A Few Hundred People Turned To Bone

Harry Eastlack normally dwells in a glass case in the Mütter Museum, at the College of Physicians of Philadelphia, not far from the death cast of Chang and Eng, the original Siamese twins, and a host of other anatomical curiosities. Before Harry died, six days shy of his fortieth birthday, he bequeathed his body to his treating physicians. Harry's body was now what it had sought to become all of his life: pure bone. While he was alive, Harry never met another person with FOP. Fred Kaplan, an orthopedic surgeon and the world's leading authority on FOP, thought the time had come for others to meet Harry. Harry's family enthusiastically agreed.

"I saw a woman today who finally became hard as wood all over," the French physician Guy Patin wrote to a colleague in 1692. This perfunctory note is the first clinical description of FOP. "It may be the strangest disease there is," Kaplan says. "It's the closest thing you'll find in real life to Kafka's Metamorphosis."

Even people whose knowledge of skeletal anatomy comes from Halloween costumes or cartoons recognize that Harry is out of the ordinary. Normal skeletons collapse into piles of loose bones if the flesh and connective tissue that joined them in life are removed. To be displayed in a human-shaped arrangement, skeletons must be "articulated"—rigged together with fine wires and glue. Harry offered little challenge to the articulator's craft, because his skeleton was already nearly fused into one piece. A transformation that begins in childhood and progresses relentlessly throughout life turns the muscles, tendons, and ligaments of FOP sufferers into bone. Sheets of bone cover Harry's back like a carapace. Ribbons and struts of bone lock his skull to his spine, span and immobilize his shoulder and hip joints. Thin stalagmites and stalactites of bone launch themselves from his pelvis and thighs. A slender white bridge across Harry's vacant rib cage delicately but firmly welds his upper arm directly to his breastbone.

FOP is not fatal, though patients often die young, starving after their jaws freeze shut or succumbing to respiratory problems if new bone bends their bodies and constricts their lungs. Well-meaning attempts to break free the joints or to carve away excess bone invariably make things worse. The FOP body believes that its heterotopic ("other" + "place") bone is normal, and heals these perceived injuries with more bone than was there before. Any injury to muscle or connective tissue, including falls and simple bumps, can precipitate a "flare-up." The area becomes hot, red, swollen, and painful, and within days or weeks forms a piece of new bone. A joint can lock overnight, never to move again. Even the muscle trauma of a childhood immunization may induce the body to form a spur of new bone. Sufferers may end up fused in a standing position, so rigid that they can sleep leaning in a corner, or perpetually sitting, or twisted to one side. Otherwise they are perfectly healthy, and with today's improved nutrition and medical care can live to ripe old age. They are normal people trapped in personal prisons.

In 1987, while Kaplan sat picking his way through a journal article on bone and genetics, a student, Jeff Tabas, dropped in to chat.

"Do you understand this stuff, Jeff?" Kaplan asked.

"Of course I do, Dr. Kaplan. We have to know that to get into medical school." Jeff explained introns, exons, and gene splicing. "You know, Dr. Kaplan, a whole world has opened up since you were in medical school. Maybe you should learn something about it."

Kaplan did. He bought genetics textbooks and read them straight through. He took a crash course in genetics at the Jackson Laboratory, in Bar Harbor, Maine. His imagination captured by this mysterious new field, Kaplan began looking for someone with whom he could have a sabbatical.

One day Kaplan sat talking to medical students in a doctors' lounge. A dark-haired, bearded stranger a few years older than he walked in and began to listen. Eventually he introduced himself as Michael Zasloff and asked whether Kaplan had ever heard of a disease called FOP. Kaplan had two FOP patients and had often thought about the disease, though not very productively. Medicine offered no conceptual framework for it. After a few hours of conversation with Zasloff, though, Kaplan knew where he was going to spend his sabbatical, and that he and Zasloff would study the genetics and molecular biology of FOP. From this chance encounter was born an interdisciplinary collaboration that has yielded profound and surprising insights, not only into FOP but also into the process by which skeletons are made.

"I saw a young lady sitting in the waiting room with her neck and head stiffly posed quite askew. The left side of her neck was terribly swollen, and she was clearly in significant pain." Monica Anderson was eight years old. McKusick had diagnosed her FOP when she was three. The disease had been quiescent until a few days earlier, when she whipped her head around while on an amusement-park ride, inflicting just enough trauma to trigger a flare-up. Monica was fortunate that McKusick had already identified her disease. Few other physicians in the world had even heard of FOP. Too often, when terrified parents rushed their children to the hospital at the first flare-up, doctors mistook the alarming tissue growth for aggressive malignant tumors and ordered emergency surgery or chemotherapy. A prominent surgeon amputated the entire right arm and shoulder of one little girl whose condition he tragically misjudged.

