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Flatworms yield insights into mystery of regeneration

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 see the same thing.

For centuries scientists have puzzled over this biological phenomenon, but only recently have they understood that these creatures are a gold mine for exploring how stem cells regenerate damaged tissue. Now, scientists at MIT, the Whitehead Institute for Biomedical Research and the University of Utah School of Medicine have begun to understand how the planarian flatworm achieves 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 MIT Associate Professor Peter Reddien of biology, lead author on a paper that appeared in the Nov. 25 issue of the journal Science. Reddien is also a Whitehead associate member.

The human anatomy is no stranger to regeneration. If you think about all the times you have cut or 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. 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 cut a planarian slice as small as 1/279th of the animal and it will still turn into a complete adult. And while the planarian anatomy is much simpler than that of higher mammals, the worms still have differentiated tissue such as skin, intestine, musculature and brain. These organs are maintained -- and re-created -- 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. "This has been worked out by evolution." The question, of course, is how.

In May 2005, Reddien and his then-colleagues at the 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 raised an obvious question: Exactly how does smedwi-2 control the planarian's ability to regenerate?

As reported in Science, the team discovered that smedwi-2 does not regulate the stem cells themselves, but 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 that can 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.

"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. An additional author of this work is from Harvard Medical School.

A version of this article appeared in MIT Tech Talk on December 14, 2005 (download PDF).

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