COVER STORY: SEPTEMBER 13, 1999 VOL. 154 NO. 10

Over the past decade or so, neurophysiologists have been focusing in on a particular molecule they believe could well be at least one version of Hebb's coincidence detector. Called N-methyl D-aspartate, or NMDA, this substance sits at the ends of the dendrites, the branchlike projections that protrude from nerve and brain cells, waiting to respond to incoming signals. Like other receptor molecules, NMDA reacts to a chemical cue--in the case of learning and memory formation, glutamate--emitted by the axon from a neighboring cell.

	ALSO IN TIME
	Brainteaser The ethics of engineering minds Pills An industry devoted to memory supplements Viewpoint The discovery disproves two common fallacies

But unlike other receptors, NMDA doesn't find this signal sufficient. It must also receive an electrical discharge from its own cell. Only when both cells are talking at once does the NMDA receptor turn on. It then permits calcium ions to flow into the host cell, which somehow--no one knows the details yet--makes the cell easier to turn on next time around. This phenomenon, known as long-term potentiation, is believed to be the essence of one type of memory formation.

NMDA's role in learning and memory isn't just theoretical. It has been known for years that blocking NMDA receptors with drugs, or knocking them out completely at the genetic level, makes animals learning-disabled, even amnesiac. Administering drugs that stimulate the receptor, conversely, tends to improve memory.

Tsien and his team took the next logical step. "A decade ago," says Stanford neuropsychiatrist Dr. Robert Malenka, "if you had asked, Would it be possible to manipulate a higher cognitive function like learning and memory by changing a single molecule? most scientists would have looked at you as if you were crazy."

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."

There remains the nagging question of what it means precisely to say that Tsien & Co. have created a smarter mouse. "What is it that is being tested?" asks Gerald Fischbach, director of the National Institute of Neurological Disorders and Stroke. "That's the problem with mouse behavior. It's not clear that we're talking about the same thing when we talk about learning in a rodent and learning in a human."

Tsien concedes that using the emotive word intelligence in the paper was sure to generate controversy. "We really don't mean to suggest," he explains, "that human intelligence is the same as animal intelligence. But I would argue that problem solving is clearly part of intelligence, and learning and memory are crucial to problem solving. And these mice are better learners, with better memories, than other mice."

But Tsien doesn't claim that he and his colleagues have found the unique genetic key to intelligence or even to memory. "It's likely that brain plasticity involves many molecules," he says. "This is just one of them." On the other hand, he asserts--and his critics would not disagree--that "intelligence does arise out of biology, at least in part." How much remains the great question. Whatever the answer, little Doogie surely represents an important step in unraveling what role our genes play in constructing not just memory but all the other attributes of the human mind. And clearly he won't be the last.

With reporting by David Bjerklie and Alice Park/New York, J. Madeleine Nash/Chicago and Dick Thompson/Washington


PAGE 1 | 2 | 3