Zasloff's residency at Children's Hospital in Boston had familiarized him with many esoteric pediatric diseases, he told me, but nothing at all like this. "So I began to ask questions of Victor McKusick, who was probably the world expert on FOP at the time: 'Dr. McKusick, what do these lesions mean?' He said, 'I don't really know.' 'What do you think is causing it?' He said, 'I don't know.' I asked, 'What are we going to do about it?' He said, 'Well, I can tell you what doesn't work.'"

McKusick's classic textbook, Heritable Disorders of Connective Tissue, discusses FOP at great length within a chapter on other disorders. A few hundred cases had been reported since Guy Patin's single sentence in 1692, yet the level of understanding had barely increased. The disease was so strange and rare that not only weren't there any answers but no one was even asking questions.

Zasloff, a man irresistibly drawn to unexplained anomalies, studied records of past NIH and Johns Hopkins cases, pored over histology slides, and asked McKusick to refer new FOP patients to him. Zasloff began to formulate theories, but the time, sometimes the scientific techniques, and above all the patient population he needed simply were not there. He began a small clinical study to see whether he could pharmacologically inhibit the formation of heterotopic bone—work that yielded modest yet discernible results.

"My senior staff at NIH weren't against this project," he says, "but basically they couldn't have cared less. It was regarded by a lot of people as a waste of time and money." With his small and varied patient population, a statistically valid study was virtually impossible to construct. "So a lot of people asked, 'Even if you do this clinical trial, what does it mean?' Well, to the FOP patients it could mean a lot."

In 1986 Zasloff serendipitously discovered a new family of potent antibiotics in the skin of the African clawed frog. Work on "magainins," as he called them, from the Hebrew word for "shield," quickly commandeered his attention and the full resources of his lab. Zasloff's efforts to develop magainins as therapeutically useful drugs were frustrated within the bureaucracy of the NIH, and he ultimately left to continue his work at the University of Pennsylvania. A company was founded to commercialize his discovery.

Unfortunately, Zasloff's departure meant the demise of his FOP program. A colleague notified all FOP patients that they need not bother to return. Being turned away from the NIH, often the last resort for people with rare or "orphan" diseases, was a devastating blow. "It's like going to Mecca," Fred Kaplan says, "and being told that there is no hope."

One of the abandoned victims was a woman in her late twenties named Jeannie Peeper. Her disease had been diagnosed by an astute University of Michigan physician when she was four, and she'd had a normally active childhood until ninth grade, when her left hip and shoulder suddenly seized up. Still, she finished high school, moved to Florida, and earned a degree in social work while living on her own. Two weeks after graduation she fell and injured her right hip, an accident that cost her all mobility in that joint. Peeper was referred to Zasloff in 1985 (she was told he was the only doctor in the world who cared about FOP) to ask whether a hip replacement could help her. He said it could not.

Medically, Zasloff could do little for Jeannie Peeper except explain what was going wrong with her body. But during their periodic conversations his understanding and sympathy and the mere fact that he knew others like her made her feel less isolated in her disease. When, during a visit in October of 1987, he told her of his impending move, she asked if he could introduce her to another FOP patient. Zasloff put her in touch with Monica Anderson, by then a college student, and each young woman spoke to a fellow sufferer for the first time in her life.

As a parting gift, Zasloff gave Jeannie Peeper the complete list of living FOP patients known to the NIH—a scant eighteen names. He suggested that she might want to form a pen-pal club. Instead, her curiosity whetted by her conversation with Monica Anderson, Peeper mailed out letters and questionnaires asking for date of diagnosis, hobbies, interests, and a few other medical and personal details. Eleven people promptly replied, among them Nancy Whitmore, in Michigan, who was already active as an advocate for the handicapped. Rather than a pen-pal club they started a newsletter, the FOP Connection; the first issue was published in early 1988, funded by Peeper's Social Security checks. In June they incorporated the International FOP Association, with Peeper as president and Nancy Whitmore as vice-president. An FOP community had been born.

