Fetal Neuron Grafts Pave the Way for Stem Cell Therapies

Rcjohnsen rcjohnsen at aol.com
Tue Feb 29 05:29:28 EST 2000

Fetal Neuron Grafts Pave the Way for Stem Cell Therapies

Marcia Barinaga

A decade of experimental treatments using fetal neurons to replace brain cells
that die in Parkinson's disease can provide lessons for planning stem cell

    Swedish neuroscientist Anders Björklund and his colleagues may have caught
a glimpse of what the future holds for the treatment of failing organs. For
more than 10 years, Björklund has been part of a team at Lund University in
Sweden that has been grafting neurons from aborted fetuses into the brains of
patients with Parkinson's disease. In many cases, the transplanted cells have
dramatically relieved the patients' symptoms, which include slowness of
movement and rigidity. That is just the kind of therapy that stem cell
researchers hope to make routine for treating all sorts of degenerative
diseases, if they can coax the cells to develop into limitless supplies of
specific cell types that can be used to repair or replace damaged organs.
    Although the current Parkinson's treatment uses fetal cells that have
already developed into a particular type of neuron, the promising results
represent a "proof of principle that cell replacement actually works," says
Björklund. The results have given researchers increased confidence that, if
they can manipulate stem cells to develop into the kind of neuron the Lund
group and others are using--a big challenge--the new cells would take over the
work of damaged cells in the brains of Parkinson's patients. If so, Parkinson's
treatment could be among the first applications of stem cell therapy.
    The successes have also increased the urgency of developing stem cell
treatments, because despite their promise, there are many reasons that fetal
cells will never be widely used to treat Parkinson's disease. The reasons range
from ethical concerns, such as the protests by antiabortionists that led the
governor of Nebraska to urge that research involving fetal tissue be shut down
at the University of Nebraska (Science, 14 January, p. 202), to the fact that
there will never be enough fetal tissue to treat all the people who need it.
Parkinson's disease afflicts 1 million people in the United States alone.
   Researchers are now looking closely at the results from fetal cell
transplants for lessons that will help guide future work with stem cells. There
are still many hurdles to overcome, but this first round of cell replacement in
the brain sets a "gold standard" that stem cells must meet if they are to
become the basis for new Parkinson's treatments, says neuroscientist and stem
cell researcher Evan Snyder of Harvard Medical School in Boston.
    Parkinson's disease is a logical candidate for cell replacement therapy, in
part because conventional treatments have had limited success. The disease is
caused by the death, for unknown reasons, of a particular group of brain
neurons that produce dopamine, one of the chemicals that transmit signals
between nerve cells. Afflicted people lose the ability to control their
movements, ultimately becoming rigid. Treatment with levodopa (L-dopa), a drug
that is converted to dopamine by the brain, alleviates these symptoms, but as
the neurons continue to die, L-dopa's effectiveness wanes. Researchers first
tried replacing the dopamine-producing cells by grafting into the affected
region cells from the adrenal medulla gland. These cells are not neurons, but
they make dopamine and can be coaxed to become neuronlike. The treatment
reversed Parkinson's symptoms in rats, but produced little lasting improvement
in human patients, probably because the cells died or stopped making dopamine,
says John Sladek, chair of neuroscience at the Chicago Medical School.
    Researchers have had better luck grafting immature neurons taken from
aborted human fetuses. Dozens of patients who have received these experimental
dopamine-neuron grafts over the past 10 years have had up to a 50% reduction in
their symptoms. And the effects appear to last. Using positron emission
tomography to image the brain, Olle Lindvall of Lund University and a team of
colleagues in Lund and at Hammersmith Hospital in London reported in the
December issue of Nature Neuroscience that, in one patient, the transplanted
neurons are still alive and making dopamine 10 years after the surgery. That's
encouraging, says neurotransplant researcher Ole Isacson of Harvard Medical
School: Whatever killed the brain's own dopamine-producing neurons doesn't seem
to have killed the transplanted cells.
    Still, fetal cell transplants are plagued by problems that can never be
overcome. Aside from ethical concerns about scavenging neurons from aborted
fetuses, there are practical issues. It takes six fetuses to provide enough
material to treat one Parkinson's patient, in part because as many as 90% to
95% of the neurons die shortly after they are grafted. Indeed, Lund's Björklund
says, the cell supply is so limited that researchers have not even been able to
test some possible avenues for fetal cell transplants. The neurons that die in
Parkinson's originate in a brain region called the substantia nigra and send
their long axons to several other areas, where they release dopamine. So far,
