Flatworms yield insights into the
mystery of regeneration
CAMBRIDGE, Mass. (November 21, 2005) — If you
take a planarian flatworm and chop it in half, something
extraordinary happens: One section grows a new head,
the other a new tail, and soon you have two new flatworms.
Chop it into quarters, or eighths, and you'll notice
the same thing. For centuries scientists have puzzled
over this biological phenomenon, but only recently have
they understood that these creatures are a goldmine
for exploring how stem cells regenerate damaged tissue.
Now, scientists at Whitehead Institute for Biomedical
Research and University of Utah School of Medicine have
begun to understand the biological processes of how
the planarian flatworm achieves in itself what scientists
hope to one day accomplish in the clinic: complete regeneration
of damaged tissue.
"This paper is a starting point for investigating
the cellular basis of regeneration," says Whitehead
Associate Member Peter
Reddien, lead author on the paper that will appear
in the November 25 issue of the journal Science.
The human anatomy is no stranger to regeneration. If
you think about all the times you have cut and scraped
your hands, it's amazing how intact they are. Even more
dramatic is the human liver: Remove a chunk and it grows
back. Researchers hope to one day harness the power
of stem cells to regenerate, say, heart tissue, or pancreatic
tissue, or nerve tissue. But at the moment, regeneration
is still one of biology's greatest black boxes.
Enter the planarian flatworm.
One is hard pressed to find in nature a more dramatic
example of regeneration. You can even cut a planarian
slice as small as 1/279th of the animal and still have
it turn into a complete adult. And while the planarian
anatomy is much simpler than that of higher mammals,
they still have differentiated tissue such as skin,
intestine, musculature and brain. These organs are maintained
— and recreated — by planarian neoblasts,
a kind of stem cell that shares characteristics with
both adult and embryonic stem cells. Like adult stem
cells, neoblasts are located in adults with mature tissue.
But like embryonic stem cells, they may be capable of
turning into any kind of cell type in the body.
"Planarians have solved exactly what people want
to accomplish with regenerative medicine," says
Reddien, who is also an associate professor of biology
at MIT. "This has been worked out by evolution."
The question, of course, is how.
In May of 2005, Reddien and his then-colleagues at
University of Utah completed the first high-throughput
RNA interference screen of planarian genes, with results
published in the journal Developmental Cell.
The researchers painstakingly silenced 1,065 genes one
at a time with RNAi techniques, and found 204 genes
of interest that had corresponding genes in other species,
including humans.
One of these genes, called smedwi-2, stood out. When
smedwi-2 was disabled, the flatworm was suddenly unable
to regenerate at all, and its body curled into a stationary,
irregular position. (This set of defects was similar
to that of animals in other experiments in which all
the stem cells in the planarian were killed with irradiation.)
This raised an obvious question: Exactly how does smedwi-2
control the planarian's ability to regenerate?
"The question is significant," says Alejandro
Sanchez Alvarado, Professor of Neurobiology and Anatomy
at the University of Utah School of Medicine and senior
author on the paper. "Smedwi-2-like genes are found
throughout nature, from plants to humans. In fact, a
homolog of this gene is found in human blood stem cells."
As reported in Science, the team discovered that smedwi-2
does not regulate the stem cells themselves, but rather
it controls cells produced by stem cells.
When a stem cell divides in two, one of the daughter
cells is a stem cell, and the other is a cell whose
function can be to replace a specific type of cell.
When smedwi-2 is disabled, however, this second group
of cell types can't carry out its function. Smedwi-2
regulates regeneration through overseeing and enabling
the reparative activity of these cells. The precise
mechanism by which they do this is unclear. Still, this
paper marks the first instance in which a planarian
gene has been studied at this level of resolution.
"Planarians provide us with a new paradigm to
study the function of stem cells," says Sanchez
Alvarado, who is also a Howard Hughes Medical Institute
investigator. "The mechanisms that are found in
this animal are likely to be conserved in the regulation
of stem cells in higher organisms like us."
"This gives us some answers about how stem cells
are controlled in planarians, and it's starting to hit
at the basic science of stem cells," says Reddien.
"It also has a broader application for understanding
the biology of regeneration. We're still at the very
beginning of the basic science phase, but this is a
good start."
This research was funded by the National Institutes
of Health and by the Helen Hay Whitney Foundation.
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