X-Message-Number: 10659
Date: Fri, 30 Oct 1998 15:58:15 -0500
From: Jan Coetzee <>
Subject: New brain cells for old ones.
DOGMA OVERTURNED
Upending a long-held theory, a study finds that humans
can
grow new brain neurons throughout life--even into old
age
Rats can do it. So can opossums, songbirds, marmosets--why, even
tree shrews. But every
biology student is taught that humans cannot produce new neurons
anywhere in their brains
once they have matured. That is a limitation--damage from abuse,
disease and injury never
heals--but it is also an evolutionary advantage, because it means
that memories, imprinted in
webs of neurons, can persist undisturbed for a lifetime. Or so
the theory has gone for more
than a decade.
Now it appears that that fundamental dogma of medicine is wrong;
at the very least, it is far
too sweeping. Two neuroscientists, one American and one Swedish,
have collected the first
persuasive evidence that mature, even elderly, people do create
additional neurons by the
hundreds in at least one important part of the brain, a section
of the hippocampus called the
dentate gyrus. At press time, the paper was still under review
for publication by Nature
Medicine.
The scientists do not know what the new cells do nor whether the
same process, called
neurogenesis, occurs elsewhere in the brain. But others in the
field say that even though the
discovery probably will not yield medical applications for many
years, it is a major advance
nonetheless. "Once you accept that the brain has some plasticity
after all, you have to rethink
approaches to lots of problems," says Gerd Kempermann of the
University of Regensburg in
Germany.
For more than two years, Fred H. Gage of the Salk Institute in
San Diego and Peter S.
Eriksson of the G teborg University Institute of Clinical
Neuroscience conducted an
experiment that was thought to be nearly impossible, for two
reasons. First, they needed fresh
brain tissue but not from just any spot. The best place to look
for newly formed neurons is
the hippocampus, which is where they are produced most often in
lower mammals. But the
hippocampus is nestled deep in the temporal lobes of the brain.
"It is very fragile," Eriksson
says, and damage to it can destroy a person's ability to learn,
because it appears to control
which experiences are filed away into long-term storage and which
pass into oblivion.
Biopsies are thus out of the question.
The second problem, Gage explains as he opens a door in his San
Diego laboratory to reveal
a darkened room full of postdoctoral researchers looking at brain
cells through high-tech laser
microscopes, is that 60-day-old neurons look just the same as
60-year-old ones. The only
well-accepted way to mark nascent cells, neurons or otherwise, is
to inject the subject with
either tritiated thymidine or bromodeoxyuridine (BrdU), chemicals
that can serve as a building
block of DNA but that can be detected by film or fluorescence.
Cells won't take up these
chemicals until they begin to divide and manufacture DNA. When
that happens, some of the
chemical will be incorporated into the DNA of the offspring, and
the young cells will shine for
the camera. Unfortunately, both tagging chemicals are toxic to
humans. So when Eriksson, on
sabbatical at Salk in 1995, began talking to Gage about searching
for neurogenesis in humans,
there seemed no ethical way to do it.
But after Eriksson returned to Sweden, he found a way. "One day I
met this oncologist in the
operating room; we were both on call," Eriksson remembers. "I
asked him whether he knew
anyone giving BrdU to patients, and he said yes; in fact, he knew
of a study in which seven
people with cancer of the tongue or larynx were getting it."
Because newborn cells take up
BrdU, researchers can use it to help monitor how fast a tumor is
growing.
Eriksson tracked down the doctor in charge of the study, and they
made a deal: whenever one
of the patients died, the doctor would ask the family's
permission to remove the
hippocampus. If they agreed, then Eriksson would be summoned.
Five times from 1996 until
this past February, Eriksson got a call, then jumped in the car
and sped over to the hospital to
watch as a pathologist pulled out a fingertip-size lump of
brain--still warm in one
instance--from cadavers aged 57 to 72. He then immediately
stained the samples with NeuN, a
marker that (as far as is known) attaches only to neurons.
"You need to get the samples within 24 hours, before the cells
lose too much of their
integrity," Eriksson explains. But the boyish, normally jovial
face of the 39-year-old scientist
falls as he allows that the work was a touch gruesome. "When your
success is based on
someone's death, it makes you sad," he says. "It was heartening,
though, to tell the families
about what good might come from the results of the experiment."
Indeed, the results were surprising. Stepping layer by layer
through the stained sections of the
dentate gyrus with their laser microscopes, the scientists saw
cell after cell lit both green and
red. The green meant that the cells had picked up BrdU and thus
must have been born while
the chemical was in the bloodstream, during the patients' cancer
treatments. The red came
from NeuN, indicating that the new cells were indeed neurons.
"It was an amazing feeling to see them, in every sample, right
where we expected they would
be," Gage says. "Neurogenesis occurs, and it occurs throughout
life. More than that, these
new neurons survive for years." One of the patients had received
his last BrdU injection 781
days before his death. "Most important," Gage adds, "it is not an
isolated, rare event." In all
five patients, each cubic millimeter of dentate gyrus held 100 to
300 newly fledged neurons.
That may not sound like a lot, especially considering that the
dentate gyrus is no bigger than a
BB. But a few neurons can go a long way, Kempermann points out.
"Fewer than 50 cells are
thought to control breathing," he says; damage to a couple
thousand neurons by Parkinson's
disease can cause terrible debility.
By the same token, adding a few new neurons to a damaged part of
the brain might help the
organ repair itself. "That is the real significance of this
work," says Pasko Rakic, head of the
neurobiology department at Yale University and a chief proponent
of the no-new-neurons
theory. "To be useful, new neurons must develop connections with
their neighbors. [Gage
and Eriksson] haven't shown that that happens. And new cells have
not been shown in the
cerebellum, the cerebral cortex or the thalamus," regions most
often damaged by injury or
disease. "But this work does suggest the possibility of finding a
factor that can encourage cell
proliferation elsewhere in the brain."
"It allows us to think about growing neurons for
transplantation," Eriksson elaborates. "In
experiments at the University of Lund, transplanted fetal cells
greatly reduced the symptoms
of Parkinson's disease, an effect that lasted for years. But
there are ethical concerns with
using cells from aborted fetuses." Now there can be reasonable
hope of eventually using adult
tissue instead.
Such clinical benefits, Eriksson predicts, "are 10 years away, at
best." Gage concurs:
"Nothing here can be immediately translated to help a person in a
wheelchair." That will have
to wait until scientists learn much more about where the
progenitor cells that give birth to new
neurons exist in the brain, what chemical signals spur them to
divide, and what determines
whether newly created cells become neurons or some other kind of
brain matter. Both
scientists have animal experiments under way to tackle those
tough questions. But it may be
years before their peers elsewhere can arrange to get the human
tissue needed to confirm their
discovery and to build sound medicine on it. So, most likely,
"the general spirit of the dogma
will live on," Eriksson concedes. "This represents one exception
to it; that's all." But where
there once seemed only an impenetrable wall, the outline of a
door has appeared.
--W. Wayt Gibbs in San Diego and G teborg, Sweden
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