Brain Stem Cell Is Discovered, Twice
By NICHOLAS WADE
The elusive neural stem cell, the founding cell from which perhaps the
whole brain develops, has at long last been discovered -- again.
In an unusually direct disagreement, two scientists say they have
discovered the site in the brain where neural stem cells lurk, but each has
a different candidate.
Stem cells can both renew themselves and generate the more specialized cell
types of the organ to which they belong. Though the adult brain was long
thought to be incapable of repairing itself, biologists found in 1992 that
the brain can generate new neurons in some cases, so must possess a hidden
reservoir of neural stem cells.
The nature and hiding place of the neural stem cells at once became
questions of high interest. The cells might help replace those that are
lost or damaged in Parkinson's, Alzheimer's and other brain diseases. And
study of the stem cells' ability to generate the brain's many different
cell types could help tease out the blueprint for the brain's extraordinary
architecture, a precisely wired mechanism of 100 billion neurons and at
least 1 trillion supporting cells. So there was considerable excitement
among brain biologists in January when Dr. Jonas Frisen of the Karolinska
Institute in Stockholm reported he had found the source of the neural stem
cells in rats' brains, assumed to be typical of all mammalian brains in
this respect, including humans. The stem cells known from other organs are
plain, featureless blobs of protoplasm that show no signs of
differentiation, the term for when a stem cell's progeny assume their
mature roles. But the neural stem cells discovered by Dr. Frisen were
differentiated. Not only that -- and maybe only a trained developmental
biologist can appreciate the full shock and horror of his finding -- the
cells sported long, active hairs. Besides this clever disguise, the cells
were occupying the most menial role in the brain's grand electrical house:
they were lining the ventricles, the fluid-filled central chambers of the
brain. The cells' waving hairs project into the fluid and keep it moving.
When a living cell is isolated and placed in fluid, it will scoot around
the dish, propelled by its beating hairs.
Despite the surprise that a differentiated cell could repeal its fate and
become a stem cell again -- imagine a pensioner growing back into a
teen-ager -- Dr. Frisen's result was generally accepted. It was published
in Cell, a journal known for its high standards. But last week Cell
published a second paper with an explicitly contradictory result. It came
from Dr. Arturo Alvarez-Buylla at Rockefeller University in New York. And
it said the neural stem cells were not the ventricle liners but rather the
star-shaped cells called astrocytes that lie one layer in from the
ventricle lining.
Why would a scientific journal publish two articles saying different
things? Essentially because both seem to be carefully done experiments and
it is too early to tell which is right. Both authors did extra tests to
address the skepticism of reviewers, said Dr. Benjamin Lewin, the editor of
Cell. "We should of course have liked to resolve the differences between
the papers," but the two scientists' work was hard to compare, he said.
"Finally we decided that each paper has to be judged on its own merits --
that is, in effect, to ask whether it makes a good case for the validity of
the proposed stem cells, irrespective of the other paper." Some experts
who have read both articles say their apparently discrepant results may
prove reconcilable. It could be the brain has more than one type of stem
cell, or that Dr. Frisen's liner cells turn into Dr. Alvarez-Buylla's
astrocytes and then into neural stem cells. Dr. Frisen also believes some
kind of reconciliation is likely to emerge. ''I think we are both right and
both cells are involved in this process," he said. Dr. Alvarez-Buylla,
however, believes his result is right and Dr. Frisen's is not. He said he
had tried to induce the liner cells to make the three main lineages of
brain cells, the best current test of neural stem cells, but could not even
get them to divide. Of the two competitors in the neural stem cell race,
Dr. Alvarez-Buylla has probably been under greater stress. Dr. Frisen's
paper was published first, so the Rockefeller group came from behind. "It
has been a very hard four months for us," Dr. Alvarez-Buylla said. "I
guess the reviewers thought his data were more convincing than ours and
that's why we had to do these extra experiments.".
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The contradictory findings of two scientists may yet be reconcilable,
experts say.
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Dr. Alvarez-Buylla had been studying the regenerative capacity of neurons
in the mouse's olfactory bulb, the part of the brain that registers smell.
Under the microscope he noticed trains of new neurons traveling into the
bulb from the layer behind the ventricle lining. It was his interest in
finding their source that led him to the astrocytes. He and Dr. Frisen
agree on the surprising fact that the stem cells are hiding out as
differentiated cells. Both the liner cells and the astrocytes are mere
support cells, a class known as glial cells and dull cousins of the
neurons.
"It was a battle against two fronts, against the dogma that glial cells are
far removed from working as a progenitor, and also against the other
group," Dr. Alvarez-Buylla said. The most compelling of Dr. Frisen's
tests was that he could isolate a single liner cell and show that it could
be made to develop into the three main lineages of brain cells, as would be
expected of a stem cell. Although Dr. Alvarez-Buylla could not make the
liner cells divide at all, he kept them under test for only two weeks,
whereas Dr. Frisen's recipe called for six weeks, said Dr. Ben A. Barres of
the Stanford University School of Medicine. Dr. Derek van der Kooy of the
University of Toronto said neural stem cells originate not in the liner
cell layer but in the layer behind it, as Dr. Alvarez-Buylla asserts. But
he is not persuaded that the astrocytes are the neural stem cells. "I am
leaning toward Alvarez-Buylla's story but I'm not convinced of his either,"
he said. Dr. van der Kooy's results were published last month in the
Journal of Neuroscience. Does it matter who is right? Yes, because
figuring out the precise lineage of the brain's various cell types is
essential to learning how it is constructed and how to heal it, said Dr.
Evan Y. Snyder of the Harvard Medical School. "This is not an arcane battle
between neurobiologists fighting over definitions but will reflect on how
we can harness this to the repair of the brain," Dr. Snyder said.
But figuring out the tree of brain cell lineages may require tools that are
not yet in hand. Biologists like to identify cells through unique proteins
on their surfaces, known as markers. But no markers unique to neural stem
cells have been found. So neither Dr. Frisen's nor Dr. Alvarez-Buylla's
work is decisive, said Dr. Fred Gage of the Salk Institute in La Jolla,
Calif. "They are both good experiments but they are both, by the absence of
definable markers, inconclusive," he said. Even the assumption that the
brain has a single kind of originating stem cell, as does the blood-forming
system of the bone marrow, may be incorrect. Maybe primitive cells from
different tissues combine to form the brain, meaning that it is generated
from more than one kind of stem cell. And a difficulty with tracing cell
lineages is that for every cell a more primitive ancestor can be found
until one reaches the egg cell.
"So while it's an important exercise in understanding the origins of cells,
the answer may not be as definite as the question implies," Dr. Gage said.
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