When Jeannie Peeper was born in 1958, there was only one thing amiss: her big toes were short and crooked. Doctors fitted her with toe braces and sent her home. Two months later, a bulbous swelling appeared on the back of Peeper’s head. Her parents didn’t know why: she hadn’t hit her head on the side of her crib; she didn’t have an infected scratch. After a few days, the swelling vanished as quickly as it had arrived.
When Peeper’s mother noticed that the baby couldn’t open her mouth as wide as her sisters and brothers, she took her to the first of various doctors, seeking an explanation for her seemingly random assortment of symptoms. Peeper was 4 when the Mayo Clinic confirmed a diagnosis: she had a disorder known as fibrodysplasia ossificans progressiva (FOP).
The name meant nothing to Peeper’s parents—unsurprising, given that it is one of the rarest diseases in the world. One in 2 million people have it.
Peeper’s diagnosis meant that, over her lifetime, she would essentially develop a second skeleton. Within a few years, she would begin to grow new bones that would stretch across her body, some fusing to her original skeleton. Bone by bone, the disease would lock her into stillness. The Mayo doctors didn’t tell Peeper’s parents that. All they did say was that Peeper would not live long.
“Basically, my parents were told there was nothing that could be done,” Peeper told me in October. “They should just take me home and enjoy their time with me, because I would probably not live to be a teenager.” We were in Oviedo, Florida, in an office with a long, narrow sign that read The International Fibrodysplasia Ossificans Progressiva Association. Peeper founded the association 25 years ago, and remains its president. She was dressed in a narrow-waisted black skirt and a black-and-white striped blouse. A large ring in the shape of a black flower encircled one of her fingers. Her hair was peach-colored.
Peeper sat in a hulking electric wheelchair tilted back at a 30-degree angle. Her arms were folded, like those of a teacher who has run out of patience. Her left hand was locked next to her right biceps. I could make out some of the bones under the skin of her left arm: long, curved, extraneous.
“It’s good to finally meet you,” she said when I walked in. Her face was almost entirely frozen; she spoke by drawing her lower lip down and out to the sides. Bones had immobilized her neck, so she had to look at me with a sidelong gaze. Her right hand, resting on her wheelchair’s joystick, contained the only free-moving joint in her body. It rose and swung toward me. We shook hands.
Peeper’s condition is extremely rare—but in that respect, she actually has a lot of company. A rare disease is defined as any condition affecting fewer than 200,000 patients in the United States. More than 7,000 such diseases exist, afflicting a total of 25 million to 30 million Americans.
The symptoms of these diseases may differ, but the people who suffer from them share many experiences. Rare diseases frequently go undiagnosed, or misdiagnosed, for years. Once people do find out that they suffer from a rare disease, many discover that medicine cannot help them. Not only is there no drug to prescribe, but in many cases, scientists have little idea of the underlying cause of the disease. And until recently, people with rare diseases had little reason to hope this would change. The medical-research establishment treated them as a lost cause, funneling resources to more-common ailments like cancer and heart disease.
In 1998, this magazine ran a story recounting the early attempts by scientists to understand fibrodysplasia ossificans progressiva. Since then, their progress has shot forward. The advances have come thanks in part to new ways of studying cells and DNA, and in part to Jeannie Peeper.
Starting in the 1980s, Peeper built a network of people with FOP. She is now connected to more than 500 people with her condition—a sizable fraction of all the people on Earth who suffer from it. Together, members of this community did what the medical establishment could not: they bankrolled a laboratory dedicated solely to FOP and have kept its doors open for more than two decades. They have donated their blood, their DNA, and even their teeth for study.
Meanwhile, the medical establishment itself has shifted its approach to rare diseases, figuring out ways to fund research despite the inherently limited audience. Combined with Peeper’s dedication, this sea change has enabled scientists to pinpoint the genetic mutation that causes her disease and to begin developing drugs that could treat, and possibly even cure, it.
Although rare diseases are still among the worst diagnoses to receive, it would not be a stretch to say there’s never been a better time to have one.
When Peeper’s parents received their daughter’s diagnosis, they didn’t tell her. She enjoyed a kickball-and-bicycles childhood in Ypsilanti, Michigan, and only became aware of her disorder when she was 8.
“I remember vividly, because I was getting dressed for Sunday school,” she told me. She realized that she could no longer fit her left hand through her sleeve. “My left wrist had locked in a backwards position”—the result of a new bone that had grown in her arm.
Peeper’s doctors took a muscle biopsy from her left forearm. Afterward, she wore a cast for six weeks. When it came off, she couldn’t flex her elbow. A new bone had frozen the joint.
Over the next decade, as Peeper grew more bones—rigid sheets stretching across her back, her right elbow locking, her left hip freezing—she became accustomed to pain.
But, like most kids, she adapted. When she could no longer write with her left hand, she learned to use her right. When her left leg locked, she put a crutch under her arm and tipped her body forward to walk. She even learned how to drive. After graduating from high school, Peeper lived on her own in an apartment, taking classes at a local college.
