Even more important, according to Brenner, Fugu will help scientists understand "how genes get switched on and off." Solving this problem will be the task for biology in the next few years, he says—"not just to decipher the mechanism of switching, but to understand the language, what is specified."

There are two ways to view a gene's function, Brenner says. One is to identify the protein that the gene makes and its molecular activity—the nuts-and-bolts approach. The other way is to define "the gene's meaning to the organism." He uses the ras gene as an example. "It's a GTPase, an enzyme that interacts with other things in a signaling pathway. That's all it knows, and that's what you can read from the protein sequence," he says. "But in Drosophila, ras has a meaning in the eye; in C. elegans, it has a meaning in the vulva; in humans, it has a meaning in the regulation of cell growth. In yeast it's something different again. In each case, the meaning of the pathway is completely different.

"It's nice to know there are these mechanisms and pathways and they're invariant," he adds. "Well, they jolly well should be invariant! It's their control, their meaning, that changes."

In trying to decipher what a gene means for an organism, biologists need to be wary, Brenner warns. A gene may be expressed because its particular product is needed in a particular cell at a particular time—or it may be turned on simply because the organism can't be bothered to turn it off.

"Biology actually has three values: yes, no, and don't care," he declares. "That's what evolution generates.... You can, for instance, have the organism's genes turned on by a general mechanism so they're all on, and then you switch them off in various places. Or you can have them all off, and then switch them on in various places. Okay? Now, for things that are common to many cells, it's best to do it the first way—that is, to say no to some genes. For genes whose products are present in only a few cells, it's best to do it the second way, which is to say yes only to the ones you need there.

"The trouble arises when you come to more complicated combinations of these, and now you have to specify combinatorial functions. The solution may be to say, 'Look, I'll have these genes on in these cells; for the others, I don't care whether they are on or off.' This minimizes the regulation." Unless scientists understand which strategy is used, he says, they risk jumping to false conclusions when they see that a gene is switched on.

Brenner believes it is important to identify the "control words" that carry out such strategies, and he has started to do so. "Essentially, we've let nature do the experiments for us," he says. "We've taken two lineages that separated 450 million years ago and focused on certain systems they have in common, such as the immune system or the neuroendocrine system. We wanted to test the hypothesis that not only are the genes in these systems conserved, their regulation is conserved as well.

"If I had two human lineages that separated 450 million years ago, I'd have no problem in finding out, because during that time anything that was nonessential would have been randomized by mutation, and only that which is essential would be retained. Of course I don't have two human lineages that separated then, but I've got humans and I've got fish; and by focusing on common, highly conserved functions, you can begin to find the control words."

He has already identified a few of these words, he says. Working with a region of Fugu DNA that contains a homolog of the human gene for oxytocin (a brain hormone), Brenner and colleagues at the National University of Singapore inserted this bit of Fugu DNA into a rat's genome. (They chose the rat because there are excellent maps of its brain structures, Brenner explains.) "We found that the fish oxytocin was specifically expressed in the rat, in the same cells as the rat oxytocin," he reports. "And it also responded to the same signals. So, as far as the rat is concerned, it's reading the information there in exactly the same way.

"This means that those two pieces of DNA from fish and rat, with their many control sequences, have the same value. Therefore, we could sequence these two pieces and see what is similar, or identical, between them. And we found little fragments of DNA, 14 base pairs, that were totally identical. These are the control words."

Seeking such control signals has been made easier by scientists' growing ability to mix and match pieces of different organisms, Brenner says. "We're not committed, as we were when I started working with C. elegans, to having one organism in which you would do everything," he points out. "Today we can range far and wide. We can get the genes from one source and the cells or organism from a different source."

Ultimately, Brenner would like to define all the control words in human DNA—the commands that shape our physiology. "If we could understand the controls, we could start the real analytic work," he says. "We could reinvent physiology. And we could understand why we are different from chimpanzees or from any other of the great apes. That, I think, will be the most exciting thing we can do."

— Maya Pines

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Sydney Brenner keeps opening new fields of research in his drive to learn how genes generate a functioning organism. He recently received a special award from the Lasker Foundation for his "50 years of brilliant creativity in biomedical science" followed by a Nobel Prize in Physiology or Medicine in 2002.

Photo: Kay Chernush

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