proteins. They defend
E. coli
in two ways. Some of them embrace
E. coli’
s jittery proteins and guide them back into their proper shape. Others recognize heat-snarled proteins that have been damaged beyond repair. They slice these hopeless proteins apart, leaving harmless fragments to be recycled.

Heat-shock proteins are lifesavers, but
E. coli
can’t keep a supply of them on hand for emergencies. They are among the biggest proteins in its repertoire, and to survive a blast of heat
E. coli
may need tens of thousands of them. Making heat-shock proteins in ordinary times would be like paying the local fire company to park all its trucks in your driveway just in case your house catches fire. On the other hand, when you need a fire truck, you need it fast. If
E. coli
takes too long to manufacture heat-shock proteins, it can die while it waits to be rescued.

This tricky trade-off attracted the attention of John Doyle, an engineer at the California Institute of Technology, and his colleagues. In past years, Doyle had developed a theory for designing control systems for airplanes and space shuttles. In
E. coli
he recognized a piece of natural engineering just as impressive as anything he had helped to build. He and his colleagues began to analyze its heat-shock proteins and the way
E. coli
uses them to survive.

They found that
E. coli
controls its supply of heat-shock proteins with feedback. For engineers, feedback is what happens when they allow the output of a circuit to become an input. A thermostat uses a simple form of feedback to keep the temperature of a house stable. The thermostat senses the temperature in the house and turns on the heater if it’s too cold. If the temperature gets too high, it shuts the heater down.

E. coli’
s defense against heat works a lot like a thermostat as well. The key protein in its thermostat is called sigma 32. Even when the temperature is cool,
E. coli
is constantly reading the gene for sigma 32 and making RNA copies. But at normal temperatures the RNA folds in on itself, and so
E. coli
cannot use it to make a protein. At normal temperatures the microbe is loaded with sigma 32 RNA but no actual sigma 32 protein.

Only when
E. coli
heats up can the sigma 32 RNA uncrumple. Now the ribosomes can read it and make huge amounts of sigma 32 protein. Each sigma 32 protein quickly finds some of
E. coli’
s gene-reading enzymes and leads them to the genes for heat-shock proteins.
E. coli
thus makes tens of thousands of heat-shock proteins in a matter of minutes.