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.