Meanwhile, in Florida, Peeper was building her network. When families got an FOP diagnosis, they would find their way to her organization and talk with Peeper. She put her education in social work to good use, introducing frightened families to the logistics of life with FOP. “She gave me a lot of hope,” says Holly LaPrade, a Connecticut woman who was 16 when she first spoke to Peeper. “She told me how she went to college, how she had a degree, how she had founded this organization, and about all the people she had become friends with.”
Peeper asked Kaplan, whom she’d met through Zasloff, to become IFOPA’s medical adviser, and he traveled to Florida to attend the occasional gatherings Peeper organized for fellow patients and their families. These events were a medical boon for him, offering the rare opportunity to examine dozens of patients in a single weekend. From those exams and conversations, Kaplan began assembling a natural history of the disorder.
The group’s members gave him more than their stories and DNA: they began raising money. Nick Bogard, whose son Jud had been diagnosed with the disease at age 3, organized a golf tournament in Massachusetts that raised $30,000. That money allowed Kaplan to host the first scientific conference about FOP, in 1991. Other families hosted barbecues, ice-fishing tournaments, swim-a-thons, bingo nights. In 2012 alone, Peeper’s organization raised $520,000 for research. That’s not much compared with, say, the $1 billion that the NIH distributes each year for diabetes research. But these funds were crucial for Kaplan, who sought to escape the rare-disease trap. IFOPA’s money—as well as gifts from other private donors and an endowment accompanying Kaplan’s professorship at Penn—made it possible for him to work single-mindedly on FOP for more than two decades.
In 1992, Kaplan hired a full-time geneticist named Eileen Shore to help establish a lab for the disorder. Shore had worked on fruit-fly larvae as a graduate student, and as a post-doctoral researcher, she had studied the molecules that allow mammal cells to stick together as they develop into embryos. Kaplan didn’t mind that Shore knew almost nothing about FOP. What he wanted in a geneticist was an expertise in development: the mystery of how the body takes shape.
First, they set out to understand how the disease worked. Based on their conversations with patients, they learned that bone growth could be caused by even slight trauma to muscles. A tumble out of bed or even a quick brake at a stoplight might cause a flare-up—a swelling that may or may not lead to new bone growth. A visit to the dentist could do the trick, if the jaw was stretched too far. Even a flu shot to the biceps was enough. Some flare-ups subsided without any lasting effect, while others became nurseries for new bone.
Most people with the condition develop their first extra bone by the age of 5. Their second skeletons usually start around the spine and spread outward, traveling from the neck down. By 15, most patients have lost much of the mobility in their upper bodies.
Ninety percent of people with FOP are misdiagnosed at first, and many doctors take biopsies before they realize what they’re dealing with. “I see the scars, and I say to the parents, ‘Can you get me the biopsy?,’ ” Kaplan says. “Because it’s sitting in a closet somewhere. Those samples are like gold.”
Examining the biopsies, Kaplan, Shore, and their students worked out the microscopic path of FOP: At the start of a flare-up, immune cells invade bruised muscles. Instead of healing the damaged area, they annihilate it. A few progenitor cells then crawl into the empty space, and in some cases give rise to new bone.
“Your muscle isn’t turning to bone,” says Shore. “It’s being replaced by bone.”
Everything Shore and Kaplan observed fit nicely with Zasloff’s original theory: FOP is the result of cells that produce too much BMP. To test that idea, Shore and Kaplan drew blood from their patients. (This procedure doesn’t trigger new bone growth, remarkably enough.) In 1996, they reported in The New England Journal of Medicine that the blood cells of people with the condition contain an abundance of a particular protein called BMP4. For the first time, scientists had found a molecular signature of the second skeleton. They hoped they had also found a path toward a cure.
Eighty percent of rare diseases are caused by a genetic mutation. For example, severe combined immunodeficiency—the “bubble boy” disease that robs children of an immune system—most commonly arises when a gene called IL2RG is altered. Normally, the gene helps signal immune cells to develop. If the signal goes quiet, children never gain a full immune system and can’t fight infections.
To treat rare diseases, scientists first look for the broken gene. Kaplan and Shore suspected that FOP was caused by a genetic mutation that led the body to make too much BMP4. In the early 1990s, they didn’t have access to today’s sophisticated genome-sequencing tools, so they began sorting slowly through the human genome’s 20,000 genes.
