Medicine's Next Level

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.

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 Small, and they have since fallen out of favor with mainstream scientists. Rolipram, a drug originally intended to treat depression, works in much the same way the new phosphodiesterase inhibitors do. But its nasty side effects--patients inevitably throw up after taking it--have made it an impractical solution, and although still on the market, it is not indicated for memory boosting.

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 intended to keep the brain's gears well greased. There's compelling evidence for some of them, particularly crossword puzzles. Learning a new language may also be an effective memory booster. And the old saw about fish being "brain food" is also, in some respects, true--a diet heavy 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. And even if that research never turns into anything in pharmaceutical form, it still holds plenty of exciting potential for those seeking to understand how memory works. Science may have made considerable progress since the '70s, but 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. It's a startling finding that could have major implications for brain science. "Why has evolution come up with this channel and put it in this region of the brain if it impairs memory?" Siegelbaum wonders. He 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 you remember where you were when JFK was shot, your channels were probably closed at the time. If you don't remember what you had for lunch last Wednesday, well, maybe they were closed on your lunch break.) If Siegelbaum is 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.

© 2004