http://www.theatlantic.com/magazine/archive/2013/06/the-mystery-of-the-second-skeleton/309305/
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).
Her 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.
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.
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.
“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.”
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. 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.
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.
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.”
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.
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.
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. Kaplan kept searching. If the culprit wasn’t that particular protein, he reasoned, it might be one of its known associates. Kaplan and Shore inspected gene after gene, year after year. But they failed to find a mutation unique to people with FOP.
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.”
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.”
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.”
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.
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.
http://en.wikipedia.org/wiki/Fibrodysplasia_ossificans_progressiva
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