“Based on what we already knew about FOP, we could make an educated guess and say, ‘I think this is a likely gene,’ ” Shore told me. “And then we sequenced it and looked for mutations.”
The first candidate was, of course, the gene that produces BMP4. Shore and Kaplan sliced this gene out of cells from people with FOP, sequenced it, and compared it with a version taken from people without the condition. Unfortunately, the two versions were a perfect match.
When Kaplan’s colleagues heard the disappointing news, they offered him their sympathies. A mutation of the BMP4 gene would have been such a nice story, they said. Kaplan kept searching. If the culprit wasn’t that particular protein, he reasoned, it might be one of its known associates. By the late 1990s, scientists had discovered a few of the other genes that BMP4 depends on to get its job done—genes that are required to switch the protein on, for example, and genes that make receptors onto which it can latch. Kaplan and Shore inspected gene after gene, year after year. But they failed to find a mutation unique to people with FOP.
Meanwhile, IFOPA set up a Web site, which attracted anxiously Googling parents, many from other countries. The group arranged for some of those families to attend its gatherings, along with foreign doctors who wanted to learn how to recognize the disorder. When these doctors went home, they added more patients to the network. Eventually, this broadening community led Kaplan to patients who had children who also suffered from the disorder.
Studying families is one of the best ways to pinpoint a mutated gene. By comparing the DNA of parents and children, geneticists can identify certain segments that consistently accompany a disorder. Because most people with FOP never have children, Kaplan and Shore had assumed they couldn’t use this method. But then the online patient network began surfacing exceptions: a family in Bavaria, one in South Korea, one in the Amazon. All told, seven families emerged; Kaplan traveled to meet a few of them and draw their blood.
Back in Philadelphia, Shore and her colleagues examined the DNA from these samples and narrowed down the possible places where the FOP gene could be hiding. By 2005, they had tracked the gene to somewhere within a small chunk of Chromosome 2. “It was a huge step,” says Shore. “But there were still several hundred genes in that region.”
By a fortunate coincidence, scientists at the University of Rochester had just studied one of those several hundred genes. They had discovered that the gene, called ACVR1, made a receptor. The receptor grabbed BMP proteins and relayed their signal to cells. In the margin of the paper in which the scientists described ACVR1, Kaplan wrote, “This is it.”
Shore and her staff inspected the gene as it occurred in people with FOP. The same mutation appeared in precisely the same spot in every patient’s cells. Once they had double- and triple-checked their results, once they had written a paper describing the mutation, Kaplan and Shore planned a press conference. In the spring of 2006, Kaplan called Peeper to tell her something she had doubted she would live long enough to hear.
“We need you to come to Philadelphia,” he said. “We’ve found the gene.”
A rare disease is a natural experiment in human biology. A tiny alteration to a single gene can produce a radically different outcome—which, in turn, can shed light on how the body works in normal conditions. As William Harvey, the British doctor who discovered the circulation of blood in the 17th century, observed more than 350 years ago, “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths.”
Take Jeannie Peeper’s second skeleton: In many ways, it is profoundly normal. The new bones contain marrow. If fractured, they heal nicely. They are much like the bones of other mammals, of reptiles, of fish. In all those animals, bones develop under the control of the same network of genes—a network that, having shaped the bodies of our pre-vertebrate ancestors, is older even than bone itself.
What is not normal is when these bones form. Normally, new bones develop only in embryos. As children grow, those bones extend; when those bones break, new cells repair them. But almost no one develops entirely new bones outside the womb.
Finding the FOP mutation was a coup, but Kaplan and Shore still had no idea how it worked. They set about studying baby teeth from young patients, as well as mice they genetically altered, to observe the mutation in action. Seven years later, they had pieced together an understanding of the far-reaching effects. The ACVR1 receptor normally grabs onto BMP proteins and relays their signal into cells. But in people with FOP, the receptors become hyperactive. The signal they send is too strong, and it lasts too long. In embryonic skeletons, the effects are subtle—for example, deformed big toes. Only later, after birth, does the mutation start to really make its presence known. One way it does this, Shore and Kaplan learned, is by hijacking the body’s normal healing process.
