In 1578, a British mathematician proposed an incredible boat called a submarine. Science fiction writer Jules Verne fantasized in 1865 that humans would fly to the moon. More recently, news reports have celebrated the idea that, with the application of some scientific knowledge, lost human limbs might grow back. Will this sensational idea, like others before it, come true? Even regeneration enthusiasts hesitate. "It's reasonable to think about regenerating specific cell types, like neurons," says HHMI investigator Alejandro Sánchez Alvarado, a molecular biologist at the University of Utah. "But something as complex as a hand? Before we even embark on that in humans, we need to do so much more." Sánchez Alvarado has spent the past decade studying an invertebrate model of animal regeneration: a freshwater flatworm called Schmidtea mediterranea, or planaria. This flatworm can fully regenerate from a fragment as tiny as 1/279th of the original organism. Sánchez Alvarado and his colleagues have begun to unveil the flatworm's regenerative machinery in detail, using RNA interference—a technique that systematically silences targeted genes to determine their function. In 2005, his lab conducted the first large-scale gene inhibition study of planaria, as reported in Developmental Cell. Of 1,065 genes screened, the team identified 240 associated with specific developmental processes or defects. In particular, they identified cells that potentially regulate stem cells, regeneration, and homeostasis—a cell's dynamic equilibrium. Building on that work, the lab is now deconstructing seven major signaling pathways in planaria, all known to govern cell signals. "How do progenitor cells work?" asks Sánchez Alvarado. "When are they on and off? Which cells activate them—and in turn, what types of cells do progenitors activate?" The advantage of the fast-growing flatworm, he says, is that experiments to address these questions can be performed more quickly than in vertebrate models such as the zebrafish. "Regeneration is more than just early development played out again in maturity," Sánchez Alvarado adds. "The same basic protein players are at work, but their regulation is different. And that's what makes it fascinating." —K.B.

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