"These are from Justin," says Ruth McCarrick-Walmsley, as she slides a dish of cells under a microscope. The view through the eyepiece includes an array of silvery cells, fanned out in curved lines, looking like a school of fish. These bone progenitor cells, derived from an eight-year-old's baby teeth, represent a major advance in finding a cure for a rare, devastating disease that has stymied research for years.
Fibrodysplasia ossificans progressiva, or FOP, is the only disease known to turn one differentiated tissue into another. "It truly is a metamorphosis," says Fred Kaplan, an orthopedics professor at the University of Pennsylvania—the muscles, ligaments and tendons gradually become bone, locking people in deformed poses.
In Kaplan's office, photographs of people with FOP cover his shelves and walls. "These are pictures of patients of mine," Kaplan says with pride, "they're really my children from all over the world." Kaplan has personally seen all 700 people in the world who have been diagnosed with FOP. He also discovered the aberrant gene that causes FOP, and recently he and his collaborators became the first to figure out how to obtain tissue samples from patients without exacerbating their condition.
The difficulty in researching FOP is that any injury to an affected patient, such as a biopsy or removing extra bone, actually causes the disease to flare up and spark "explosive" bone growth within soft tissues. "We had been using cells from the blood of patients," which can be safely harvested, says Eileen Shore, Kaplan's Penn colleague. "But we were unable to differentiate [the blood cells] to look at those cells in the process of becoming bone cells," which would give Shore some insight into why cells from FOP patients differentiate when they shouldn't.
But other scientists had found a way to harvest connective tissue progenitors, capable of generating bone, from dental pulp (PNAS, 100:5807–12, 2003), and Shore seized on the idea. All she needed was the baby teeth, which possess more highly proliferative progenitors compared to adult teeth, from people with FOP.
"As a mom, I never pictured doing that with my children's baby teeth," says Wendy Henke from her home in Middletown, Del. Her son Justin was diagnosed with FOP in 2007, and the Henkes were immediately interested in helping with Kaplan and Shore's research. Now whenever Justin or his siblings, who do not have FOP, lose a baby tooth, they call up McCarrick-Walmsley, Shore's lab manager—and the actual tooth ferry. "Yes," McCarrick-Walmsley says, "sometimes you'll see me flying down I-95" to transfer the teeth from Delaware to the lab. McCarrick-Walmsley has been able to get more than 30 passages out of the cells, and differentiate them into bone cells. (Teeth from the other Henke children serve as controls.) "I think it was a brilliant move to obtain tissue," says Paul Yu at Massachusetts General Hospital, who has collaborated with Kaplan on other projects.
In Kaplan and Shore's first study using these progenitors, they found that cells derived from people with FOP differentiated faster than normal cells (J Bone Miner Res, 23:305–13, 2008). Shore says the findings are consistent with their interpretation of the disease-causing mutation, in the gene for activin receptor IA. The receptor is part of the bone morphogenetic pathway, and Shore says the mutation keeps the pathway primed for bone growth, when it normally should be turned off completely. When a trigger happens—like a bruise or muscle strain—the pathway is instantly powered up to generate bone in places it shouldn't.
Having these cells at their disposal means the team can start testing potential drugs. Several months ago, Yu and his colleagues used an FOP mouse model—derived from a genetic mutation different from that in humans—to show that inhibiting the bone morphogenetic pathway slowed the out-of-control bone growth (Nature Med, 14:1363–9, 2008). Kaplan is confident that he will be able to find a treatment for FOP with drugs "that will be able to block this renegade process and turn what is a nightmare condition into hopefully what is someday nothing more than an inconvenience."