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Alejandro Sanchez Alvarado

A discovery by scientists at the Howard Hughes Medical Institute, University of Utah, just might lead to one of the most astounding advances in medicine: regeneration of limbs or organs.

The find, by the team of Alejandro Sanchez Alvarado, Kyle A. Gurley and Jochen C. Rink, was published earlier this month by Science Express, an online site maintained by the American Association for the Advancement of Science. Articles in Science Express have been selected for later printing in the journal Science.

Sanchez Alvarado is a professor in the Department of Neurobiology and Anatomy, while Gurley and Rink are postdoctoral fellows in Sanchez Alvarado's lab. This work took place over about the past year, Alvarado said.

The article, "Beta-Catenin Defines Head Versus Tail Identity During Planarian Regeneration and Homeostasis," involves research with freshwater planarians, or flatworms. These swimming, carnivorous little worms are able to regenerate missing parts. If a head is sliced from one, it grows a new head, eyes, brain and all; if a predator bites off the tail, it will regrow a tail.

Flatworms aren't rare. According to an ecology report written by Bridgette Jenne and placed on the Internet by Westminster College in Salt Lake City, "These small, free-living flatworms are found under rocks in the fresh water of Emigration Creek where it crosses the campus of Westminster College. ... We have identified the Emigration Creek species as Dugesia tigrina, a common North American flatworm."

Somehow, after a head is amputated, the flatworm section that remains will know it's missing a head, "so it'll grow a head," Alvarado said. "Why doesn't it make a tail?"

He, Gurley and Rink used a process called RNA interference to eliminate "specific messenger RNA molecules before they can get a chance to make the protein they encode," he said. One gene they aimed at is called Beta Catenin, which is important both to biology and disease. If it does not work correctly in humans, it causes cells to proliferate wildly, sometimes resulting in colon cancer.

But the same gene is needed to replace cells that die regularly, such as skin and blood cells, he said.

Although flatworm and human ancestors may have diverged onto separate evolutionary trees 400 million years ago, they share this genetic system. "Whether it's in a worm or a human," Sanchez Alvarado said, "the molecular functions are preserved."

B-Catenin works with another gene called Adenomatous polyposis coli (APC), which helps to control tumors in humans, especially in the colon, he said.

"Both of them appear to be essential for letting the amputated tissue know what to regenerate" in flatworms, he said.

If flatworms with suppressed B-Catenin are sliced somewhere on its body, "heads will grow ... no matter where you cut." Whatever parts are cut off, "essentially you get heads to grow."

"Ordinarily, the APC gene helps to control the levels of B-Catenin protein to regulate its action," he said. But if the APC is eliminated, B-Catenin protein accumulates in the animal. "So now there's an excess of Beta-Catenin," he said. When flatworms missing the APC gene are cut, "we get tails."

APC and B-Catenin work together in "sort of a seesaw type of relationship."

Even so, how does the flatworm know whether to produce a head or a tail? The team believes molecules outside the cell may initiate the process.

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These molecules occur in different levels throughout the body of the flatworm, Sanchez Alvarado thinks. They may form "a functional gradient from the very tip of the head to the very tip of the tail of the animal." The level of this material that interacts with the cell may be a signal telling where on the body the amputation happened, and therefore, what to regrow.

A step toward prompting regeneration in other forms of life may be to look at how these processes interact in animals unable to regenerate.

Knowing where to check, he said, "now we can look ever more closely than we could before."

Will the discovery be useful in regenerating human tissue? Sanchez Alvarado replied, "Although much more research is needed to definitely answer this question, our findings are likely to increase our understanding about regeneration events in animals, including humans."


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