What Makes Us Different?

Sunday, Oct. 01, 2006 By MICHAEL D. LEMONICK AND ANDREA DORFMAN
ILLUSTRATION FOR TIME BY TIM O'BRIEN
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As a result, progress is maddeningly slow. And while he can't reveal details, Paabo says he'll soon be announcing in a major scientific journal the sequencing of 1 million base pairs of the Neanderthal genome. And he says he has 4 million more in the bag. Rubin, meanwhile, is also poised to publish his results, but refuses to divulge specifics. "Paabo's team has significantly more of a sequence than we do," he says. "Some of the dates will differ, but the conclusions are largely similar."

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Although Paabo admits that he still hasn't learned much about what distinguishes us from our closest cousins, simply showing he can reconstruct significant DNA sequences from such long-dead creatures is an important proof of concept. Both he and Rubin agree that within a couple of years a reasonably complete Neanderthal genome should be available. "It will tell us about aspects of biology, like soft tissue, that we can't say anything about right now," Rubin notes. "It could tell us about disease susceptibility and immunity. And in places where the sequence overlaps that of humans, it will enable us to compare a prehistoric creature with chimps." Someday it may even be possible to insert equivalent segments of human and Neanderthal DNA into different laboratory mice in order to see what effects they produce.

WHAT IT ALL MEANS

Precisely how useful this information will be is hard to assess. Indeed, a few experts are dismissive of the whole project. "I'm not sure what Neanderthals will tell us," says Kent State's Lovejoy. "They're real late [in terms of human evolution]. And they represent, at best, a little environmental isolate in Europe. I can't imagine we're going to learn much about human evolution by studying them." Lovejoy is even more dismissive about claims that ancestors of chimps and humans interbred, arguing that using mutation rates in the genome to time evolutionary changes is extraordinarily imprecise.

In fact, even the most ardent proponents of genome-comparison research acknowledge that pretty much everything we know so far is preliminary. "We're interested in traits that really distance us from other organisms," says Wisconsin's Carroll, "such as susceptibility to diseases, big brains, speech, walking upright, opposable thumbs. Based on the biology of other organisms, we have to believe that those are very complex traits. The development of form, the increase in brain size, took place over a long period of time, maybe 50,000 generations. It's a pretty complicated genetic recipe."

But even the toughest critics acknowledge that these studies have enormous potential. "We will eventually be able to pinpoint every difference between every animal on the planet," says Lovejoy. "And every time you throw another genome, like the gorilla's, into the mix, you increase the chances even more."

Some of the differences could have enormous practical consequences. Since his discovery that human cells lack one specific form of sialic acid, which was accomplished even before the human genome was decoded, Varki and his collaborators have determined that 10 of the 60 or so genes that govern sialic-acid biology show major differences between chimps and humans. "And in every case," says Varki, "it's humans who are the odd one out." Such revelations could probably lead to a better understanding of such devastating diseases as malaria, aids and viral hepatitis—and likely do so faster than by studying the human genome alone.

For most of us, though, it's the grand question about what it is that makes us human that renders comparative genome studies so compelling. As scientists keep reminding us, evolution is a random process in which haphazard genetic changes interact with random environmental conditions to produce an organism somehow fitter than its fellows. After 3.5 billion years of such randomness, a creature emerged that could ponder its own origins—and revel in a Mozart adagio. Within a few short years, we may finally understand precisely when and how that happened.