Science, 25. Feb 2000, Vol 287, No. 5457, page 1421
Fetal Neuron Grafts Pave the Way for Stem Cell Therapies
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 therapies.
Marcia Barinaga
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 I 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 suggests.
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."