When pain from a fall kept her in bed for three days, her parents, who had recently retired to Florida, begged her to move in with them. She caved, enrolling at the University of Central Florida. There she earned a bachelor’s degree in social work, interning at nursing homes and rehabilitation centers. In 1985, three weeks after graduating, Peeper tripped over a blanket in her parents’ home. “My hip hit the corner of an end table,” she said, “and that changed my life.”
Her body responded to the fall by growing another bone. She could feel her right hip freezing in place. She knew that if she couldn’t stop it, she would probably never be able to walk again. Before the fall, Peeper had been planning on getting a job as a social worker. Now she couldn’t even get dressed by herself. On top of it all, she was lonely. She assumed that, of the 6 billion–odd people in the world, she was the only one with a second skeleton.
“I don’t know how to explain it,” she told me. “I never dwelled on it—Is there someone else? Could there be someone else?—in my thinking. I thought I was the only one with this condition. That’s all I had ever known.”
Peeper asked her doctors back in Michigan about getting one of her locked hips replaced with an implant. They referred her to a National Institutes of Health physician named Michael Zasloff. Zasloff had been trained as a geneticist, and sometimes he would encounter patients with rare genetic disorders; in 1978, he met a young girl with FOP. “I’d never seen anything quite like it,” Zasloff told me. “I had no idea what it was.”
When Zasloff asked his adviser, Victor McKusick—at the time the world’s greatest clinical geneticist—what caused fibrodysplasia ossificans progressiva, McKusick told him he didn’t have a clue. So Zasloff headed to the medical library.
The first detailed report of the disease dates back to 1736. A London physician named John Freke sent a letter to the Royal Society about a patient he had just seen:
There came a Boy of a healthy Look, and about Fourteen Years old, to ask of us at the Hospital, what should be done to cure him of many large Swellings on his Back, which began about Three Years since, and have continued to grow as large on many Parts as a Penny-loaf, particularly on the Left Side.
Freke noted how superfluous bones arose from the boy’s every neck vertebra and rib: “Joining together in all Parts of his Back, as the Ramifications of Coral do, they make, as it were, a fixed bony Pair of Bodice.”
In the generations that followed, doctors recorded almost nothing more about the disease. Zasloff found only two papers from the 20th century. He was in the worst position a doctor can be in: he didn’t know how to help a young patient in pain, and he had nothing to tell her distressed parents. He decided to adopt FOP as part of his research.
As a geneticist at the National Institutes of Health, Zasloff had the greatest medical resources he could desire at his disposal. But he still struggled to get his hands on information about FOP—largely because he was hard-pressed to find anyone who had it. Zasloff took over the care of a few patients who had been referred to McKusick, and he began accepting new referrals. But many doctors didn’t even know what the disease was, let alone how to diagnose it. Over a decade, Zasloff managed to examine 18 people with FOP. That made him the world’s expert on the disease.
When Peeper visited Zasloff in 1987, he told her that a hip implant would be impossible. He had learned this lesson the hard way. Years earlier, he’d taken a biopsy from a patient’s thigh, and the trauma had triggered the growth of a new bone. He suspected that the biopsy Peeper’s doctors had taken from her arm years earlier had caused it to freeze.
Before meeting Peeper, Zasloff had mostly treated children, whose youth and parents had buffered them from a full awareness of their fate. But in Peeper, Zasloff could sense the encroachment of profound solitude. She knew no one who could begin to understand her experience. So although Zasloff could offer her no medicine, he realized he could put her in touch with his other patients.
To Peeper, the list of 18 names Zasloff gave her was a revelation. “I thought, I need to do something to connect everyone, to let everyone know all these people are out there,” she said. Back home in Florida, she sent a letter and questionnaire to everyone on the list. Some of Zasloff’s patients had died, but 11 surviving ones wrote back: an artist and a bookkeeper, a little boy and a middle-aged woman.
Peeper responded to each letter, and she and her correspondents became friends. She began arranging to meet some of them, in order to lay eyes for the first time on someone else with her condition. “I just assumed that everybody was going to look like me,” she told me. But FOP is fickle in the positions in which it freezes people. One woman Peeper met was locked in a horizontal position and lived on a gurney. Another’s torso was angled backwards. Peeper met a girl who had lost an arm to a misdiagnosis: her doctors had thought the swelling in her left arm was a tumor. When they performed surgery, her arm began bleeding uncontrollably and they had to amputate it.
Four times a year, Peeper sent out a newsletter she called “FOP Connection.” She included questions people sent her—What to do about surgery? How do you eat when your jaw locks?—and printed answers from other readers. But her ambitions were much grander: she wanted to raise money for research that might lead to a cure. With a grand total of 12 founding members, she created the International Fibrodysplasia Ossificans Progressiva Association (IFOPA).
Peeper didn’t realize just how quixotic this goal was. FOP had never been Zasloff’s main area of research. As the director of the Human Genetics branch of the NIH, he had discovered an entirely new class of antibiotics, and in the late 1980s, he left the NIH to develop them at the Children’s Hospital of Philadelphia. His departure meant that no one—not a single scientist on Earth—was looking for the cause of FOP.
