A genetic breakthrough for bodies turning to bone

Editor’s note: This story was originally published on April 24, 2006.

In Frederick Kaplan’s office at the Hospital of the University of Pennsylvania, not a folder or book is out of place. Photos of patients crowd the walls, but these, too, are orderly.

The tidiness makes the black T-shirt hanging from the window especially jarring. "Anarchy," it says, in blood-red letters.

The shirt was a gift from a Dutch teenager, the orthopedic surgeon said last week, pointing to a photo of a pretty blond girl. When he last saw her, she had worn one just like it. She talked through clenched teeth, not because of her anger - she was angry - but because a rare disease had turned her jaw joints into bone, locking her mouth nearly shut, stealing her ability to eat, kiss or cough normally.

That's the horror of fibrodysplasia ossificans progressiva. FOP cripples and immobilizes victims by turning their muscles, tendons and ligaments into bone. Any attempt to surgically remove the extra bone triggers explosive new growth.

"I told her I liked her shirt," Kaplan, 54, recalled. "She was surprised. She probably thinks I'm an old guy, a scientist with no sense of humor. "

After she mailed him the shirt, he made her a promise. "One day we will solve the anarchy of FOP," he wrote back.

Kaplan and his collaborators have just taken a huge leap toward that goal: They have pinpointed the genetic mutation that causes FOP, setting the stage to develop a drug treatment.

Their achievement, the culmination of 15 years of work, was published online yesterday in Nature Genetics.

They stressed that the significance goes far beyond the obscure, untreatable disorder. The FOP gene, called ACVR1, is crucial to the body's development, growth and repair. Understanding how it malfunctions in FOP - something they are now racing to do - could help treat head trauma, joint replacements, osteoporosis, fractures, bone malformations and more.

Still, it was the FOP families who were truly thrilled by the discovery. Out of the estimated 2,500 FOP patients worldwide, Kaplan's team personally knows almost 600.

"That it would be found in my lifetime is the most extraordinary gift I've ever received," said FOP patient Jeannie Peeper of Winter Springs, Fla., who at 47 has survived two years beyond the average FOP life span.

Kaplan, a gracious, erudite man with a fondness for inspirational quotes and instructive metaphors, said: "It was like climbing up a mountain. We had no idea how treacherous and difficult this would be. But we're finally at the summit. "

In 1991, Kaplan stood at the bottom of that mountain with Michael Zasloff, then a pediatrician and biochemist at Penn, and Eileen Shore, who had recently earned her doctorate there in cellular and molecular biology. Each was professionally - and emotionally - invested in finding the defect that, as Kaplan says, "turns a light bulb into an atom bomb. "

But the goal seemed almost quixotic.

Modern analytical techniques for linking genes to diseases require large populations and generations of families with the illness. Neither existed for FOP. Even though it was first described in medical literature nearly 300 years ago, there was not a single documented case of a parent and child with it. The disease made getting married and having children a near-impossibility.

The other modern gene-hunting approach - looking deep within the cell - would be impractical until the researchers had a better idea where to search among the human genome's six billion pairs of DNA.

And there was the problem of money. FOP wasn't exactly a hot area of government-funded research. Who would pay to equip and staff a lab?

The answer turned out to be the FOP families, a resourceful and courageous cadre led by Peeper.

In her early 20s, after earning a degree in social work, she faced life in a wheelchair because of hardening hips. She traveled in 1985 to the National Institutes of Health in Bethesda, Md., to consult the leading expert on FOP - Zasloff.

He had no medical fixes, but eventually shared with her the names of his far-flung FOPpatients - all 18 of them.

"I learned I wasn't alone," she said. "I thought there were no other FOP patients. "

In 1988, she used her Social Security checks to found what grew into the International FOPAssociation. It raises an average of $500,000 a year for research. It also identifies and unites FOPfamilies, primarily by enlightening doctors.

For Bob and Jennifer Snow of Santa Maria, Calif., the organization was "a lifeline" when their daughter Stephanie, now 15, was diagnosed after more than a year of wild guesses.

"The one and only thing doctors gave us was the International FOP's brochure," Jennifer Snow said.

