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