The Dna Recipe

That project was left to a new generation of scientists. Not until the 1990s, when new molecular techniques became available, was the genetic control for the ZPA's operation unraveled.

A major breakthrough happened in 1993, when Cliff Tabin's laboratory at Harvard started hunting for the genes that control the ZPA. Their prey was the molecular mechanisms that gave the ZPA its ability to make our pinky different from our thumb. By the time his group started to work in the early 1990s, a number of experiments like the ones I've described had led us to believe that some sort of molecule caused the whole thing. This was a grand theory, but nobody knew what this molecule was. People would propose one molecule after another, only to find that none was up to the job. Finally, the Tabin lab came up with a novel notion, and one very relevant to the theme of this book. Look to flies for the answer.

Genetic experiments in the 1980s had revealed the wonderful pattern of gene activity that sculpts the body of a fly from a single-celled egg. The body of a fruit fly is organized from front to back, with the head at the front and the wings at the back. Whole batteries of genes are turned on and off during fly development, and this pattern of gene activity serves to demarcate the different regions of the fly.

Tabin didn't know it at the time, but two other laboratories—those of Andy MacMahon and Phil Ingham—had already come up with the same general idea independently. What emerged was a remarkably successful collaboration among three different lab groups. One of the fly genes caught the attention of Tabin, McMahon, and Ingham. They noted that this gene made one end of a body segment look different from the other. Fly geneticists named it hedgehog. Doesn't the function of hedgehog in the fly body—to make one region different from another—sound like what the ZPA does in making the pinky different from the thumb? That parallel was not lost on the three labs. So off they went, looking for a hedgehog gene in creatures like chickens, mice, and fish.

Because the lab groups knew the structure of the fly's hedgehog gene, they had a search image to help them single out the gene in chickens. Each gene has a distinctive sequence; using a number of molecular tools, the researchers could scan the chicken's DNA for the hedgehog sequence. After a lot of trial and error, they found a chicken hedgehog gene.

Just as paleontologists get to name new species, geneticists get to name new genes. The fly geneticists who discovered hedgehog had named it that because the flies with a mutation in the gene had bristles that reminded them of a little hedgehog. Tabin, McMahon, and Ingham named the chicken version of the gene Sonic hedgehog, after the Sega Genesis video game.

Now came the fun question: What does Sonic hedgehog actually do in the limb? The Tabin group attached a dye to a molecule that would stick to the gene, enabling them to visualize where the gene is active in the limb. To their great surprise, they found that only cells in a tiny patch of the limb had gene activity: the ZPA.

So the next steps became obvious. The patterns of activity in the Sonic hedgehog gene should mimic those of the ZPA tissue itself. Recall that when you treat the limb with retinoic acid, a form of vitamin A, you get a ZPA active on the opposite side. Guess what happens when you treat a limb with retinoic acid, then map where Sonic hedgehog is active? Sonic hedgehog becomes active on both sides—pinky and thumb—just as the ZPA does when it is treated with retinoic acid.

Knowing the structure of the chicken Sonic hedgehog gave other researchers the tools to look for it in everything else that has fingers, from frogs to humans. Every limbed animal has the Sonic hedgehog gene. And in every single animal that we have studied, Sonic hedgehog is active in the ZPA tissue. If Sonic hedgehog hadn't turned on properly during the eighth week of your own development, then you either would have extra fingers or your pinky and thumb would look alike. Occasionally, when things go wrong with Sonic hedgehog, the hand ends up looking like a broad paddle with as many as twelve fingers that all look alike.

We now know that Sonic hedgehog is one of dozens of genes that act to sculpt our limbs from shoulder to fingertip by turning on and off at the right time. Remarkably, work in chickens, frogs, and mice was telling us the same thing. The DNA recipe to build upper arms, forearms, wrists, and digits is virtually identical in every creature that has limbs.

How far back can we trace Sonic hedgehog and the other bits of DNA that build limbs? Is this stuff active in building the skeleton of fish fins? Or are hands genetically completely different from fish fins? We saw an inner fish in the anatomy of our arms and hands. What about the DNA that builds it?

Enter Randy Dahn with his mermaid's purses.

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