The global network has helped spread what the Penn team has learned about how to treat FOP patients. Or more accurately, how not to treat them.

Although FOP can progress without warning, a flare-up often follows a minor trauma. A fall, a bruise, even an injection can trigger a painful, swollen nodule that turns to bone. Too often, doctors assume it is cancer, so they do biopsies - or worse.

The cover of the FOP association's first scientific symposium catalog in 1991 shows a self-portrait by a one-armed child. The artist, an 8-year-old American Indian, lost her right arm to an unnecessary amputation.

In 1992, Kaplan got a phone call from a former medical student who had set up a practice in Georgia.

"Fred," the young doctor said, "I have a father and his three children in my office, and I think they have that disease you're interested in. "

"What do their toes look like? " Kaplan asked excitedly.

The doctor went back to check. All four had malformed big toes. The classic sign of FOP, it is the only clue when otherwise healthy-looking babies are born.

"I'll be on the next plane," Kaplan said.

That first multigenerational FOP family was proof that the disorder was hereditary. The researchers would eventually get blood samples from four more such families.

The scientists would also come to recognize that, while the bone growth in FOP seems like biological anarchy, it follows the pattern of bone formation in the embryo, spreading from the neck and spine to the shoulders, elbows and then the lower limbs. In effect, patients grow a second skeleton.

That was an important observation. Clearly, the gene driving FOP was a primal and powerful one. And the mutation occurred in the sperm or egg, which meant not only that it could be inherited, but that it could profoundly confuse some of the body's stem cells - the primitive cells that give rise to tissues throughout the body.

By last year, laborious molecular analysis of blood samples from five multigenerational families enabled the team to home in on about 200 genes on one chromosome. That was still a vast genetic neighborhood. Ideally, researchers should have enough patients to narrow the possible disease culprits to about 10 genes.

Among the 200, Kaplan's group was particularly interested in a gene known as ACVR1. It carried instructions - written in the DNA code that is the language of life - for a protein involved in bone-making.

A whole family of such proteins had been isolated in other labs around the country since the first was found in 1988. What's more, studies had shown that in chickens and zebra fish, the ACVR1 gene could be changed in a way that would trigger an animal version of FOP.

Still, the search was frustrating. Again and again, one of the lab's less-experienced young scientists would excitedly say, "I think I've found it. " Then Shore, 51 - as meticulous and cautious as she is persevering - would recheck the data and find a mistake or misinterpretation.

Finally, last August, senior researcher Meiqi Xu came into Shore's office and, in a jubilant but hushed voice, said: "I've found the gene! "

"Meiqi is like me; she's normally very calm," Shore said last week. "She's an excellent technician. I had some questions and wanted to do more confirmatory tests. But within a week, I was convinced. "

Tests showed the defective ACVR1 gene was carried by affected members of all five families, as well as 32 FOP patients who had out-of-the-blue, or "sporadic," mutations. More than 150 "controls," including 47 healthy members of FOP families, did not have the mutation.

Unlike most diseases, FOP is caused by an infinitesimally small molecular mistake: a single DNA letter out of six billion is mutated, which prompts a bone-making protein to change a single one of the 509 amino acids that normally enable it do its job.

Kaplan says finding this change was like narrowing down from the genetic universe to ever-smaller geographic locations, then to a house, a room, a piece of furniture, a drawer, a hidden cubbyhole, and finally, "a miniature gold box" containing "the skeleton key. "

Hard as the mutated gene was to find, it is ideal from a therapeutic perspective because it can be blocked using known techniques, said Zasloff, now a professor of surgery and pediatrics at Georgetown University Medical Center.

If FOP can be arrested, or even prevented, it might be possible to stop the mysterious, debilitating bone formations that often occur after hip replacement surgery, head trauma, and spinal-cord injuries in people who don't have FOP.

But equally exciting is the prospect of turning the catastrophic mutation into a tool.

“Perhaps someday we will be able to harness the mutation that causes the renegade bone formation and make bone in a controlled way,” Kaplan said. “We still have a long way to go, but finally we can see above the clouds, and the view is promising.”