Living Circuits

To an engineer, a circuit is an arrangement of wires, resistors, and other parts, all laid out to produce an output from an input. Circuits in a Geiger counter create a crackle when they detect radioactivity. A room is cast in darkness when a light switch is turned off. Genes operate according to a similar logic. A genetic circuit has its own inputs and outputs. The lac operon works only if it receives two inputs: a signal that E. coli has run out of glucose and another signal that there's lactose to eat. Its output is the proteins E. coli needs to break down the lactose.

E. coli has no wires that scientists can pull apart to learn how its circuits work. Instead, they must do experiments of the sort Jacob and Monod carried out. They observe how quickly the bacteria respond to their environment, how quickly they make a certain protein or clear another one away. Scientists combine the results of experiment after experiment into models, which they use to make predictions about how future experiments will turn out. The fundamental discoveries that Jacob, Monod, and others made about E. coli have led other scientists to pick apart the circuitry of other species, including us. But in the fifty years since Jacob squirmed in a cinema seat, scientists have continued to pay close attention to E. coli. They discovered intriguing patterns in E. coli's circuitry, which they mapped out in more detail than in of any other species, and they've discovered that E. coli's circuitry mimics the sort of circuitry you might find in digital cameras or satellite radios.

To prove that I'm not dabbling in idle metaphor, I want to probe the wiring of one of E. coli's many circuits. This particular circuit controls the construction of E. coli's flagella. It has taken the work of many scientists over many years to discover most of the genes that belong to this circuit. But in 2005, Uri Alon and his colleagues at the Weizmann Institute of Science in Rehovot, Israel, figured out what the circuit does. It acts as a noise filter.

Engineers use noise filters to block static in phone lines, blurring in images, and any other input that obscures a true signal. In the case of E. coli, the noise is made up of misleading cues about its environment. With the help of a noise filter it can pay attention only to the cues that matter. It's important for E. coli to ignore noise when it builds a flagellum because the process is a lot like building a cathedral.

The microbe must switch on about fifty genes, which make tens of thousands of proteins. Those proteins must come together in a tightly choreographed assembly. First the motor must insert itself in the membranes. A syringe has to slide through the center of the motor, which then injects thousands of proteins into the growing tail. The proteins squirm through the hollow shaft and emerge to form its new tip. The process takes an hour or two, which for E. coli can mean several generations. A new microbe inherits a partially built tail and passes it on, still unfinished, to its descendants.

By the time E. coli has finished building these flagella, the crisis may be long over. All that energy will have gone to waste. So E. coli keeps tabs on its surroundings, and if life does seem to be getting better, it stops building its flagella. The only problem with this strategy is that a sign of better times may actually be a fleeting mirage. If E. coli abandons its flagella when a single oxygen molecule drifts by, it may end up stranded in a very dangerous place. To E. coli these false signs are noise it must filter out of its circuits.

To explain how E. coli filters out noise, I will draw a wiring diagram. An arrow with a plus sign means that a signal or a gene boosts the activity of another gene. A minus sign means that the supply of protein is reduced. The first link in this circuit is from the outside world to the inner world of E. coli. When the microbe senses danger, it sometimes responds by producing a protein called FlhDC.

Stress Fill DC

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.

Stress -U FlhDC Flagella g eres -U 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.

Stress -U. FlhDC—* Flagella genes Flagella

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:

FlgM"

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.

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