Waiting for the Electrician, or Someone Like Him

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If our genes are wired like circuits, does that mean nature is an electrician?

One of the most important sorts of jobs that genes do is to switch other genes on or off. The classic example comes from Escherichia coli, and how it eats milk. (I’m afraid Escherichia coli will be progressively infecting this blog in the months to come, as I finish my new book on this remarkable bug.) Escherichia coli can make the enzymes necessary for digesting lactose, the sugar in milk. But it normally doesn’t, because it makes proteins that clamp onto its DNA next to these genes and prevent gene-reading enzymes from reaching them. If lactose should seep into the microbe, however, the molecule binds to the repressor proteins and causes them to change shape and fall off the DNA. If another protein, which signals a drop in other kinds of sugar, also grabs the DNA near the genes, Escherichia coli begins to crank out the lactose-digesting enzymes, and the milk feast begins.

It turns out that in any cell, many hundreds of genes may switch other genes on and off this way. A single gene may only make proteins if it is grabbed by many kinds of proteins, and its own protein may switch on many genes in turn. Those proteins may switch on still other genes, creating a cascade of switches.

Scientists have mapped the links between these genes in Escherichia coli, yeast, and other species. (Here’s a striking image of the networks in several species of bacteria.) They’re far from random. They have a hierarchy, with a few genes exerting major influences on the others. Even at their smallest scales, they show patterns. Consider just three genes. You can link them in many way (just try connecting three dots with arrows). It turns out that in cells, a few arrangements of arrows (known as motifs) turn up far more often in genetic networks than would be expected if the genes were linked randomly.

One of those common arrangements is particularly intriguing–shown here on the left of this figure. One gene, X, controls two other genes, Y and Z. Y, in turn, also controls Z. Electrical and computer engineers may have a sense of deja vu looking at this diagram. It’s a common element in circuit design, called a feed-forward loop. Engineers wire circuit components in feed-forward loops for many purposes. Uri Alon of Tel Aviv University and his colleagues were among the first to discover the abundance of feed-forward loops in nature. They proposed that these loops must serve some useful function that had been favored by natural selection. They zeroed in on a few key examples to test their hypothesis. And they gotten some pretty impressive results.

The genes that control when Escherichia coli builds its spinning tails, for example, are arranged in a feed-forward loop. After studying this loop closely, he and his colleagues concluded that it works as a noise filter. The gene X in this particular loop acts as a switch to turn on genes for constructing the tails (Z in this diagram). Gene X usually switches on in response to some kind of stress that Escherichia coli would do well to swim away from. X also causes gene Y to build up in the microbe, which also turns on the same tail building genes. If the stress should briefly drop, Escherichia coli stops expressing gene X. But that doesn’t shut down the tail construction right away, since there’s enough proteins from gene Y floating around to continue the project. If the stress disappears for good, however, Y disappears too, and the microbe abandons the project. Only strong signals of change get through this noise filter, which can ignore the minor meaningless static.

Alon’s work has become hugely influential, but it is now drawing some deep skepticism. Just because something looks like a circuit doesn’t mean it actually works like one.

Last year, French scientists considered the important of motifs–in evolution and in the functioning of a cell–by comparing several closely related species of yeast. If motifs played a vital role in survival, they might be conserved over evolutionary time. But the French scientists found that feed-forward loops and other motifs have been subject to as much evolutionary change as other interactions between genes.

The scientists then looked at what several motifs in yeast actually do (or don’t do). They chose motifs that are part of networks involved in functions such as pumping out toxins and starting the process of cell division. If you only looked at the shape of these motifs–the way the genes are joined–you might assume that they must be acting like a circuit, filtering and otherwise processing signals in important ways. But in each case, the scientists showed that none of the major steps of information processing take place in the motifs. The genes in the motifs are only important as parts of much larger networks. The scientists proposed that the abundance of feed-forward loops and other motifs was just a mirage produced by an incomplete understanding of how genes influence one another.

And a few days ago Dutch scientists launched another attack on the feed-forward loop, called simply “Feed Forward Loop Circuits as a Side Effect of Genome Evolution”. (It’s in press at Molecular Biology and Evolution, and you can get the full pdf for free here.)

The Dutch scientists wondered whether an abundance of feed-forward loops could emerge spontaneously, even if natural selection was not favoring them. They built a model for network evolution, based on an earlier one published in 2004. They built a network of genes, each of which had sites at which proteins could bind to them and cause them to be expressed. They then allowed the network to evolve according to rules based on what scientists know about how actual genes evolve. The genes could lose their binding sites or they could acquire an extra copy of a binding site. The entire genome could be accidentally duplicated. Genes sometimes disappeared, and sometimes proteins that switched on one gene began to switch on another.

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Initially the model produced a random network, which came as no surprise. (The graph marked here as A.) But over time, something odd occurred. Some genes began to get more and more connected to other genes. And after about 100 generations, a large number of feed-forward loops appeared in the network, in what the scientists liken to an avalanche. In this picture, the feed-forward loops are marked in C as white circles. The scientists did not have to build in any advantage to feed-forward loops that could make them the object of natural selection. They emerged spontaneously from mutating networks. “Selection on individual circuits,” the scientists conclude, “is not needed to explain their abundance.”

I am very curious to see where this debate goes. One possibility that comes to mind is that the flagella-building feed-forward loop is a spandrel. In 1979 Stephen Jay Gould and Richard Lewontin spandrel. argued that many structures in living things got their start through no help from natural selection. They used the metaphor of the spandrel, the triangular space formed between an arch and its supporting wall. The spandrel was merely a side-effect of the arch, which painters made use of by covering them with images. Perhaps feed-forward loops emerge spontaneously through evolution, without any adaptive value of their own. In many cases they never become adaptations in their own right. But in some cases, they do turn out to process information in a useful way. I won’t predict where this debate will go–except perhaps to bet that scientists will not simply sit back and declare, “Design! My work is done.” I guess I like to stick to safe bets.

[Title thanks to Firesign Theater, soundtrack to my twisted youth.]