Brain cells derived from human embryonic stem cells improved the
condition of rats with Parkinson's-like symptoms dramatically, but
the treatment caused a significant problem – the appearance of brain
tumors – that scientists are now working to solve. The study is
featured on the cover of the November issue of Nature Medicine.
The work was reported by neurologist Steven Goldman, M.D., Ph.D.,
professor of Neurology at the University of Rochester Medical Center
and chief of its Division of Cell and Gene Therapy, and Neeta Roy,
Ph.D., assistant professor of Neurology at Cornell's Weill Medical
College.

"The results are a real cause for optimism," said Goldman. "These
animals with severe Parkinson's symptoms had a dramatically improved
outcome after treatment. Now we have a new problem to work on, how
to achieve the same benefit without creating tumors. But we expect
to be able to solve this problem within the next year or two, using
new approaches to cell sorting that we've been developing."

"All in all, this is the way medical discoveries move forward: One
step at a time."

Goldman has spent much of his career creating ways to isolate stem
cells, discovering the molecular signals that help determine what
specific types of cells they become, and then re-creating those
signals to direct the cells' development. It's the versatility of
stem cells that make them so attractive. If scientists like Goldman
are successful directing their development, such cells could provide
a ready source of cells custom made to treat a given disease – for
instance, myelin-producing cells for multiple sclerosis, or the
specific types of cells that die in patients with Parkinson's or
Huntington's diseases.

In the experiment reported in Nature Medicine, Goldman, Roy and
colleagues set out to grow brain cells called neurons that produce
dopamine, a crucial brain chemical lacking in patients with
Parkinson's. They began by isolating human embryonic stem cells,
then using genes such as "sonic hedgehog" and fibroblast growth
factor 8 that make chemicals in the normal brain environment. Such
signals are the body's natural way of directing stem cells to
develop into the specific cells needed.

Past attempts at using stems cells to make this type of neuron had
achieved modest success, but only relatively small numbers could be
produced in tissue culture. To improve upon this, Roy and Goldman
attempted to re-create the natural environment of the developing
brain as much as possible, so it would seem to the stem cells that
they were developing in the part of the brain where dopamine neurons
are normally made. The team did so by raising the cells together
with brain cells known as astrocytes, which had come from the same
brain region. These cells have long been known to play a crucial
role nourishing neurons.

The result was that more than two-thirds of the stem cells developed
into precisely the type of cell needed to treat Parkinson's disease –
dopamine-producing neurons. That percentage is far higher than any
previous experiment had achieved.

The team then injected the cells into the brains of rats with
Parkinson's-like symptoms, and watched for 10 weeks. While rats with
the disorder walked in circles when prompted to move, as if they
were chasing their tails, rats transplanted with the new cells
recovered normal function and eventually stopped walking in circles.
By eight weeks after treatment, the tail-chasing behavior ended
completely, and they were walking and running normally.

Yet when the brains of the animals were examined, the team found
tumors within the brain grafts. Goldman said the tumors sprang from
stem cells that had started on the road to becoming neurons, but
then stalled in their development and grew out of control. The team
is working on ways to filter out those cells, to reap the benefits
while avoiding the side effects of the approach.

"The appearance of tumors was disappointing, but not surprising,"
said Goldman. "The goals of this experiment were to create a
population of cells that had many more dopamine neurons than
previous attempts yielded, and to measure whether a group of cells
with so many of these neurons would yield real-life benefits in
terms of behavior. We accomplished both tasks. The cells improved
the disease symptoms dramatically, beyond what we expected.

"In this first attempt of the technology, we did not attempt to try
to absolutely purify the cell population that was transplanted –
thus the brain tumors. The experiment confirmed that we need to have
an absolutely pure cell population, and we are working on ways to do
that."

1-Dec-2006(EurekAlert) -