In the mid-1980s, physician Fred Kaplan met a little girl with fibrodysplasia ossificans progressiva (FOP). Watching the disease progress in the girl “was like watching a molecular terrorist attack her body,” he says. In this and other FOP patients, soft tissues and muscles metamorphize into bone, essentially forming a second skeleton and rendering movement impossible.
Few people were working on FOP when Kaplan met this patient, but he felt compelled to give the disease his full attention. In 1991, Kaplan, the Isaac and Rose Nassau professor of orthopaedic molecular medicine in orthopaedic surgery, partnered with geneticist Eileen Shore, now a research associate professor of orthopaedic surgery, and set up a lab to study FOP.
It has been a tremendously fruitful partnership. After 15 years of research and numerous donations from families of children with FOP and friends (including Diana Weiss, who endowed Kaplan’s professorship after being inspired by stories of children with FOP), they discovered the gene that causes the disease in August 2005.
It was an incredible moment for the researchers. “It’s like the Everest of skeletal biology,” says Kaplan. “You can see a clear horizon in many different directions towards an understanding of how the body creates its skeleton and knows when to stop.”
Q. What is the current treatment for FOP?
FK: It’s just a matter of making the children more comfortable, perhaps slowing down the severe inflammation that occurs. It doesn’t alter the natural history of the disease in any substantial way. We’re caught between these two eras. We have symptomatic treatments that are really in the Middle Ages, compared to the vision and the potential of what this new discovery can make possible. Someday we will hopefully be able to truly strike at the roots of this disease with treatments that are based upon our discovery rather than hacking at the branches.
You look back at the past history of FOP and the papers that had been written over the last 300 years from the time the condition was first described … people had tried so many different remedies for FOP. They were almost all embraced with great enthusiasm and later shown to be almost completely useless. I think it dawned on us that here we had this horrendous disease, no one was working on it, and you just couldn’t guess at what the answer to this was going to be. It was extremely obvious to all of us if we were going to make any progress, we needed to know the cause of this disease at the cellular, genetic level.
ES: It was clear that there was a single gene that was changed in these people. They’ve lost a normal control that prevents cells from forming bone where we don’t normally have it and don’t want to have it.
Q. I’ve heard it described as a light switch that can’t be turned off.
FK: We’re trying to understand what kind of switch it is and how it’s working and in what cells and in what context it’s working, whether it can’t be turned off or has several settings or whether it’s always on or whether there are conditions that turn it on and make it more difficult to turn off. Those are questions we haven’t solved yet.
There are features of the condition that are still baffling to us. We know the gene, and we know the damage that’s caused in the gene but we don’t understand why the children are not constantly forming bone. The formation of bone is episodic. It seems to be associated with injury. Injuries are associated with inflammation. What is the relationship between inflammation and regeneration? Is there an inflammatory trigger to bone formation in these children that might exist in normal individuals, but it’s controlled or tempered? That could give us a very important handle on how to make bone. What is the relationship between this gene and stem cells? What is the relationship between inflammation and stem cells? The skeleton is the only organ that when it’s severely damaged, can repair itself completely without scar. Almost all of the steps that [bone] goes through in healing are very similar to the initial formation of the skeleton, with one exception—you don’t have inflammation when you form [your skeleton] in the womb. When you regenerate it after birth, there’s inflammation. That’s what we’re seeing here with FOP as well.
Q. Since FOP is so rare, was it difficult to find families to study?
FK: [It took] close to 15 years to set up the infrastructure with tremendous help from families and donors and people around the world.
There were lots of people who would see these patients, but sometimes they weren’t appropriately diagnosed. Misdiagnosis of this condition is profound. There is about a 90 percent misdiagnosis rate. Many of the children have unnecessary procedures that either don’t help them or cause harm and some as a result have suffered amputations. Some kids have been given chemotherapy that damages their organs. The education of doctors about how to recognize FOP, how to diagnose it appropriately and send them to us was no small task and without that, it would have taken even longer to find the gene.
Q. When was it clear what you had discovered?
FK: By the time we presented it to the families, we had already done the work to make absolutely sure that this was the gene. When they saw it, it came to them as a revelation. To us, it was, is it? Maybe? No it can’t be! Well, maybe it could be.
ES: When we first saw it in a few patients, we didn’t know. As you start building up a case, you start seeing the same change in essentially all the patients. We looked at over 150 people without the disease and we never saw the change. The change occurs in a portion of the gene that gives information about what the protein sequence is going to be.
Q. Is designing a drug the next step?
FK: The immediate next steps are designing the tools that we need to determine the exact function and consequences of the mutation and understanding how this genetic linkage affects cells, tissues and organs in animals. Eileen has been working really hard to develop [a mouse] model, where it is genetically identical to the mutation that’s caused in FOP.
ES: They basically will be, in genetic terms, like an FOP patient. That will be terrific to understand the biological consequences of the mutation. We’ll be able to look through early embryonic development, skeletal formation, early stages before birth.
FK: Eileen and I have talked to Mary Mullins [in the Department of Cell and Developmental Biology] about making FOP zebrafish.
ES: They’re little fish with a skeleton and they grow much faster than mice. The overall goal certainly is treatment and to develop a way to correct or compensate or alter the function of the mutant receptors.
Q. How have the families reacted to this news?
FK: A year-and-a-half ago, if a genie appeared and said you can have one wish … this is what we’d wish for—to understand the genetic cause of this condition. … It is truly our superhighway to the hope of a treatment.
ES: We know what we’re fighting now.
FK: We know what the enemy looks like. Hope is a powerful medicine. You can just read that on their faces. They know there will be episodes of FOP between now and the time we have an effective treatment and some know maybe the treatment won’t be in time for them, but I think it has a therapeutic effect to know that someday there will be treatments that will be able to stop this and give hope to another generation of children.
Originally published on October 5, 2006.
Originally published on October 5, 2006