Peter Reddien had a tough decision to make. In 2002, he was on the verge of completing his Ph.D. at the Massachusetts Institute of Technology (MIT), where he had studied programmed cell death in the roundworm Caenorhabditis elegans with HHMI investigator H. Robert Horvitz. Should he stay in the well-established field of C. elegans research or go in a new direction—investigating the biologically complex but little-studied process of regeneration? "You only have to see a salamander regrowing its arm or a planarian regrowing its head to get excited about the problem," he says.
Reddien was intrigued by the prospect of working with planarians—flatworms about the size of a match head that are masters of regeneration. In the library, he discovered "a large body of old, classic literature on planarians" and "some new literature that suggested a lot of potential." If a part of a planarian's body is severed, it can grow a new part quickly, and an entire flatworm can regenerate itself from a fragment 1/300th its original size. The molecular biology of regeneration was almost completely unknown, and "it is one of the grand problems of biology that easily captures the imagination," says Reddien.
Ultimately, he chose a fellowship with Alejandro Sánchez Alvarado, an HHMI investigator at the University of Utah who had begun studying regeneration in planarians a few years earlier at the Carnegie Institution's Department of Embryology in Baltimore. There, Sánchez Alvarado learned about the technique known as RNA interference, or RNAi—developed by Carnegie researcher Andrew Fire and HHMI investigator Craig Mello—in which small RNA molecules are introduced into cells to suppress the activity of specific genes. For his postdoctoral project, Reddien used RNAi to turn off hundreds of genes in planarians one by one, identifying for the first time many of the genes involved in regeneration. So far, he has analyzed approximately 1,500 planarian genes and found similar human genes for well more than half of those required for normal regeneration.
Along the way, Reddien had to overcome some problems with using RNAi in planarians. For example, planarian researchers had been mixing bacteria-producing RNA designed to turn off genes with pureed liver and feeding it to their organisms, but the planarians were not enthusiastic about consuming their food. One day Reddien turned off the light in the laboratory while he went out for a bite to eat. "When I turned on the light and started the feeding, it worked very well," he says. Since then—although scientists don't know why the technique is effective—planarian researchers have kept their organisms in the dark until they are ready to eat.
Since returning to MIT as a faculty member, Reddien has been investigating in greater depth some of the critical genes involved in planarian regeneration. For example, his laboratory uncovered a mechanism that answers a classic problem posed by geneticist Thomas Hunt Morgan more than a century ago: How does a planarian know which end of its body to grow back when the head or tail is cut off? Reddien's laboratory discovered that a specific gene is required for a correct decision. Inactivating this gene caused animals to regenerate a head instead of a tail at the wound site, resulting in a worm with two oppositely facing heads. The gene was the first one found to be required for "regeneration polarity"—a process that may be a crucial factor in tissue regeneration in other organisms.
Reddien believes that planarians are poised to become a powerful new model system to investigate basic biological processes. Several years ago, he and several colleagues convinced the National Institutes of Health to fund the sequencing of the planarian genome, which has greatly accelerated research with the organisms. "Soon we should know many of the critical factors that are involved in the key steps of regeneration," he says. "Then we can ask what similar factors do in other organisms, including mammals."
Deciding to work on planarians was "definitely a risk," says Reddien. "But that was part of the excitement. I had a gut feeling that it would work out. And even if it had failed, I wouldn't have been happy if I hadn't tried."