Stem Cells Show Power To Predict Disease, Drug Toxicity, Maybe Autism
By Terry Devitt. http://www.news.
For the first time, scientists have used human embryonic stem
cells to
predict the toxic effects of drugs and provide chemical clues to
diagnosing
disease.
Writing this week in the journal Stem Cells and Development, a
team
led by UW-Madison biologist Gabriela Cezar reports the use of
all-purpose
stem cells to elicit and identify the telltale chemical signals
secreted by
the cells when exposed to a drug known to cause autism.
The work is important because it is a critical first step toward
fulfilling the promise of embryonic stem cells not only to screen drugs
for
safety but one day, possibly, to use the cells themselves as crucibles
for
making new drugs. What's more, the work shows that stem cells have an
immediate clinical application as they generate chemicals, biomarkers,
that
can be used to predict the onset of disease, much like cholesterol or
sugar
in the blood can be used to forecast heart disease or diabetes.
"We're measuring active metabolites produced by the cells in
response
to an insult," explains Cezar, a UW-Madison professor of animal
science.
"These are de facto signatures of what is happening in response to a
drug or
a disease state."
In the new study, Cezar and her colleagues measured the response
of
undifferentiated stem cells as well as precursor neural cells to the
drug
valproate, which is known to cause autism in the offspring of a small
percentage of users. The drug is used to treat epilepsy, bipolar
disease and
migraine headaches.
Cells exposed to the drug, according to the new study, secreted
more
of the small-molecule chemicals involved in development and in brain
cell
signaling than unexposed cells.
"Some of the chemicals we detected are critical for formation of
the
brain," Cezar explains. "It seems the drug may induce excess chemicals
that
alter neural development.
An increase in glutamate metabolism in cells exposed to
valproate, for
example, may be a critical clue to understanding what goes wrong in
development to cause autism: "Excess glutamate kills neurons," says
Cezar.
"If you have higher levels during the formation of the brain, you may
have
fewer neurons of different types. In autism, there are areas of the
brain
where you have fewer neurons" than would occur under ordinary
circumstances.
"Autism is a condition that begins during pregnancy," notes
Cezar. "In
this study, we asked what could valproate tell us about autism given
its
known involvement in a small percentage of cases? How does it make
brain
development different?"
Cells of all kinds use so-called small-molecule chemicals as a
way to
communicate with other cells. Precise communication between cells is
essential for normal development and the health of an organism. Such
chemicals can be detected in blood, suggesting it may be possible to
devise
simple tests that can provide disease diagnosis before birth or shortly
after.
"These are small molecules that are indicators of susceptibility
to
disease," says Cezar.
The work by Cezar and her colleagues, including noted central
nervous
system expert Fred Gage of the Salk Institute, opens a raft of
possibilities
for early disease diagnosis of developmental disorders. In short, the
ability to tune in to the chemical chatter of stem cells may become a
promising new window to helping scientists figure out, at the most
fundamental level, what goes wrong to cause things such as birth
defects and
miscarriage.
In addition, the work shows how human embryonic stem cells and
early
precursor cells can be used to screen drugs for potentially harmful
effects.
Drug discovery and testing had been predicted to be one of the first
technologies to emerge from embryonic stem cells.
In terms of drug discovery and screening, human cells offer an
alternative to animal testing that may be more accurate and could help
ferret out safety issues that animal models fail to identify.
The new study was supported in part by grants from the Draper
Technology Innovation Fund and the UW-Madison Graduate School.
In addition to Cezar and Gage, authors of the new study include
Jessica A. Quam, Alan M. Smith, Guilherme J.M. Rosa, and James F.
Brown, all
of UW-Madison; Marian S. Piekarczyk of the WiCell Research Institute;
and
Alysson R. Muotri of the Salk Institute.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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