the baffling intelligence of a single cell

I want to tell the story of a beautiful phenomenon in biology. In some sense it’s the prototype of much of the activity of life. The phenomenon is the way in which an individual cell of E. coli forages for nutrients. This process, known as “chemotaxis”—the “chemo-” for chemical and the “taxis” from the Greek τάξις, for tactics—is intelligence in one of its most elemental forms. An individual E. coli has no brain, obviously, and is even many orders of magnitude simpler than a human cell, and yet already it possesses something like a sense of smell, drive, even a memory. Chemotaxis recasts E. coli not as some aimless gut-pest but rather as an exquisitely sophisticated physical computer. I’m also telling this story because I never liked the way biology was taught in high school. It was too much about the names of things. A subject so vast is spoiled by a textbook, which can only point at the endless parade of stuff-there-is-to-know. It’s better approached with questions—like “what’s happening when you smell?” or ”what is a fever, actually?”—that contemplate narrow, deep slices. Chemotaxis is a great slice: it’s a triumph of systems biology—we understand it holistically but also in fine detail at almost every level. It acquaints you with many of the most important motifs in biology, including the way in which protein structure determines function; how membranes control the information flow into cells; and how chemical modifications store and communicate state. It involves one of the most sophisticated and beautiful pieces of molecular nanotechnology, the flagellar motor. And it helps give an intuition for how a bag of unthinking chemicals could possibly give rise to a being. The 30,000-foot view Even with simple rules, the E. coli finds food more often than not The basic idea is this: E. coli “smells” chemicals it’s attracted to with a set of nose-like receptors and decides how to swim. Depending on what it senses, it can either use its flagellar tails to swim forward—this is known as a “run”—or it can spin in a random direction (a “tumble”). By running when the getting is good and tumbling when it isn’t, the E. coli takes a meandering path toward the attractant. A little more detail now: there are half a dozen or so rotors on the E. coli’s body, each controlling a long whip-like tail that flows behind it. When all the rotors are spinning in the same direction, the tails join together into a coil that torques the cell forward into a run. When even one rotor is spinning against the others, the coil unbundles and E. coli spins into a tumble. In a uniform chemical environment, the E. coli swims in a random walk by balancing runs with periodic tumbles. By default, a run lasts about a second, or ten times longer than a tumble. The rate of runs versus tumbles, and their relative duration, is carefully tuned to balance “exploitation” and “exploration”: if runs happened too often or lasted too long, E. coli would range too widely and zip past its food; too seldom or too short, and it’d likely never find food in the first place. But how is this balance achieved? The crux of it is a signaling molecule called CheY (pronounced “KEY-why”). CheY is constantly bouncing around in the cytoplasm of the E. coli, interacting with both the receptor complex (the “nose”) and the rotors, carrying information between them. In the steady state, when CheY encounters the receptor complex, it gets chemically modified, or “phosphorylated,” at a certain rate to become CheY-p. Unlike the unmodified version, CheY-p has a strong affinity for the rotors, and when enough copies bind to one, it reverses its spin, causing a tumble. The trick is that when the nose detects an increase in the concentration of attractant, that steady turning of CheYs into CheY-ps is interrupted. As a result, fewer CheY-ps bind to the rotors; fewer reversals take place; and so the E. coli runs more and tumbles less. In other words, the all-important relative rate of runs versus tumbles is determined entirely by how often the CheY→CheY-p process churns—and this, in turn, is determined by how much attractant is detected by the nose. You can see this process in action in the interactive illustration. Try altering the ratio of CheY-p (white) to CheY (blue) by adding some attractant (pink). You‘ll end up inducing a long run. Less attractant More attractant Why do you need all this complexity? You could imagine a system in which the motors themselves responded directly to attractant. We’ll see later on that the stream of CheY-ps acts as a kind of adaptable, tunable chemical amplifier. “Bacterial cells can amplify signals more than 50-fold; that is to say, a 2% change in receptor occupancy can bring about a 100% change in the output of the system at the flagellar motors. This feature allows cells to sense minute changes in concentration—less than three molecules per cell volume!” The story gets more complicated: adaptation If the system were as described