Developmental Biology, Genetics
Whitehead Institute for Biomedical Research
Dr. Reddien is also associate professor and associate department head of biology at the Massachusetts Institute of Technology and member of the Whitehead Institute for Biomedical Research. He was an HHMI early career scientist from 2009 to 2014.
Genetic Control of Regeneration
All organisms have some ability to repair wounds, but only a handful can replace whole body parts. Peter Reddien became fascinated with this great mystery of biology, known as regeneration, as a graduate student at the Massachusetts Institute of Technology (MIT). "Animals regrowing limbs, regrowing parts of their heart, lower jaws, new heads—these phenomena are so amazing," Reddien says. "One can't help but get excited."
Before Reddien could begin to explore this mysterious phenomenon, however, he needed to find an organism to study. At the time, he was studying programmed cell death in the worm Caenorhabditis elegans, a well-established model organism. But these worms don't regenerate. Scientists interested in regeneration often study hydra or salamanders, but Reddien settled on a tiny cross-eyed flatworm called planaria. Alejandro Sánchez Alvarado, an HHMI investigator at the University of Utah, had established his lab with planarians, and he'd recently shown that he could use small strands of RNA to suppress the activity of genes in these worms, a technique called RNA interference, or RNAi. "The ability of RNAi to perturb genes in planarians was a huge step forward that I thought would make this system the one for me," Reddien says.
Planarians, often found in streams or high school biology classrooms, have wowed scientists with their regenerative powers for more than a century. In the late 1800s, American biologist Thomas Hunt Morgan found that even a tiny sliver of tissue—1/279th of the original flatworm—could give rise to a whole new animal. "It's a classic model system," Reddien says, but modern molecular biologists have largely ignored planarians. For example, when Reddien chose to work with the organism, he couldn't find a single report of a genetic defect in planaria linked to regeneration. "This is the bread and butter of geneticists for studying a biological phenomenon," he says. By inhibiting genes in an organism and assessing what goes wrong, researchers can gain insight into how genes function normally.
In 2002, Reddien joined Sánchez Alvarado's laboratory as a postdoctoral fellow. "Alejandro was already working with planarians when I joined, but it was the very early stages of gene-function studies," Reddien says. He used RNAi to turn off more than a thousand of the more than 20,000 genes in the planarian genome one by one. "I couldn't wait to come in every morning," Reddien says. "No one had seen defects in regeneration like these caused by inhibiting genes. We were seeing the first ones, and we didn't know what we would see the next day." The team produced 240 distinct phenotypes, including worms with lesions and pigmented spots. Some of the phenotypes involved animals that could only swim sideways. Others couldn't move at all. Others could not regenerate. These myriad phenotypes helped Reddien and Sánchez Alvarado pinpoint key genes involved in regeneration.
In 2005, Reddien started his own lab at MIT, where he became an HHMI early career scientist in 2009. His goal is to decode the instructions that guide regeneration in planarians and determine how those instructions are executed. He has already made impressive headway. Reddien's group found that planarians are equipped with stem cells, called cNeoblasts, able to become any type of cell in the worm's body and that these cells give rise to new tissue during regeneration. Just one of these stem cells is enough to regenerate an entire worm. His lab has also discovered how wounded planarians manage to regrow body parts in the right places. When a planarian suffers any kind of injury, a signaling pathway called Wnt instructs the regenerating cells to grow a tail. When the worm needs a head, a gene called notum kicks in, dampening the Wnt pathway. Silencing notum or genes in the Wnt pathway generates worms with multiple heads or tails. Planarians possess many of the same genes that humans do. So understanding how these worms regrow missing tissue may help advance the field of regenerative medicine.
Reddien's path hasn't always been easy. He had to help figure out the best way to culture the planarians and feed them for RNAi experiments. He had to develop new tools and assays. But it's been the perfect path for him. "I like adventures in science. I like launching off into the unknown."