Harry Eastlack looked like any other baby when he was born in Philadelphia in 1933, save for an inward-turned big toe, but at age ten, he developed a swelling and stiffness in his neck and back. The group of Philadelphia doctors that treated Harry would soon discover that the soft tissues of his body including muscles and cartilage were slowly, painfully transforming into bone, twisting and fusing the young man’s body until his death at age 40. His plight is known as fibrodysplasia ossificans progressiva (FOP), and it’s caused by an autosomal dominant mutation, usually arising de novo in 2 out of every million people. In the last talk at the 2008 Society for Developmental Biology meeting in Philadelphia, Eileen Shore from the University of Pennsylvania School of Medicine talked about her work from bedside to bench with children with FOP.
After a long search over many years for a handful of families who have passed on the trait across generations, she and a group of researchers were able to link the disease to a single base substitution in a gene for a bone morphogenetic protein type I receptor called ACVR1 in 2006. In the years since, Shore and a group of collaborators has worked to define how this tiny mutation could cause such a devastating disease. In cell culture, in zebrafish, and biochemically, a picture began to emerge of a pathway that is not completely turned on but is very sensitive to a ligand. Recently Shore and colleagues have had success in engineering a mouse with the mutant gene knocked in. Though they haven’t finished developing the line, chimeras containing both the mutant gene cells and normal mouse cells have a similar inward turned big toe on their feet and are beginning to show signs of bone formation in soft tissues. Hopefully, using these chimeras, her group will be able to breed a pure line of mice with the disorder in which drugs to treat the disease can be screened and tested.
It was a stirring story and a great preparatory talk leading up to the meeting’s closing celebration at Philadelphia’s hallowed Mutter Museum at the College of Physicians of Philadelphia. Harry Eastlack decided at age 20 that he would donate his skeleton to advance research on the disease that plagued his life, and it is a centrepiece to the Mutter’s amazing exhibits. See pictures here. They’re a chilling reminder of what can happen when development goes awry.