And no one was likely to. Zasloff’s powerful position in the scientific establishment had afforded him the liberty to study the disease, but for younger scientists looking to make their names, rare diseases were a big risk. FOP was just as complex as diseases that were 100,000 times more common. But with so few patients to study, the odds of failing to discover anything about it were high. When the NIH’s grant reviewers decided which projects to fund, those odds often scared them away.
For Peeper’s plan to work, she’d need someone who was prepared to risk his or her career.
One day last November, Frederick Kaplan, the Isaac and Rose Nassau Professor of Orthopedic Molecular Medicine in Orthopedic Surgery at the University of Pennsylvania, was sitting cross-legged on the floor of an exam room. Kaplan, 61, is a small, precise man. On the day I visited his clinic, he was dressed in a blue shirt, charcoal pants, and a tie covered in faces that looked like they had been drawn by children.
“How’s kindergarten?” he asked, looking up.
Above him, sitting in a chair, was a dark-haired 5-year-old from Bridgewater, New Jersey, named Joey Hollywood. His parents, Suzanne and Joe, sat in the corner of the exam room. Joey liked towering over his doctor. He smiled down at Kaplan as he kicked his legs under one arm of the chair and then slipped them under the other. “I ride the bus,” he said.
“Joey,” Kaplan said, “let’s play Simon Says.” Kaplan stood up and slapped his hands to his sides. Joey swung out of his chair and stood as well. Kaplan twisted his head to the left to look at Joey’s parents. Joey did not turn his neck. Instead, he pivoted on his feet to turn his entire body. Kaplan turned back to Joey and raised his arms to the ceiling. Joey tipped up his hands at his sides.
“He’s quite adaptive,” Joe said. “At school they were horrified to find he was using his face to turn on light switches. So they gave him a stick.”
“Can we slip that nice shirt off?,” Kaplan asked. “I’m just going to check your back.”
Joey let Suzanne draw his shirt over his head, revealing two tangerine-size mounds on his back, each faintly filigreed with veins.
Joey was born with malformed big toes, like Peeper and most other people with FOP. A few months later, a lump appeared on his back. “When I saw it,” Suzanne told me, “I said, ‘That can’t be normal.’ ”
Joey’s symptoms came and went, but not until the fall of 2011, when he was 4, did it become clear that something was seriously wrong. Bones had grown in his neck, freezing it hard as stone. The Hollywoods were referred to Kaplan, who has replaced Zasloff as the world’s leading FOP expert. A few months later, Joey’s right arm fused to his ribs, and more swellings appeared on his back.
As Joey munched on pretzels, his parents asked Kaplan about the risks of hearing loss (in young patients, ear bones sometimes fuse together), and about what had happened to Kaplan’s other patients.
“I’ve seen 700 patients with FOP around the world, and it’s clear that there’s a lot of different ways to divide patients,” Kaplan said. One identical twin might be only mildly affected, while the other would be trapped in a wheelchair. Some patients developed a frenzy of bones as children, and then inexplicably stopped. “I’ve seen it go quiet for years and years.”
“So it’s very unpredictable,” Joe said, hopefully.
Suzanne looked over at Joey. “This is my son every day,” she said. “I don’t want to have him look back at his childhood and say, ‘My parents were always sad.’ ”
“When you’re here, we focus on FOP,” Kaplan told her. “Remember the things that are important and helpful for Joey to live as safe a life as he can.” He shrugged his shoulders. “And then forget the FOP.”
When Kaplan started out as an orthopedic surgeon in the late 1970s, he treated patients with a wide range of common bone diseases, such as osteoporosis and rickets. In the mid-1980s, however, he became interested in genetics. He suspected that for many of his patients’ treatments, a pipette of DNA would become more useful than a bone saw.
In 1988, Kaplan met Michael Zasloff. Zasloff had just left the NIH and moved to Philadelphia, but he was still hoping to find someone to take up his FOP research. He’d heard through the Penn grapevine that Kaplan had become interested in genetics, so when he spotted him at a clinic, Zasloff introduced himself and immediately asked Kaplan whether he had heard of the disease.
Kaplan did in fact have two adult patients with the condition, but it held no unique interest for him. Then Zasloff told Kaplan about an idea he was playing around with. Some scientists had recently injected a kind of protein called BMP into mice and found that the animals developed little bony marbles in response. Zasloff wondered whether extra BMP might be the secret to FOP.
He could tell Kaplan was curious. He suggested they work on the disease together.
“I don’t think you want me in your lab,” Kaplan told him. “I’m an orthopedic surgeon. I’m not a scientist.”
Zasloff persisted, asking Kaplan to join him for some upcoming appointments he had with young FOP patients, including a baby named Tiffany Linker.
“That was it,” Kaplan told me. “In an adult, you see what’s already past. When you meet a child, it’s like seeing a beautiful building, and a plane’s about to destroy it.”
Kaplan began by setting up a space in one of Zasloff’s labs and learning how to conduct molecular-biology experiments. Within two years, his obsession had surpassed even Zasloff’s, and he’d devoted himself entirely to the disease. His colleagues were mystified; at the time, rare diseases were still considered professional suicide. “They would say, ‘You are absolutely insane to work on this,’ ” Kaplan recalls.
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.
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