The Rules of the Skeleton

Yesterday, Nature reported that researchers have identified more than half a million regulatory DNA changes that distinguish humans from other great apes, and then tested them in cells involved in making cartilage to see which ones changed the way genes are switched on and off. They found 15,077 changes that affected gene activity in these cells. Many were involved in genes that control cartilage and the material surrounding our bones. The researchers found a substantial reduction in molecules that help human cartilage hold water and withstand pressure, which may help explain why our joints are more vulnerable to degenerative disease than those of other great apes.¹

»A small change in when something happens can become a large difference in what something becomes«

In a famous 1975 paper, geneticist Mary-Claire King and biologist Allan Wilson proposed that the differences between humans and chimpanzees might lie less in the proteins themselves than in the way genes are regulated. Perhaps the important evolutionary changes were not new parts but different instructions for using old ones.²

This is actually quite easy to understand. Imagine two orchestras. Even if both have the same instruments, one might use them to play Bach, the other death metal. The difference lies in which instruments are played, when, how loudly, and for how long. Similarly, evolution doesn’t need to invent a new instrument. It can change the score.

For fifty years, though, this was much easier to propose than to demonstrate. The new study turns that famous evolutionary intuition into something that can be experimentally interrogated. The researchers took hundreds of thousands of human-specific DNA changes and measured whether the human and ape versions actually altered gene activity in cells involved in forming the skeleton. They were not mainly looking at the genes themselves, but at the stretches of DNA that tell genes when, where, and how strongly to operate. Some changes seem to have altered the behaviour of cartilage cells and, in turn, the physical material of the skeleton. The chain is simple: the parts were already there; the rules for using them changed; that changed the material; the changed material changed the form; and the changed form helped produce a body that could walk upright, support a larger brain, and develop a different jaw.

This is where Nobel Prize-winning biologist François Jacob’s idea of evolution as tinkering becomes useful.³ Jacob essentially says that evolution doesn’t work like an engineer given a clean sheet of paper and a specification. It works with what’s already lying around. A change in regulation can alter the timing, location, or intensity of an existing biological process. A small change in when something happens can become a large difference in what something becomes.

And tinkering has consequences. The same evolutionary changes that helped make us what we are may also have left us with joints that are more susceptible to degeneration. Evolution has no requirement to produce a perfect design. It produces workable arrangements from inherited material – compromises – under whatever constraints happen to exist. The skeleton we inherited isn’t so much a perfected design as a compromise that happened to work.

We tend to look at biological form as though it were the result of a specification: a body has this shape because it needs to do this. But evolution has no architect sitting outside the system. It has history, inheritance, mutation, selection, constraint, and an enormous amount of accumulated stuff that cannot simply be thrown away. In a way, the form is a record of the rules that produced it.

This is close to what the biologist and mathematician D’Arcy Wentworth Thompson was getting at in his 1917 book On Growth and Form.⁴ Thompson’s famous transformations showed how one biological form could be related to another not by inventing an entirely new geometry, but by deforming the coordinates of an existing one. Form could be understood as the visible consequence of a transformation. In that framing, a skeleton looks less like a collection of parts than the visible trace of rules acting on inherited parts. The remarkable thing about yesterday’s paper is that, after half a century of waiting, we can finally begin to see how those rules become form.

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