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These questions will occupy the three labs (and any others that crop up from their descendants) for the next decade. Newmark’s group has set out to understand how neoblasts become other kinds of cells, particularly germline cells. Planarians can resorb their whole reproductive tract in times of starvation and then regrow ovaries, testes, sperm, and eggs when food is plentiful again. They also regenerate germ cells after amputation.
His lab group has identified genes that block germ cell differentiation and a subset of these genes are specific to flatworms. Newmark jumped on that subset, because it opens up an opportunity to understand a neglected tropical disease.
Schistosomiasis affects 200 million people worldwide who come in contact with waters infested by a close planarian relative, the schistosome. The female worms lay eggs in an infected human, causing inflammatory reactions that can damage the liver and intestines and cause malnutrition and learning difficulties in children. Newmark’s findings could lead to a way to disrupt egg production in schistosomes.
“It’s fascinating biology and we’re in a good position to contribute to understanding a very important disease that’s not getting much attention,” he says.
Reddien’s group continues to pursue genes he identified in the RNAi screen that gave some of the most interesting regeneration defects. In a follow-up screen, he and his postdoctoral fellow Chris Petersen discovered the most eye-catching worm to date.
“Chris came across the two-headed phenotype. When I looked through the microscope I just about fell out of my chair. We knew we had something very important,” says Reddien.
Morgan had observed the two-headed worm, which plays a perpetual game of tug-of-war with itself, a century earlier. But Petersen and Reddien were in a better position; they knew which silenced gene had caused the oddity. It was beta-catenin, a key molecule in the Wnt signaling pathway that controls body plan polarity in many animals during embryonic development. Beta-catenin transmits the Wnt signal into the cell’s nucleus, where it directs changes to a set of other genes’ expression levels.
The two showed that, normally, beta-catenin turns on genes that suppress head formation and promote tail formation. However, when beta-catenin is absent, the default is to produce a head at any wound site, according to their 2008 Science paper. At the same time and also published in Science in 2008, Sánchez Alvarado’s group created an animal with boosted levels of beta-catenin; when its head was amputated, a tail grew back instead.
“This is the type of science you dream about as a kid. We are studying processes that are dramatic and broadly important,” says Reddien. He says this study captivates him because it hammers home the idea that choices are being made at the sites of wounds. He wants to uncover how those decisions happen.
“We could not ask these questions in Drosophila or C. elegans. Planarians’ biology is very different and they enable a whole suite of questions that couldn’t be addressed in existing model systems that do not regenerate robustly,” notes Reddien.
Brenton Graveley, one of a handful of scientists starting to use planarians in biomedical research, gives Sánchez Alvarado, Newmark, and Reddien all the credit. “The three of them brought planarians into the molecular era,” says Graveley, a molecular biologist at University of Connecticut Health Center in Farmington.
The early genome work by Sánchez Alvarado and Newmark that showed planarian genes were closely related to human genes “propelled planarians to the forefront,” he adds. “If you are not going to work on human or mouse cells, then the leap in translating what you find in planarians to actual human stem cell function is going to be much shorter,” he notes.
Sánchez Alvarado speaks fondly of his quirky, but potentially powerful, pet organism: “What model system isn’t funky? C. elegans has such a defined cell lineage, it’s uncanny. Morgan chose Drosophila because they were such prodigious egg layers. All model organisms got chosen because they exaggerate a particular biology.”
Sánchez Alvarado remembers the flight home after the fountain-foraging expedition in Barcelona. He and Newmark camouflaged the cooler of live worms with cardboard and duct tape. “It looked so suspicious, but they let us through.”
The journey into planarian self-renewal has been both adventurous and arduous. “It was hard,” he admits. “But when you look at the animal, and the wild type is already unbelievable—I mean, the guillotine would not work on this guy—I thought, ‘If we can actually go in and perturb these things, how amazing it would be.’”