Discover, January 1, 1996
In evolution, fast small changes add up to slow big ones. A mutation happens in a blink of an eye. Then natural selection acts on the mutations in many individuals, and a species gradually adapts to its surroundings over thousands or millions of years. Magnificent transformations then take place, such as that of fish into land vertebrates 360 million years ago. Until recently, no one would have dared dream that we could ever follow a genetic trail such as the one from fin to hand. But an experiment this past year made that dream a reasonable one.
Researchers wondered for decades how the uniform cells of an embryo figured out how to organize themselves into a body. How did they know which end was the head? In the 1980s researchers found much of the answer in a set of genes called Hox, which tell a cell where along the body’s axis it is located. Remarkably, Hox genes are lined up along the chromosomes in the same order as the body segments for which they are responsible–neck genes, for example, come before spine genes. Each Hox gene produces a protein that travels to certain other genes in the same cell and switches them on in order to create the structures appropriate to their zone. Even more remarkably, Hox genes apparently direct the development of all animals, from worms to humans.
Recent research has shown that they also control the development of limbs, not only giving coordinates to the cells but deciding which ones should rapidly divide in the embryo, thus laying the groundwork for the skeleton and other final components of the limb. For example, Denis Duboule of the University of Geneva and his co-workers removed one of the last Hox genes in a mouse, and as a result the end of its spine and the tips of its front toes were stunted. You should imagine your shoulder as the equivalent of your neck and your wrist as the equivalent of your sacrum, says Duboule. In hindsight, this isn’t too surprising; a limb is still basically an axis, like a spine.
Many dramatic changes in body plans that have marked the history of evolution, researchers now suspect, may come down to minor adjustments of Hox genes. In an experiment published this past June, Duboule’s team demonstrated that the transition from fin to hand might have been one of them. To do so, they followed the activity of Hox genes in a developing fin. As a bud of cells emerged from the side of zebra-fish embryos, they stained the tissue with a compound that revealed in which cells the Hox genes were producing their managerial proteins.
They found that the Hox genes were active along an axis that grew away from the body along the back edge of the bud. Along this axis, cells proliferated rapidly, condensed into cartilage, and split into the branches of radial bones that fish use to paddle their fins. But then the Hox genes shut off. At that point other genes helped guide the growth of dermal bone, a scaly stiffening material that filled out the rest of the fin.
This pattern of growth is reminiscent of the first stages of limb development in a land vertebrate. Experiments on lab mice have shown that at first the pattern of Hox genes marks a fishlike axis going out along the back edge of the bud. In a mouse’s front leg or your arm, this part of the axis became the humerus, radius, and ulna. But at the point where the Hox genes shut down in a fish, they keep going in a land vertebrate, and the skeletal bone of the limb keeps growing. The end of the limb hooks around to become wrist bones; rapidly dividing cells branching off this hook become fingers.
Ten years ago, most researchers thought the transition from fin to hand required a massive reorganization of the bones involved, and therefore of the DNA that produced it. But it now appears that perhaps the only real change between a fish and a four-footed land animal was timing– in tetrapod embryos the Hox clock may simply have run a little slower, so that each Hox gene stayed on a little longer. You don’t touch the other genes, you don’t touch the proteins–this is difficult, it is playing with the devil, says Duboule. Instead you simply slow it all down or speed it up. No one knows yet how a developing embryo can measure the passage of time and thus set its Hox clock, but Duboule thinks someone is going to find out soon. The coming 20 years are going to be so tremendous. I’m pretty sure that we’ll be able to understand macroevolution on the molecular level. Perhaps not reproduce it, but…well, let’s see…
Copyright 1996 Discover Magazine. Reprinted with permission.