David Plotz in Slate on Building Supermen (Memory)

From: J. Hughes (jhughes@changesurfer.com)
Date: Tue Mar 11 2003 - 19:39:49 MST

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    superman The quest to build better people.
     
    Total Recall
    The future of memory.

    By David Plotz

    Posted Tuesday, March 11, 2003, at 12:32 PM PT

    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.

    David Plotz is Slate's Washington editor. You can e-mail him at
    plotz@slate.com.



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