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
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.
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