The following is from the August issue of Discover Magazine.
Brain Watch=20
Brain, Heal Thyself
BY JOSIE GLAUSIUSZ=20
Once brain cells die--from aging, injury, or disease--they=20
can't be replaced. Or can they?=20
Researchers are trying to stimulate new growth in old brains.
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 da=
y out
for decades. The skin, liver, gut, and perhaps ot=
her
organs are also thought to have their own stem ce=
lls
that replace injured and dead cells. Not so the b=
rain:
The conventional wisdom has long been that it doe=
sn't
have stem cells--perhaps in part because it would=
have
a hard time holding on to memories if its cells w=
ere
constantly being replaced. Instead the brain star=
ts out
with more cells than it ordinarily needs in a lif=
etime.
"Nature gives you too many brain cells to start w=
ith 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."=20
Nevertheless, the conventional wisdom on brain st=
em
cells is changing these days. Although no one has=
yet
conclusively isolated stem cells from an adult ma=
mmal's
brain, Weiss and other researchers have induced
mouse brain cells to act like stem cells in the l=
ab. And
they have found good reason to hope that it may o=
ne
day be possible to get cells in the adult human b=
rain to
act like stem cells--and perhaps replace tissue t=
hat has
been damaged by stroke or by a disease such as
Huntington's or Parkinson's.=20
One of the leaders in this new field is Evan Snyd=
er, at
Harvard Medical School. In 1992 he announced that
he and his colleagues had removed "stemlike" cell=
s
from the brains of newborn mice. Specifically, th=
e cells
came from the cerebellum--a motor-coordinating ar=
ea
of the brain that continues developing for a brie=
f
postnatal period. These immature cells were
amorphous and flat, lacking the long, delicate
connecting fibers--the axon and dendrites--of mat=
ure
neurons. Under normal circumstances these cells w=
ould
rapidly differentiate into specialized cells and
would no
longer reproduce themselves. But Snyder infected =
them
with a retrovirus carrying a gene that prompted t=
he
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 mye=
lin
that insulates neurons.=20
Although their genesis was somewhat artificial, S=
nyder
claims that his manipulated cells meet the requir=
ements
of true stem cells: they can reproduce and mainta=
in
themselves, and they can give rise to all the maj=
or cell
types in the brain. But were they just a laborato=
ry
curiosity? To find out, Snyder injected the genet=
ically
engineered cells into the brains of newborn mice,=
with a
genetic marker that allowed him to track them. (T=
he
marked cells turned blue when exposed to a specia=
l
stain.) After the mice matured, he killed them an=
d
examined their brains.=20
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 mor=
e,
after
differentiating, the cells had ceased dividing, j=
ust as
normal brain cells would--possibly because of som=
e
innate brain signal that dampens division. To dat=
e,
Snyder has injected his stemlike cells into more =
than
1,000 mice without once seeing the uncontrolled c=
ell
growth that makes a tumor.=20
Snyder's long-term goal, however, was to see whet=
her
his implanted cells could repair some kinds of br=
ain
damage. And in recent experiments, he has found t=
hat
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 suppl=
y is
cut off, as it is in a stroke. Snyder thinks that
the cells
may migrate and mature so readily because they ar=
e
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 thei=
r
neighbors. Ordinary mature brain cells, he specul=
ates,
have lost the ability to respond to such signals,=
or the
signals may somehow be suppressed.=20
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 accumula=
tes
in the brains of children with the disease, causi=
ng
severe
mental retardation and death. Snyder found that o=
nce
inserted into mouse brains, the genetically engin=
eered
cells began producing the enzyme at levels though=
t to
be sufficient to alleviate symptoms of the diseas=
e 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.=20
Weiss, meanwhile, has taken a different approach =
to
cell repair in the brain. He has been working wit=
h 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 smel=
l.
Weiss
has found that by treating subependymal cells wit=
h a
protein called epidermal growth factor, or EGF, t=
he
cells, like those in Snyder's experiments, reprod=
uced
both themselves and the three major brain-cell ty=
pes.
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, howev=
er,
take advantage of the fact that actively dividing=
cells
have not yet differentiated into specialized tiss=
ue.=20
Recently, Weiss and his colleagues Constance Crai=
g
and Derek van der Kooy of the University of Toron=
to
have found that injection of EGF into mouse brain=
s
spurred the growth of new neurons. These cells sp=
read
into regions near the subependymal layer, includi=
ng the
striatum, which is involved in regulating motor
functions.
This is significant, because in people with Hunti=
ngton's
disease, neurons in this region die. "Something t=
hat I
would consider to be very primitive--simply infus=
ing
EGF--seems to have the potential to replace the
neurons that are lost in Huntington's disease," s=
ays
Weiss.=20
For now, the gap between experiments with laborat=
ory
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 smal=
l to be
effective for anything but the repair of tiny inj=
uries.
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.=
=20
"Sometimes, when the brain is really massively
damaged," says Snyder, "it tries to evoke these s=
ame
mechanisms but just can't quite do it to the exte=
nt that
you care about. What I take away from this is tha=
t the
brain wants to repair itself--there are cries for
help, so
to speak. Now, if we understand the language of t=
hose
cries, I think we can jump into that breach and h=
elp
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."=20
=A9 Copyright 1996 The Walt Disney Company=20
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