DEPRIVED OF OUR BLOOD-FORMING stem cells, we
would all quickly die. These bone-marrow cells
replenish red and white blood cells day in and
day out for decades. The skin, liver, gut, and
perhaps other organs are also thought to have
their own stem cells that replace injured and
dead cells. Not so the brain: The conventional
wisdom has long been that it doesn't have stem
cells--perhaps in part because it would have a
hard time holding on to memories if its cells
were constantly being replaced. Instead the brain
starts out with more cells than it ordinarily
needs in a lifetime. "Nature gives you too many
brain cells to start with and assumes that you
won't do anything silly like get into a boxing
ring or ride a motorcycle without a helmet," says
Samuel Weiss, a neuroscientist at the University
of Calgary in Canada. "And in most cases nature
has done well, because most of us don't need
replacement."
Nevertheless, the conventional wisdom on brain
stem cells is changing these days. Although no
one has yet conclusively isolated stem cells from
an adult mammal's brain, Weiss and other
researchers have induced mouse brain cells to act
like stem cells in the lab. And they have found
good reason to hope that it may one day be
possible to get cells in the adult human brain to
act like stem cells--and perhaps replace tissue
that has been damaged by stroke or by a disease
such as Huntington's or Parkinson's.
One of the leaders in this new field is Evan
Snyder, at Harvard Medical School. In 1992 he
announced that he and his colleagues had removed
"stemlike" cells from the brains of newborn mice.
Specifically, the cells came from the
cerebellum--a motor-coordinating area of the
brain that continues developing for a brief
postnatal period. These immature cells were
amorphous and flat, lacking the long, delicate
connecting fibers--the axon and dendrites--of
mature neurons. Under normal circumstances these
cells would rapidly differentiate into
specialized cells and would no longer reproduce
themselves. But Snyder infected them with a
retrovirus carrying a gene that prompted the
cells to divide. Not only did the cells
reproduce, they also began spinning off the three
main types of mature brain cells: the
message-carrying neurons; astrocytes, cells that
surround the capillaries, forming the blood-brain
barrier; and oligodendrocytes, which make the
myelin that insulates neurons.
Although their genesis was somewhat artificial,
Snyder claims that his manipulated cells meet the
requirements of true stem cells: they can
reproduce and maintain themselves, and they can
give rise to all the major cell types in the
brain. But were they just a laboratory curiosity?
To find out, Snyder injected the genetically
engineered cells into the brains of newborn mice,
with a genetic marker that allowed him to track
them. (The marked cells turned blue when exposed
to a special stain.) After the mice matured, he
killed them and examined their brains.
Snyder found that the marked cells had indeed
differentiated into neurons and other brain
cells--their destiny dependent on the site at
which they had settled--and some had formed
normal synaptic connections with existing brain
cells. What's more, after differentiating, the
cells had ceased dividing, just as normal brain
cells would--possibly because of some innate
brain signal that dampens division. To date,
Snyder has injected his stemlike cells into more
than 1,000 mice without once seeing the
uncontrolled cell growth that makes a tumor.
Snyder's long-term
goal, however, was to see
whether his implanted cells could repair some
kinds of brain damage. And in recent experiments,
he has found that they probably can. For example,
when he injected the cells into newborn mice with
artificially induced stroke, the cells migrated
into damaged areas. Some differentiated into
neurons and oligodendrocytes, the cells most
commonly injured when the oxygen supply is cut
off, as it is in a stroke. Snyder thinks that the
cells may migrate and mature so readily because
they are responding to developmental signals
analogous to those that occur in the
embryo--growth factors, perhaps, that in this
case are put out by dying neurons or their
neighbors. Ordinary mature brain cells, he
speculates, have lost the ability to respond to
such signals, or the signals may somehow be
suppressed.
In his latest research, Snyder and his colleagues
are using his "stem cells" to perform a type of
gene therapy. They spliced into the cells a gene
that codes for an enzyme missing in children with
Tay-Sachs disease. This enzyme breaks down a
cellular waste product in the brain. Without the
enzyme, the waste accumulates in the brains of
children with the disease, causing severe mental
retardation and death. Snyder found that once
inserted into mouse brains, the genetically
engineered cells began producing the enzyme at
levels thought to be sufficient to alleviate
symptoms of the disease in humans. In a brain
with Tay-Sachs, he thinks, the stem cells might
naturally tend to spread and produce their
crucial enzyme throughout the damaged brain.
Weiss, meanwhile, has taken a different approach
to cell repair in the brain. He has been working
with cells taken from the subependymal layer, at
the core of the brain. In mice, this region
produces specialized cells that replace worn-out
cells in the olfactory bulb, the part of the
brain that controls the sense of smell. Weiss has
found that by treating subependymal cells with a
protein called epidermal growth factor, or EGF,
the cells, like those in Snyder's experiments,
reproduced both themselves and the three major
brain-cell types. Weiss says that both his and
Snyder's approaches promote cell division, his
method by an external signal from egf, and
Snyder's from an internal genetic command. More
research, he says, will determine which is the
more effective strategy. Both, however, take
advantage of the fact that actively dividing
cells have not yet differentiated into
specialized tissue.
Recently, Weiss and his colleagues Constance
Craig and Derek van der Kooy of the University of
Toronto have found that injection of EGF into
mouse brains spurred the growth of new neurons.
These cells spread into regions near the
subependymal layer, including the striatum, which
is involved in regulating motor functions. This
is significant, because in people with
Huntington's disease, neurons in this region die.
"Something that I would consider to be very
primitive--simply infusing EGF--seems to have the
potential to replace the neurons that are lost in
Huntington's disease," says Weiss.
For now, the gap between experiments with
laboratory mice and human cell therapy for brain
damage is enormous. Snyder and Weiss both
believe, however, that their experiments show
that the human brain has the potential to repair
itself, and that it may indeed even have its own
stem cells, only in numbers too small to be
effective for anything but the repair of tiny
injuries. Infusing it with egf might be one way
to help it; transplanting cells that have been
taken from the brains of human accident victims,
and that have been manipulated to become
stemlike, might be another.
"Sometimes, when the brain is really massively
damaged," says Snyder, "it tries to evoke these
same mechanisms but just can't quite do it to the
extent that you care about. What I take away from
this is that the brain wants to repair
itself--there are cries for help, so to speak.
Now, if we understand the language of those
cries, I think we can jump into that breach and
help out, either by supplying more of the factors
that the brain is making at a low level or
additional stem cells to augment the brain's own
supply."