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Stem cell:
A cell that can change into other types.
Embryonic stem (ES)
cell:
Cell from embryo, can become any cell
type.
Adult stem cell: Stem cell from mature animal, often from
bone marrow.
Differentiation: Process
of becoming more specialized.
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We didn't have a 2,000 lb pen (a TV camera),
so James Thomson granted us an interview to talk about where embryonic
stem (ES) cells have come since 1998, when he published his recipe
for growing them in a lab dish.
When we asked him about the most significant advances, he did not
talk directly about curing Parkinson's' disease or making Christopher
Reeve walk, but about incremental advances that may eventually allow
such breakthroughs.
James Thomson was the first to grow colonies
of ES cells. These do-it-all cells could be a boon to biology and
medicine alike. Photo by Jeff Miller,
© University
of Wisconsin.
The
first decision : Last year, Ren-He Xu of the WiCell Research Institute learned to persuade
ES cells to differentiate into trophoblasts -- the outer layer of
the embryo, which forms the outer layer of the placenta (see "BMP4
Initiates ..." in the bibliography). "It's
the earliest differentiation decision that an embryo makes, less
than a week after fertilization," Thomson says. Trophoblasts don't
appear in mouse ES cells, and were "a lineage that nobody had access
to in the human. They were a black spot." Understanding the first
differentiation would be a giant step toward understanding the entire
process of human development, he stresses. "This really gives a
brand-new model to study events" related to the implantation of
an embryo in the uterine wall. Thomson and colleagues are trying
to identify the genes that trigger the conversion to trophoblast.
Controlling genes: Researchers now have three
ways to manipulate ES cell genes. Their first technique -- chemical
transfection -- was a bit scatter-shot, only working on one cell
in 10,000. Within the last year, researchers have learned to use
a chunk of HIV's genes to genetically alter up to 90 percent of
a colony's cells (see "Stable Genetic Modification..." in the bibliography).
Another recent advance, laboring under the monstrous moniker "homologous
recombination," can change the same gene in every cell (see "Homologous
Recombination..." in the bibliography).
That allows biologists to inactivate a single gene to examine its
role. "It's a pretty big technical achievement," Thomson says, "but
it will not change anyone's world view."
Neurons appear in an embryonic stem cell culture
22 days after treatment with retinoic acid. The red color shows
antibodies to a neurotransmitter, found only on neurons. Other cell
types don't light up because they don't grab antibodies.
Photo: Courtesy Dr. Jim Huettner, Department of Cell Biology and Physiology,
Washington University in St. Louis.
Controlling fate. Researchers have also learned a bit about controlling the transformation of ES cells into specialized cells of the brain, blood vessels, heart, pancreas, liver and placenta -- a key step in transplantation therapy. Still, the crucial area of differentiation remains primitive, Thomson says. "In reality, it's not a whole lot more basic knowledge beyond what we knew from mouse ES cells. But it's nice to know that these multiple lineages are also possible in human cells." As they differentiate, stem cells respond to a chemical language consisting of growth factors released during development. Controlling this language, by growing stem cells in specific biological solutions or alongside specific cells, has been a focus of stem-cell research. But Thomson is intrigued by a different approach. "I want to look at genetic control, how the genes change as the cell goes down various pathways."
 Click
for a video of a spontaneously beating heart muscle grown from
human embryonic stem cells (2.6 MB). ©University of Wisconsin-Madison
Testing, testing : Now that they can direct ES cells to become specific cells, researchers are starting to find practical uses for those specialized cells. Human heart cells, for example, do not grow in culture, and animal hearts don't represent human hearts accurately. Consider "repolarization" -- the time that heart muscle cells need to electrically reset themselves between contractions. Sluggish repolarization can damage heart rhythm and cause heart attack. This is not a theoretical matter in the drug biz; repolarization problems have forced some drugs off the market. Now, several research groups are using heart muscle cells - derived from embryonic stem cells -- to test the effect of drugs on polarization.
Identity crisis? Perhaps the ultimate
question about embryonic stem cells still remains open: Why are
ES cells different from all other cells? "We are trying to understand
what is special in the cells," says Thomson. "It's remarkable how
little we know about pluripotency [the ability to become any other
type of cell]. If you really understand the pluripotent state, you
should be able to transition in and out of that state."
What do we know about adult stem cells, and why is everybody arguing over them?
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