Smart Genes?

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Yet that's just what Tsien & Co. did, focusing not just on the NMDA receptor but on a particular component of it. Called NR2B, it's very active in young animals (which happen to be good at learning), less active in adults (who aren't), and is found mostly in the forebrain and hippocampus (where explicit, long-term memories are formed). The researchers spliced the gene that creates NR2B into the DNA of ordinary mouse embryos to create the strain they called Doogie. Then they ran the mice through a series of standardized tests--sort of a rodent sat. In one, the mice were given a paw shock while in a box; after a few rounds, they showed signs of fear from just being in the box, having learned that a shock was likely to follow. They learned in similar fashion to be afraid when a bell sounded--a variation on Pavlov's dog experiments. In each case, the Doogies learned faster than normal mice. The same happened with a novel-object test: after becoming familiar with two plastic toys, the Doogies would show special interest when one was replaced; normal mice tended to be equally curious about a familiar object and a new one.

The altered mice grow up looking and acting just like ordinary mice, with no evidence of seizures or convulsions, according to Tsien. That's critical. The NMDA receptor shows up throughout the brain, and though calcium is crucial to learning and memory, too much of it can lead to cell death. That's what happens during a stroke: when brain cells are deprived of oxygen, they release huge amounts of glutamate, which overstimulates nearby NMDA receptors and kills their host cells. Nature may have designed NR2B-based receptors to taper off in adult brains for a reason. Some scientists fear that the altered mice may be prone to strokes. "You might worry about what happens when these animals get old," says neuroscientist Larry Squire of the University of California, San Diego.

Premature cell death isn't the only possible complication. Stanford's Robert Malenka has shown that the NMDA receptor is involved in sensitizing the brain to drugs like cocaine, heroin and amphetamines, and others are investigating its role in triggering chronic pain--two more indications that it may not be wise to try to fool Mother Nature.

It will be a while before such dangers arise, though, and--as cancer researchers have discovered all too often--it isn't even certain that what works in mice will work in people. Tsien and his colleagues believe it's not unreasonable to think it will. "The NMDA receptor in humans is nearly identical to the receptor in mice, rats, cats and other animals," he says. "We believe it's highly likely that it plays a similar role in humans."

Even so, Tsien has no plan to try tinkering with human genes--nor could he under current ethical guidelines. Drugs that can boost the action of the NR2B molecule, however, are not only ethical but already being contemplated. "Princeton has applied for a use patent for this gene," says Tsien, acknowledging his contacts with drugmakers, "although we wouldn't try to patent the gene itself."