Say you bruise your elbow, killing off a few of your muscle cells. Your immune cells would swarm to the site to clear away the debris, followed by stem cells to regenerate the tissue. As they got to work, the two kinds of cells would converse via molecular signals. Shore and Kaplan suspect that BMP4 is an essential part of that exchange. But in someone with FOP, the conversation is more of a screaming match. The stem cells kick into overdrive, causing the immune cells not just to clear the damage but to start killing healthy muscle cells. The immune cells, in turn, create a bizarre environment for the stem cells. Instead of behaving as if they’re in a bruise, these cells act as if they’re in an embryo. And instead of becoming muscle cells, they become bone.
In the context of FOP, new bone is a catastrophe. But in other situations, it could be a blessing. Some people are born missing a bone, for example, while others fail to regenerate new bone after a fracture. And as people get older, their skeletons become fragile; old bone disappears, while bone-generating stem cells struggle to replace what’s gone.
FOP may be an exquisitely rare bone condition, but low bone density is not: 61 percent of women and 38 percent of men older than 50 suffer from it. The more bone matter people lose, the more likely they are to end up with osteoporosis, which currently afflicts nearly one in 10 older adults in the United States alone. For decades, doctors have searched for a way to bring back some of that bone. Some methods have helped a little, and others, such as estrogen-replacement therapy, have turned out to have disastrous side effects in many women.
Giving someone a second skeleton is not a cure for osteoporosis. But if Kaplan and his colleagues can finish untangling the network of genes that ACVR1 is a part of, they could figure out how to use a highly controlled variation on FOP to regrow bones in certain scenarios. “It’s like trying to harness a chain reaction at the heart of an atom bomb,” he told me, “and turning it into something safe and controllable, like a nuclear reactor.”
This would not be the first time the study of a rare disease unearthed new treatment options for more-common afflictions. In 1959, Don Frederickson of the National Heart Institute discovered a strange disorder, now called Tangier disease, which caused tonsils to turn orange. The color resulted from a buildup of cholesterol, he found. Forty years later, scientists identified the mutated gene that causes Tangier disease and figured out how it helps shuttle cholesterol out of cells. Researchers are now trying out drugs that boost the performance of this gene as a way to lower the risk of heart disease.
Only recently, though, has medicine begun to formally recognize the value of the “secret mysteries” that rare diseases can reveal.
Kaplan’s office at the University of Pennsylvania is loaded like a well-packed shipping container. When I visited him there in November, he had to scooch through the narrow spaces between his desk and filing cabinets filled with X‑rays and medical reports. Framed photographs of his patients covered most of the surfaces and blocked part of his narrow window.
Kaplan pointed to a picture of Tiffany Linker, the patient who, as a baby, had persuaded him to stake his career on FOP. He told me that last July, at 23, Linker had passed away. “It’s been a rough year,” he said.
When I talked with young people with the disease, though, I was struck by their optimism. In the 1980s, Peeper had to type out letters to reach a dozen other people with her condition. Today, someone recently diagnosed with FOP can hop on Facebook, pose a question—how to drink from a glass if you can no longer raise it to your mouth, for example—and get an immediate answer from one of hundreds of people with the same disease.
One frequent topic of conversation within today’s FOP community is the possibility that a cure, or at least a treatment, may not be far away. As Kaplan, Shore, and other scientists decipher the cause of the disease, some promising drugs are emerging that may be able to stop it. At the Children’s Hospital of Philadelphia, for example, researchers have been testing a drug based on a certain type of molecule that can prevent new bone from growing in FOP mice by breaking the chain of signals that command progenitor cells to turn into bone.
The search for a cure is accelerating, thanks in part to new programs designed to incentivize the study of rare diseases. A different drug option, currently being investigated by a team of scientists at Harvard Medical School, has benefited from these programs. In a broader experiment in 2007, the scientists tested more than 7,000 FDA-approved compounds on zebra-fish embryos, watching for whether any of them affected the animals’ development. One molecule caused the zebra fish to lose the bottom of its tail fin. When the scientists looked more closely at this compound, they discovered that it latched onto a few receptors, including ACVR1—the receptor that Shore and Kaplan had recently discovered was overactive in FOP patients.