The body makes bone through two distinct mechanisms: intramembranous and endochondral formation. In the former, bone cells, or osteoblasts, sit on top of bone and secrete more bony substance, like bricklayers stacking bricks to build a wall. Intramembranous bone formation thickens the top of the skull and widens the shaft of long bones.

Endochondral bone formation is a radically different process, reminiscent of the lost-wax technique that artists use to cast sculptures. The body forms a cartilage model that is then infiltrated, resorbed, and replaced by true bone. This is how bones grow longer, and how fractures heal.

Endochondral bone formation is also the embryo's predominant method of constructing its skeleton in the first place. During the first two months after conception, primitive mesenchymal tissue condenses into pre-cartilage representations of most of the bones in the body, which gradually become cartilage and finally bone. This embryonic skeleton emerges from its undifferentiated ancestor cells in a regular sequence, the way parts of the image in an instant photograph slowly seep into view: first the back structures, then the front, head before tail, trunk before thighs and upper arms, then lower legs and forearms, ankles and wrists, fingers and, very last, toes.

When Kaplan and Zasloff decided to launch an FOP research program at Penn, the first challenge was to characterize the nature and natural history of the disease. The method and distribution of new-bone formation in FOP had never been accurately documented. A century or more of medical literature was filled with ambiguities, contradictions, and errors. Earlier investigators generally assumed that the bone formed through the intramembranous process. Perhaps they could more easily imagine pockets of renegade bone cells running amok. Kaplan's group looked at tissue samples of active FOP lesions, biopsies that had been taken before the right diagnosis was made, and determined conclusively that the disease used the endochondral pathway.

Doctors had always known that heterotopic bone did not appear randomly over the body. The neck and upper back were usually affected first. Some joints were nearly always involved, while others, such as those in the hands and feet, showed symptoms much later and to a lesser degree. Zasloff had begun studying the pattern while at the NIH, and Kaplan's group at Penn, with a steadily growing patient population, systematically surveyed forty-four people joint by joint. Most people might have a hard time accurately dating their personal histories of bumps, cuts, sprains, and breaks, but for people with FOP, injuries tend to mark memorable stages of life. "Like the last time you walk up a stair," says Andy Sando, a man in northern Michigan who lost leg mobility after a fall. "It was April 29, 1985. That's the exact date. I knew after I took that last step: I'm never going to do that again."

The researchers discovered that the age at which ossification began varied from one person to the next, but the sequence of joint involvement was almost always the same: first the neck and spine, then the shoulders, the hips and elbows, the knees and wrists, the ankles, and finally the jaw. Back to front, head to tail, trunk to appendages, proximal to distal—the pattern was hauntingly familiar, reminiscent of the sequence of endochondral bone formation in the embryo. The embryo models its skeleton by condensing undifferentiated mesenchyme cells into cartilage and then bone. In some mysterious and profoundly disturbing way the FOP body was recruiting existing connective tissue and transforming it into bone, bone that often retained the shape of the muscles or ligaments that it had once been.

"These people aren't just forming little bones here and there," Kaplan says. "They are forming a whole extra skeleton. It doesn't necessarily look like the first one, but that's what it is. It's extraordinary that a differentiated tissue like a muscle or a tendon can turn into another differentiated tissue, like a bone. It's like crossing all the lanes of a busy highway. Developmental biology is not known to work that way. You never see the brain turn into the pancreas. You never see the kidney turn into the heart. You never even see the stomach turn into the small intestine. But here you see what seems to be perfectly normal muscle turn into perfectly normal bone. Normal bone. It looks normal. It looks normal on x-ray and under the microscope. It behaves like normal bone—if it bears weight, it gets denser, and if it doesn't bear weight, it becomes osteoporotic. If you break it, it heals, just like a normal fracture. It even contains marrow. It's normal in every way except one: it shouldn't be there."

The Sandos, in their late thirties, have a vitality and a charm that transcend their surprising physical appearance. Both recline in power wheelchairs. Andy's body is virtually straight, with his legs slightly crossed, while Nancy is mildly bent at the waist. Their necks are both solidly locked. Nancy's jaw is fused, and recently Andy's fused as well, a circumstance that forced him to give up the trumpet. Their elbows are locked at nearly identical right angles; at rest they sit with their upper arms at their sides, fingers laced together, almost as though in prayer. Their wrists and fingers are barely affected, giving them the ability to manipulate things if they use a bit of ingenuity. Each has a cordless phone fastened to a two-foot-long stick. Nancy extends her reach with her "itcher stick," a wooden back scratcher that she finds invaluable. She is a surprisingly efficient typist, able to peck at an angled computer keyboard with a device she fashioned thirteen years ago—a dowel with the rubber tip of a baby pacifier taped to each end.

