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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