above, then E. coli wouldn’t have much dynamic range. Imagine: if the cell has a huge reaction to just three molecules of attractant, wouldn’t a thousand times as many just completely overwhelm it? In reality, the E. coli is able to respond sensitively across five orders of magnitude of attractant concentration. The cell learns to treat whatever concentration it stumbles into as the new normal, so that the slightest increase triggers the same hypersensitive response as always. The mechanism powering this adaptation is extremely clever. You can think of each receptor as being equipped with “struts” that have pockets in them. When the receptor is bound to attractant, its struts change shape so that these pockets open up, and become the targets for little molecules known as methyl groups. Methyl groups are ubiquitous in biochemistry: for instance, they help determine which parts of your DNA get expressed. Methyl groups bind to the structural proteins your DNA strands coil around, called histones; the “methylated” histone can kink the DNA strand into or out of view of your transcription machinery, turning it on or off. In this case, methylation serves to fill up the strut’s pockets, causing it to become more rigid. (I’m simplifying the actual physical details somewhat, as we’ll see later.) With more rigid struts the receptor’s signaling power is dampened: it takes more attractant to elicit the same response. Because there are many methylation sites per strut and many struts per receptor, there’s a wide range of possible dampening values—as if those pockets were really the holes of an elaborate wind instrument. [Bray] This wide dynamic range is what allows the bacteria not just to find a favorable environment but to keenly and speedily nose its way up a chemical gradient. No wonder a similar mechanism is used by cells in your immune system to track and hunt down invaders. Methylation of the receptors gives E. coli a “simple chemical memory.” This is a powerful and somewhat profound idea: individual bacteria can model their environment and remember important features of it by encoding that information in internal chemical modifications. E. coli “knows” whether attractant has become more or less concentrated in its surroundings going back several seconds; that helps it determine whether it’s swimming in a good or bad direction. Which is not that different in principle from what brains do. In fact one reason that it requires an artificial neural network of about a thousand elements just to model the computational capabilities of a single real neuron is that the real neuron stores so much “state” in its internal chemistry. (Here‘s an aside: should we be surprised at how resilient people can be, given the mechanisms available to a single cell for accepting previously extreme conditions as “a new normal”? No doubt our macro resilience is in some cases actually underwritten by similar cellular mechanisms.) The full picture: a complex signaling network The video above is a very legible overview of E. coli chemotaxis, from a popular textbook. It layers in even more detail, including not just the proteins that phosphorylate CheY but those that dephosphorylate it; and not just the proteins that methylate the receptors but those that demethylate it. What you come to see is that these doers and undoers define a sort of equilibrated circuit whose activity can be conveniently dialed up or down. Dennis Bray describes these sorts of circuits nicely in his book, Wetware: A Computer in Every Living Cell: In a typical signaling pathway, proteins are continually being modified and demodified. Kinases and phosphatases work ceaselessly like ants in a nest, adding phosphate groups to proteins and removing them again. It seems a pointless exercise, especially when you consider that each cycle of addition and removal costs the cell one molecule of ATP—one unit of precious energy. Indeed, cyclic reactions of this kind were originally labeled “futile.” But the adjective is misleading. The addition of phosphate groups to proteins is the single most common reaction in cells and underpins a large proportion of the computations they perform. Far from being futile, this cyclic reaction provides the cell with an essential resource: a flexible and rapidly tunable device. If the cell really needs to change the concentration of the modified protein very quickly, it can. All it has to do is to switch on or shut off the phosphate-adding reaction and the concentration will fall precipitously—at the speed of the spinning cycle. There is no buildup of products or depletion of substrates to slow down the process, as there would be in a linear chain of enzyme reactions. This is a clever way to regulate the level of some protein or metabolite. Rather than producing the thing you want via a lengthy chain reaction, you just have this running cycle that activates and then de-activates it, for example via phosphorylation and de-phosphorylation. When you want more of the active