The Harvard researchers wondered whether the drug could work as a treatment for FOP. They tinkered with the compound, creating a version that had a stronger preference for ACVR1 than other types of receptors. When they tested it on mice with an FOP-like condition, it quieted the signals from ACVR1 receptors, thereby stopping new bones from forming.
After publishing its results in 2008, the Harvard team failed to find a pharmaceutical company willing to invest in pushing the drug into human trials. The problem wasn’t that drugs for rare diseases can’t turn a profit. In fact, once they’re on the market, they can be quite lucrative. Insurance companies are willing to cover drugs that can cost tens of thousands of dollars a year if they eliminate even-more-costly types of care. But bringing a drug to market can be a hugely expensive gamble—one that companies weren’t willing to take for a potential treatment for a rare disease.
In 2011, the Harvard scientists found a backer: a new NIH program called Therapeutics for Rare and Neglected Diseases. This program collaborates with scientists to develop rare-disease drugs that can’t survive the harsh economics of the pharmaceutical establishment.
“They’re almost like the pharmaceutical company and we’re the scientific advisory board,” says Ken Bloch, one of the Harvard scientists. “From my perspective, it’s spectacular, because it fills that gap.” Researchers from the NIH program are currently running preclinical tests of the Harvard team’s drug on mice to make sure it doesn’t have any unexpected toxic side effects. They’re also tinkering with the drug to see whether they can create more-potent forms—all with an eye to getting it ready for clinical human trials.
If this particular drug, or any other one, gets to clinical trials, it will face another set of hurdles. A typical trial for a drug treating a common disease like diabetes might involve thousands of patients. That scale makes it possible to run statistical tests ensuring that the drug really is effective. It also allows scientists to detect side effects that might affect relatively few patients. But even if you enrolled every FOP patient in the United States, a trial would still be a fraction of the size of a conventional one.
In recent years, the FDA has responded to this bind by smoothing out the approval of drugs for rare diseases. If doctors can’t find thousands of patients to enroll in a clinical trial, they are now allowed to conduct smaller trials that meet certain guidelines. Obtaining a detailed medical history for each subject in a smaller trial, for example, makes his or her individual response to a certain drug all the more revealing.
This strategy can only work, however, if a high percentage of patients with a rare disease are willing to join a clinical trial. And that’s where people like Peeper become invaluable. Thanks to the active global community she created, any clinical trial for an FOP drug now has hundreds of potential participants.
On one of my visits to Philadelphia, Kaplan took me to see Harry. We met in the pillared entryway of the College of Physicians of Philadelphia, a medical society founded in 1787. Kaplan was wearing a tie covered in skeletons. We descended a flight of stairs to the Mütter Museum, an eerie basement collection of medical specimens. We passed cabinets filled with conjoined twins, pieces of Albert Einstein’s brain, and a cadaver turned to soap. We walked up to a glass case, which a curator opened for us. Inside loomed a skeleton beyond imagining.
It belonged to Harry Eastlack, a man with fibrodysplasia ossificans progressiva who asked shortly before he died in 1973 that his body be donated to science. Harry stands with one leg bent back, as if preparing to kick a soccer ball, and the other hinged unnaturally forward; his arms hover in front of his body; his back and neck curve to one side, forcing his eye sockets to gaze at the floor. Before a typical skeleton goes on display, the bones have to be wired and bolted together. Eastlack’s skeleton needed almost no such help. It is a self-supporting scaffolding, its original structure overlain with thorns, plates, and strudel-like sheets.
“The first time I saw Harry, I stood here mesmerized,” Kaplan told me, shining a red laser on a ligament in Harry’s neck that had become a solid bar running from the back of his head to his shoulders. “I’m still learning from him.”
Thanks to Kaplan’s enduring fascination with her disease, Jeannie Peeper can now realistically imagine a time—perhaps even a few years from now—when people like her will take a pill that subdues their overactive bones. They might take it only after a flare-up, or they might take a daily preventative dose. In a best-case scenario, the medication could allow surgeons to work backwards, removing extra bones without the risk of triggering new ones.
At 54, with an advanced case of FOP, Peeper does not imagine that she’ll benefit from these breakthroughs. But she is optimistic that her younger friends will, and that one day, far in the future, second skeletons will exist only as medical curiosities on display. All that will remain of her reality will be Harry Eastlack, still keeping watch in Philadelphia, reminding us of the grotesque possibility stored away in our genomes.