researchers have put the cell grafts into only one of these areas, the
putamen--and even there, they have not yet transplanted enough neurons to
restore normal dopamine levels in most cases.
    Even if researchers can develop techniques that diminish the fetal cell
die-off, there will never be enough fetuses available to make this an "everyday
procedure," says Sladek. What's more, the brain material recovered from aborted
fetuses "comes out in a form that makes it difficult to ... standardize" in
terms of quality and purity, Björklund says. This is likely why some patients
do far better than others--uncertainty that would be unacceptable in a standard
medical treatment.
    Consequently, researchers are pinning their hopes on cultured stem cells.
They would eliminate a continuing dependence on aborted fetuses, although the
ethical concerns won't be completely laid to rest unless researchers can use
stem cells obtained from adults rather than embryos (see p. 1418). And the
supply of cultured cells could be unlimited, allowing tests of grafts into the
putamen and possibly into other brain areas as well. The cell treatment,
moreover, could be standardized and controlled to assure a more predictable
outcome. "The ability to grow the cells of interest will make this a routine
technology," predicts neuroscientist Ron McKay, whose team is working on ways
to culture neural stem cells at the National Institute of Neurological
Disorders and Stroke.
   But to make this brave new world of cell replacement technology a reality,
researchers must first learn how to keep stem cells dividing for many
generations in culture and then be able to trigger them to differentiate into
the type of neuron they want. Stem cells presumably have the ability to
differentiate into any of the several different types of dopamine neurons the
brain contains, but it may be crucial to use the specific type of dopamine
neurons that die in Parkinson's. Researchers doing the fetal cell transplants
specifically select these neurons--known as nigral neurons because they
originate in the substantia nigra--when they harvest neurons for grafting from
fetal brains. Nigral neurons are "genetically programmed and designed to be a
dopamine neuron in the appropriate brain circuit," Sladek says.
    Among other things, nigral neurons may respond better to local conditions,
producing just enough dopamine. Experience with L-dopa treatment has shown that
too much of the neurotransmitter can be just as problematic as too little,
causing uncontrollable, jerky movements in patients. Researchers worry that
stem cells coaxed to develop into dopamine neurons may become one of the
nonnigral types and will not regulate their dopamine output in the appropriate
ways. "It is like putting the right alternator into your car," Sladek says. "If
you put in one designed for another model of car, it may not work as well."
    Getting stem cells to differentiate into the right type of neuron may be
only part of the problem. Neurons in their natural environment are surrounded
by support cells called glia, which nurture the neurons and even modulate their
activity, and optimal cell transplants may require replacing not only dopamine
neurons but also the glia that normally surround them, Harvard's Snyder
    But some researchers believe that the brain itself may be able to overcome
the hurdles of producing both the proper neurons and the support cells they
need. Snyder's lab has shown in animal experiments that stem cells put into the
brain can be influenced by the brain environment to differentiate into both
neurons and support cells. He envisions someday putting stem cells into
Parkinson's brains and letting the brain tell them which cell types to become.
    Even if it turns out not to be quite that simple, Parkinson's poses a much
less daunting challenge for cell replacement therapy than do other neurological
disorders. "The dopaminergic system is a fairly easy system to work with
compared to sensorimotor or visual systems or spinal cord," says Isacson. That,
he says, is because the nigral neurons lost in Parkinson's disease have a
diffuse and relatively nonspecific network of connections in the brain areas
they link up to, rather than the very intricate and precise connections made by
neurons in many other parts of the nervous system.
    The treatment of most other brain disorders would likely require coaxing
new neurons to make very precise connections, a task that no one is sure how to
achieve. But in the case of Parkinson's disease, simply getting neurons to
release dopamine in the correct general area helps patients. Because of that
difference, Isacson predicts that "it will take some time to get other diseases
to benefit from all these discoveries." Nevertheless, a successful Parkinson's
treatment based on stem cells would still be a dramatic achievement. "You would
help a huge number of patients," he says, "as many as the surgeons could do."

Science 2000 287: 1489-1493. (in Reports) [Abstract] [Full Text] 

Volume 287, Number 5457 Issue of 25 Feb 2000, pp. 1421 - 1422 
©2000 by The American Association for the Advancement of Science. 
Copyright © 2000 by the American Association for the Advancement of Science.   

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