Medicine's Next Level With new insight into the mechanisms that help keep your brain sharp, neurological researchers move closer to improving your recall with a 'memory pill'
Phillip Toledano for Newsweek Beautiful snail: The aplysia californicus is a smart slug that may unlock the secrets of memory
By By Mary Carmichael
Newsweek
Dec. 6, 2004 issue - 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 Americans' average age creeps upward, the search for medicines that will keep them sharp is accelerating. "We're all very, very avidly grinding up cells trying to get at the molecules," says Dr. Scott Small of Columbia University Medical Center.
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 CUMC 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. (Who knew it had benefits?) "These are very exciting times for treating memory loss," says Steven Siegelbaum, a neuroscientist at CUMC and HHMI. And with trials soon to yield results, they're about to get even more exciting.
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: "Most people were working on very basic problems. It was sort of an audacious goal at the time."
But audacious goals often drive equally audacious science, and Kandel, working with his sea snails, was on to something. Because the 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. Both species rely on the neural messenger cyclic AMP, which modulates a protein called CREB that can turn genes on or off. CREB is the brain's sculptor: it forms memories by reshaping the synapses, or spaces between neurons. So changes in cyclic AMP levels-and corresponding changes in CREB levels-affect the brain's ability to remodel its synapses. Less CREB equals less memory-making ability.
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 is the inheritor of the Aplysia findings. Cyclic AMP, the neurotransmitter that dictates CREB levels, is normally degraded in the brain by enzymes called phosphodiesterases. By inhibiting those enzymes' activity, MEM14 appears to boost CREB levels and 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. Researchers think that some schizophrenics ease their symptoms, including loss of memory function, by self-medicating with cigarettes.
Other companies are also in the hunt. Helicon has a phosphodiesterase inhibitor of its own. Sention, cofounded by Mark Bear of the Picower Center for Learning and Memory at MIT, has gone chemically "upstream" of cyclic AMP and CREB, modulating the neurotransmitters that direct the synthesis of proteins the brain uses as the basic building blocks of memory. Its intriguing new drug, C105 (which is largely under wraps for now), is in phase II trials. Cortex Pharmaceuticals, one of the oldest memory-booster firms, is focusing elsewhere, on molecules called ampakines, which modulate "AMPA receptors" in the brain that can strengthen the synapses. The company already has one drug, CX516, through phase II trials, although it is too weak to be a practical prescription option. A revved-up version, CX717, is in the works, and several other companies are also developing their own ampakines.
Dr. Arnold Relman, Harvard Medical School; former editor-in-chief, New England Journal of Medicine and Victoria Hale, founder and chief executive, Institute for OneWorld Health, San Francisco