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.

The practical results of this work, as well as extensive follow-up tests in mice and rats, are several new drugs now in early development at Memory Pharmaceuticals, founded in part by Kandel in 1998. MEM1414, the inheritor of the Aplysia findings, appears to enhance the brain's long-term memory functions; researchers hope it will enhance long-term memory in patients with age-related forgetfulness and even ward off the early stages of Alzheimer's disease, even though the two ailments are not related. There's also MEM1917, a drug similar to 1414; MEM1003, which protects neurons from damaging overloads of calcium, and MEM3454, a schizophrenia treatment that targets a receptor also known to respond to nicotine.

Other companies are also in the hunt. Sention has an intriguing new drug, C105 (which is largely under wraps for now), in clinical trials. Cortex Pharmaceuticals, one of the oldest memory-booster firms, is focusing on molecules called ampakines, which modulate receptors in the brain that can strengthen the synapses. The company already has one drug, CX516, through trials, though it is too weak to be a practical prescription option. A revved-up version, CX717, is in the works, and other firms are developing their own ampakines.

Researchers are reluctant to sing the praises of any of these drugs just yet. A broad class of drugs called nootropics showed potential in the 1970s, but they were "shots in the dark," says Dr. Scott Small of CUMC, and they have since fallen out of favor with mainstream scientists. Alternative medicine has also offered remedies. Ginkgo biloba, the most well known, has been a favorite for centuries. But science has been unable to verify its effectiveness, and supplements sold over the counter are often coy about their contents. Even if ginkgo does work, some pill versions may not contain enough of it to have any effect. The workable alternatives to alternative medicine, until now, have largely been limited to dozens of books containing mental gymnastics, such as crossword puzzles, intended to keep the brain's gears well greased. Eating fish--rich in omega-3 fatty acids--keeps blood vessels in the brain clear of blockages, allowing the nerve cells to function to the best of their abilities. But none of these remedies can completely halt "mild cognitive impairment" in adults; they can only slow it down.

Alternative remedies and brainteasers do have one advantage--they don't raise the troubling prospect of otherwise healthy people using the drugs for a boost, like steroids for geeks. "There's a question of whether we should be in the business of making memory boosters in the first place. Once we're in a gray area we at least need to be careful," says Small. "With people who are impaired by a subtle but real change in their brain function, we might not want to sit in judgment and say, 'No, we can't help you.' But the fact that a high-school student can't do well on the SAT--is that a disease?"

Ethics questions, no matter how valid, aren't likely to keep scientists from doing the basic research that could underlie drug development. There is still much to be learned. Siegelbaum's and Kandel's labs have stumbled on to an intriguing and heretofore unknown property of ion channels, tiny protein-based structures that can transport small charged molecules across the membranes of cells. One particular type of channel is found, among other places, in the hippocampus. Lab-created mice that lack this type of channel seem to be smarter than your average mouse, especially at typical memory-based tasks like repeated mazes. The upshot: when the hippocampal channels are in use, they appear to hinder memory. Siegelbaum suspects that neurotransmitters close the channels, rendering them moot, when the brain needs to remember something, but leave them open otherwise to screen out the ephemera of everyday life, the things that just aren't important enough to remember long-term. If he's right, the channels offer a tantalizing possibility: what if scientists could create a drug that would close them on command, allowing for total recall? "It's a bit of a daunting task," says Siegelbaum. But whether there's a pill at the end or not, it's still great science--and that's always an audacious goal.

THE QUEST FOR MEMORY DRUGS | News