Nancy led a normal life until the age of five. Then one September evening her mother started to bathe her and suddenly let out a scream. On the back of the little girl's neck, concealed beneath her long blonde hair, was a warm, reddish, doughy mass almost the size of a grapefruit. Nancy's parents rushed her to the hospital, where she spent almost six weeks while the doctors ran tests and took biopsies. She returned home with a diagnosis of terminal cancer and the bleak prognosis that she would not live until Christmas. Nancy's parents waited for the end, withdrawing as people so often do from the dying. But Christmas came and went and Nancy got no worse. In fact, once the pain of this first flare-up passed, she began to look much better. Her parents consulted a series of specialists, and after a few months had a correct diagnosis of FOP.

Until she was eight, new bone appeared in Nancy's shoulders and down her spine. For seven years her condition was stable; then, when she was fifteen, her left shoulder froze and she lost most of the motion in her left elbow. An ill-advised operation on her right elbow had the inevitable effect of making it worse. Nancy carried on normally, though instead of playing on the playground or joining sports teams she managed the school greenhouse and helped to run the office. Five years later she fell while getting into a car; a new spurt of bone growth began in her right hip and quickly progressed downward, locking her knee and ankle. Nine months later her left leg started to be affected. She began to use a walker and then a motorized scooter. At twenty-four she was fitted for a custom wheelchair.

Nancy studied computer programming and got a job in a computer store. She was so popular and successful that she left after six months to start her own consulting business. She worked forty or fifty hours a week in addition to pursuing a full schedule of volunteer activities as an advocate for the handicapped and a speaker at churches and civic-group meetings. In 1983 she gained a degree of local notoriety when, to illustrate the challenge that the sidewalks and buildings of her home town posed to the handicapped, she persuaded a newspaper reporter and a Kiwanis Club member to get into wheelchairs and carry out a set of tasks she assigned.

After work on April 12, 1985, a special bus with a wheelchair lift picked Nancy up at a client's company. The driver parked outside the house Nancy shared with her sister and brother-in-law and lowered the motorized wheelchair lift from its vertical, folded position to form a horizontal platform. She rolled herself on and locked her wheels in place. The bus service owned several vehicles with lifts made by different manufacturers, each with different hand-held controls. On the most common model the bottom one of three buttons lowered the platform to the ground. On the bus Nancy rode that day, when the driver pushed the bottom button, it folded the platform back into the bus. Nancy was catapulted backward, and ended up with her head and shoulders against the opposite side of the bus.

Over the years the muscles in Nancy Whitmore's neck had been almost entirely replaced by bone, which broke under the force of her fall, leaving her head dangling grotesquely. Fortunately, her spinal cord was not damaged, and the immediate injuries, despite appearances, turned out to be relatively minor—at least, they would have been minor in anyone else. Her body's misguided attempts to heal her assorted bruises, breaks, and sprains transformed normal muscles and tendons into bone. Irregularly shaped new spurs of bone immobilized her back and made sitting for any extended period acutely uncomfortable. She lost all remaining motion in both hips and knees. Her ankles fused. More than a year later, in a delayed response, her jaw became involved.

One feature that marks victims of FOP, one that strikes everyone who meets them, is their ability to take the unbearable in stride. The first time I spoke to Nancy on the telephone, I asked her about this, and she said perhaps it is because FOP is so slow and predictable that people who have it can see challenges coming, prepare for them, outsmart them, and delight in the triumph.

Nonetheless, the abrupt and permanent loss of some abilities can be devastating. When Nancy's jaw became rigid, she wrote a list of things she could no longer do, such as eat anything but "slurped," or pureed, meals that looked like cat food, brush the backs of her teeth or floss, stick her tongue out, yawn, cough effectively, lick envelopes and stamps, whistle, kiss, and lick her lips. She feared choking on food. Vomiting would be a nightmare. It bothered her that her young niece pretended that her dolls aspirated food and had to be suctioned.

When Nancy's body finally settled into its new shape, she went to the Mary Free Bed Rehabilitation Hospital, in Grand Rapids, to have her custom wheelchair modified. The International FOP Association had just gotten under way, and she was eager to find new members, so she asked the staff at the center to give her name and address to any other FOP patient who might pass through.

