Total Recall

The future of memory.

A map of the brain

Losing your memory is the great terror of our age. Anxious baby boomers are constantly assessing the fitness of their memories: Doc, I forgot my son’s telephone number—do I have mild cognitive impairment? Memory-related diseases are particularly alarming because they strike randomly, progress inexorably, and develop slowly enough that you know what’s happening to you. Only 4 million Americans suffer from Alzheimer’s disease, but surely 100 million of us worry about it.

A pharmaceutical truism: From great anxieties come great profits. Drug companies are pouring cash into research on memory ailments, knowing that billions await the firms that can protect memory or slow its decline. And when those drugs arrive, you can be sure the forgetful sick won’t be the only customers. Drugs will migrate from the Alzheimer’s victim to the elderly man with mild memory loss to the healthy middle-aged woman who just wants a mental pick-me-up.

Improving memory entices enhancers because it’s a shortcut to an even more tempting goal: increasing intelligence. This series is not tackling intelligence enhancement in its own right because our understanding of what intelligence is, physiologically, is still so vague. But much of what we think of as intelligence depends on memory, particularly on what’s called “explicit memory“—the memory for facts and events. Improving your explicit memory would allow you to perform many important tasks of daily life more quickly and accurately. It would make you seem smarter.

The Memory Pill

Memories, in the corners of your mind

The Background Scientists are already probing the genome for genes connected to Alzheimer’s and other memory illnesses. No doubt these genes will be understood soon, and gene therapy trials will follow. But for the moment, the most likely memory enhancement is in pill form—medicine for Alzheimer’s adapted for the healthy.

To understand how memory might be improved, you need to know a little bit about how memory works and fails. A small structure in the brain called the hippocampus is the nerve center for memory formation. The hippocampus is where the crucial switching from short-term memory to long-term memory—a process called “consolidation”—takes place. Consolidation occurs when certain new synaptic connections between neurons are made permanent (or nearly permanent) or “engraved,” as one researcher puts it. Most memory diseases involve the steady deterioration of consolidation as the ability to form new long-term memories decays. You can call on your warehouse of ancient memories, but you can’t store any new ones.

Pharmaceutical companies are taking two approaches to protect consolidation and ward off memory failure. The first approach arises from work on the formation of memory by rival scientists Eric Kandel, who has won the Nobel Prize for his work, and Tim Tully. (Each man started a company—Memory Pharmaceuticals for Kandel, Helicon Therapeutics for Tully—to commercialize his research.) Kandel demonstrated the importance of a messenger molecule called cyclic-AMP in forming memories. C-AMP stimulates proteins that strengthen the connections between neurons. Both Kandel and Tully then worked on a protein related to c-AMP called CREB (c-AMP response element binding protein). C-AMP activates CREB. CREB, in turn, helps trigger the cascade of events required for consolidation. Tully and a colleague showed CREB’s value by breeding fruit flies with exaggerated CREB production: The engineered flies had incredible memories. (Kandel did similar work in sea slugs and mice.)

Kandel’s Memory Pharmaceuticals and Tully’s Helicon are working on drugs to boost c-AMP and CREB levels. Memory Pharmaceuticals hopes to start clinical trials on a molecule that helps slow the breakdown of c-AMP, says Axel Unterbeck, its president and chief scientific officer.

The second approach, which is pioneered by Cortex Pharmaceuticals, is to make a memory amplifier. This research is spearheaded by Gary Lynch at University of California, Irvine, and Gary Rogers, Cortex’s senior vice president for pharmaceutical research. There’s a common neurotransmitter in the brain, called glutamate, and a protein that responds to it, called the AMPA receptor. When the AMPA receptor is exposed to glutamate repeatedly in a very short time, it triggers another receptor called NMDA at the same location. NMDA starts its signal by admitting calcium molecules, which had been blocked from entering the brain cell. According to Rogers, when NMDA admits the calcium, the connection at that synapse may change, if not permanently, at least for months. That synaptic change is thought to be a foundation of memory encoding and consolidation.

This gave Lynch and Rogers the idea of making an amplifier. They are developing a class of molecules called ampakines, which boost the glutamate signal through the AMPA receptor. By boosting that signal, the AMPA receptor more quickly activates the NMDA receptor. This should make it easier to encode information and to promote consolidation. Their first ampakine, Ampalex, is in Phase 2 clinical trials (out of three phases) for Alzheimer’s and mild cognitive impairment.

Remembering with the help of pharmaceuticals

The Project The memory-drug companies don’t like to speculate about memory enhancement. The FDA only approves drugs to treat the sick, not to improve the well. The companies could make enough repairing Alzheimer’s victims that they don’t need to push a just-for-the-fun-of-it memory boost.

That said, Cortex’s Rogers and Memory’s Unterbeck and Kandel believe that some of these compounds will be able to do just this. “It’s not a goal for us with our current pipeline of drugs targeting Alzheimer’s and depression,” Unterbeck says. “But at some time, it might be possible to enhance normal memory performance.”

Unterbeck and his colleagues have tested some of their compounds on normal healthy mice, and, he says, “We have shown we can improve their memory function quite a bit … with no side effects.” But it remains to be shown, he adds, how such compounds perform in human clinical trials that are currently ongoing in healthy volunteers.

Cortex has tested Ampalex in healthy adults, and the results are promising. For a 1997 study, it gave a single dose of the drug to a group of Swedish medical students. After taking the drug, the students improved their performance on tests requiring them to identify smells, navigate mazes, and make visual associations.

If drugs such as Ampalex or Memory Pharmaceutical’s molecules are found safe for impaired brains and approved by the FDA, doctors may start ordering them for younger people who are depressed, as a supplement to the usual anti-depressants. The military may prescribe them to soldiers to help them perform better in combat stress. And if the drugs prove harmless enough, doctors may eventually hand them out to high-schoolers before their SATs, or to actors before performances, or to you.

The Obstacles
The first memory drugs are in early clinical trials. No one knows if they are safe or what damage they might cause the brain over the long term. Data on how much they could boost memory function in healthy brains is sparse: The performance of mice and a few Swedish med students proves very little. Perhaps the drugs will not improve functioning memories, or perhaps they will work too well. Maybe patients will absorb too much information, cluttering their minds with useless details—the color of the shirt worn by a subway seatmate last Tuesday—and making it hard to focus on useful memories. We may need to forget just as much as we need to remember. (Other companies, in fact, are investigating forgetfulness drugs—compounds designed to help you lose a traumatic memory.)

The Timeline
If the clinical trials are a success, drugs from companies like Memory, Helicon, and Cortex might enter the Alzheimer’s market in five to 10 years. But it would probably take at least a decade for any drug to filter into the mass market—just in time for Gen Y to get dosed for its MCATs and LSATs.