THE QUEST FOR MEMORY DRUGS

To say that aplysia californicus is one of nature's least glamorous beasts would be too kind. A hermaphroditic marine snail with mottled purple skin, it keeps to itself, responding to disturbances by emitting a murky fluid that stains the water around it. Its "brain," if you can call it that, is stunningly simple, with only a few thousand oversize neurons. It is not, in short, a likely candidate for glory in the animal kingdom. But a few years from now, much of the baby-boom generation may be greatly indebted to this unprepossessing little creature. Aplysia may look homely, but to scientists hoping to develop memory-enhancing medicine, it is a thing of beauty.

Thanks to the neurological research of Nobel laureate Eric Kandel and others, Aplysia's minimal nervous system is helping scientists to make sense of how memory works on the biochemical level. The molecules of memory in sea slugs, it turns out, aren't that different from some of those in humans. They are now one of the many inspirations for drugs that may someday ward off the forgetfulness that plagues so many people as they grow older. As people's average age creeps upward, the search for medicines that will keep them sharp is accelerating.

No pill to improve memory, aside from alternative remedies of dubious effectiveness, is currently on the market. But several small biotech companies are launching drugs grounded in the latest research, with a few already in the early stages of clinical trials that could be finished in as little as "two years, if we're lucky," says Kandel, who is now at Columbia University Medical Center and the Howard Hughes Medical Institute. Some of the most promising candidates have their roots in Aplysia studies. Others take their cues from even more improbable sources like the molecular consequences of smoking, focusing on some of the same receptors that nicotine targets. "These are very exciting times for treating memory loss," says Steven Siegelbaum, a neuroscientist at CUMC and HHMI.

It has been a long, hard slog to reach this point. Scientists now know that the brain--relying on chemical cascades kicked off by neurotransmitters--first stores short-term information in the prefrontal cortex and then transforms selected bits into long-term memories via the hippocampus, a sea-horse-shaped region tucked deep in the folds of the temporal lobe above the ear. Even such fundamental knowledge was unthinkable some 30 years ago. The concept of memory is so complex that many midcentury researchers shied away from studying it, claiming any attempt would be an example of futile reductionism. Little progress was made before 1953, when one of medicine's more famous patients arrived on the scene. An epileptic, H.M. suffered intractable, frequent seizures until he had both of his temporal lobes removed. Now deprived of his hippocampus, H.M., like the protagonists of the movies "Memento" and "50 First Dates," was unable to form new memories of people, places or things.

The unfortunate patient's case clearly signaled that the hippocampus played a central role in memory formation. But two more decades would go by before researchers figured out why or how. "The biology of memory storage was really a black hole," says Kandel. "We knew very little about it 25 years ago." Kandel's idea--to use a deceptively simple organism to solve a complex problem--met with skepticism. No wonder, says Siegelbaum, a longtime collaborator of Kandel's: "It was sort of an audacious goal at the time."

But audacious goals often drive equally audacious science, and Kandel was on to something. Because his snails had such large neurons, and so few of them, Kandel was able to identify the individual nerve cells responsible for specific behaviors. Those nerve cells appeared to rely on some of the same biochemical processes that power the brains of more advanced animals. Aplysia californicus turned out to be a good model for molecular memory processes in humans.