Andy Sando was an FOP patient who lived in St. Joseph, Michigan. He went to college, worked at odd jobs, tried to make it as a cartoonist, and then studied computer graphics and design. He lived independently with minimal help, and coped without a wheelchair until he injured his leg, in 1985. Even then he relied on a manual push chair only when necessary, and otherwise staunchly defied his handicap, insisting on walking even if it wore him out. In April of 1988, however, Andy conceded that he was needlessly limiting himself by refusing a power wheelchair. He went to Mary Free Bed, where the staff told him about Nancy Whitmore. He was mildly interested in the prospect of meeting someone else with FOP, he told me recently, but he was too busy with school and other things.

"Tell him the truth," Nancy piped in.

"Well," Andy confessed, "St. Joe is a small town compared with someplace like Philadelphia, but at least we have things to do. They told me there's this woman up in northern Michigan, in the north woods. I figured she was probably some frumpy old hick. Some lumberjack's daughter in a flannel shirt. All I remembered from a trip my family took up there when I was little was that the stores were full of moccasins. So I promptly forgot about Nancy."

Nancy, though, heard about Andy. She wrote, care of the rehabilitation center, inviting him to join the IFOPA. A week later, in August of 1988, Andy telephoned. They immediately realized that they shared many interests and values. They began writing and calling each other once, twice, six times a week. They decided to meet. In the second week of October, Andy and his mother drove up to northern Michigan.

Nancy and Andy met a few more times that fall. In December they were married. As they were pronounced man and wife, Andy's brother called, "Let's get him, boys!" and several of Andy's friends grabbed the rigid groom, picked him up, and tilted him sideways to kiss the bride. A photograph in the Sandos' wedding album shows Andy nearly horizontal, with a huge grin on his face.

The Sandos' house and circumstances are models of how the severely handicapped can live independently and with dignity. A legal settlement for Nancy's accident provided money to modify the house she had shared with her sister's family, now occupied by her, Andy, and their caregivers. Her complete disability justified complete medical and personal care. The insurance company offered to pay for a nursing home. Nancy successfully argued in favor of being her own health-care provider, hiring and managing round-the-clock caregivers who would tend to her needs in her own home. Health-care economics being what they are now, both the company and Nancy got a good deal.

The Sandos call their house an "interconnected duplex." The nighttime caregiver occupies the original house, while the Sandos live in a new addition. Ramps lead to the front door and the back yard. To accommodate wheelchairs, the addition has few halls, and all doors but the front one are pocket doors that can be pushed open with one foot. The nucleus of the house is the Sandos' bedroom, or "the room of many doors," with access to both sides of the house and to the back garden. Two television sets let them watch the same program while lying in bed, despite their different body positions. The bathroom features a large hot tub to help ease the aches of FOP, with an electric hoist and a sling to maneuver them into the tub. "No one but me holds the control box when I'm in that lift," Nancy says. "I've learned."

Most of the house is one large, bright room, combining kitchen, living room, and Nancy's work space. Andy has his own small office. Each of their computers—a computer is one of the greatest boons to a person with FOP—is adjusted to its user's unique position. Kitchen counters are slightly raised, to accommodate Nancy when she stands. Light switches are low, at wheelchair height. The computers are wired to the wall switchplates, with bright red switches to distinguish them from the lights. The couple debated over floor coverings, and still are not quite happy. Most of the house is tiled, to bear the weight and friction of heavy electric wheelchairs. Elsewhere carpet lends warmth and dampens the hard acoustics. But one carpet has already been ruined by a wheelchair-battery leak—a housekeeping problem that most people don't have. For someone with FOP this house is the best of all possible worlds.

In the early 1960s Marshall Urist, an orthopedic surgeon and bone scientist at the University of California at Los Angeles, found that when demineralized bone—the essence of bone, without its calcium content—was implanted in a pouch of muscle, it induced that tissue to create a lump of bone. Urist was able to extract protein that retained this osteoinductive capacity, which he called "bone morphogenetic protein," or BMP, though he was unable to purify it completely using the technology available at the time.

More than twenty years later John Wozney and some colleagues at Genetics Institute, a Massachusetts biotechnology company, succeeded in purifying and sequencing four bone morphogenetic proteins from cow bone. In retrospect, Urist's difficulties were hardly surprising. BMP is a whole family of substances rather than a single entity (more than a dozen had been found by 1996), and each is present in the body in minute quantities. Wozney began with huge masses of raw cow bones, which were cleaned of their outer tissue and marrow and then pulverized. Forty kilograms of bone powder was treated with acid to dissolve away the calcium and other minerals that make up about 70 percent of bone's mass, leaving a rubbery residue of protein of various kinds. Ninety-five percent of this protein is collagen, which was discarded. The remainder was sorted according to protein size by gel electrophoresis, and each purified protein type was then laboriously tested in mice for its capacity to induce new bone growth. Wozney ended up with forty millionths of a gram, an invisible speck, of pure BMP.

When Zasloff saw Wozney's paper, in the December, 1988, issue of Science magazine, he showed it to Kaplan in great excitement. Zasloff had long suspected that Urist's elusive BMP might be implicated in FOP. No other known substance, after all, could produce new bone. But the most astonishing part of Wozney's paper was not that he'd been able to purify BMP. When a scientist identifies a new protein or gene sequence, he punches it into a computer database to learn whether it truly is new and whether it is similar, or homologous, to anything else. Homology provides important and sometimes unexpected clues to a molecule's function and evolutionary provenance. Sequences drift over time. All allow a certain amount of leeway, but crucial features cannot change without losing their function. Very important or fundamental sequences are generally held within strict bounds.

When Wozney looked for near matches to the BMP sequence, he found a strong similarity to the protein product of the decapentaplegic (dpp) gene. Dpp is not a human gene. It is found in Drosophila melanogaster, the fruit fly.

"My God, that's incredible!" Fred Kaplan says. "This amazing similarity of a human protein to a fly protein? How far back in evolution can we trace an ancestor common to a human being and a fly? Oh, about six hundred million years ago. The fact that the structure of any protein would be so highly conserved over that gulf in evolution suggests that this protein must be pretty important, and that nature can't tamper with it too much. But what does it do? Flies don't have bones. People don't have wings. What does this protein do in the fly?"

Zasloff and Kaplan called William Gelbart, a professor of cellular and developmental biology at Harvard University, the discoverer of and leading authority on dpp. He was coming to Philadelphia soon anyway, and a breakfast meeting was arranged at the White Dog Cafe, a popular Penn campus restaurant. Gelbart, Kaplan, Zasloff, and Jeff Tabas, the first FOP research fellow, sat down for coffee at 7:00 A.M. Just before 1:00, when Zasloff had to leave for a lecture, the waitress asked whether they cared to order lunch. These specialists in wildly different areas of science had been wholly absorbed, even incredulous, as they discovered a strangely suggestive, wholly impressionistic common ground.

The work moves more slowly than anyone would like, but in the few years since Zasloff and Kaplan met, around the same time that Jeannie Peeper founded the IFOPA, medical researchers have made important inroads. BMP is definitely involved in the disease, although it may not be the direct cause. Efforts to identify defects in the gene, or in genes that are upstream or downstream in a regulatory cascade, have thus far been in vain. How new bone forms in an embryonic pattern remains a tantalizing mystery.

Nonetheless, Kaplan's group recently found high concentrations of BMP in the lymphocytes of a large proportion of patients. This suggests an explanation for the tendency of injuries in FOP patients to heal as bone: the very cells that in normal repair swarm to the site to help in these people may carry with them doses of BMP and turn everything into bone. Kaplan will soon begin studies with a novel family of drugs to see whether the process of cartilage and bone formation can be halted. Unexpectedly, the leading candidate is a substance that Zasloff discovered in a shark while exploring for antibiotics. It inhibits the formation of new blood vessels, a necessary first step in the creation of any new tissue. Of possible significance is that the shark skeleton consists entirely of cartilage, without any bone.

In 1988 Zasloff's FOP patients were turned away from the NIH. He was gratified and vindicated when, at the end of 1993, the NIH approved a large grant for Fred Kaplan's work on the role of BMP. Grant reviewers gave the proposal a very high score, concluding that the hypothesis was "one of the most original and interesting ideas" in the field.

I have repeatedly found myself thinking of the word "heroic" in connection with FOP patients and their families. I wondered whether I had friends or relatives who would be so generous, whether I myself possessed the greatness of spirit to do as much for others as they do. I wondered why I thought of this as heroic. Being the random targets of a genetic defect should neither ennoble nor diminish these people. Malvolio's refrain in Twelfth Night ran through my mind: "Some are born great, some achieve greatness, and some have greatness thrust upon 'em." Perhaps many of us have the capacity for heroism, but few are called to show it. Those with FOP have had heroism thrust upon them.