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For an account of a similar quest to comprehend and conquer a disease, see:
"By a combination of accident and relentless logic, several researchers are closing in on ways to force tumors to show their true colors to the body's immune system."
N October 30, 1995, Harry Eastlack arrived for a two-day symposium at the
Wyndham Franklin Hotel, in Philadelphia. Forty-three families of people with
fibrodysplasia ossificans progressiva, or FOP, were joining a high-powered
assortment of orthopedic surgeons, molecular biologists, geneticists, and other
doctors and scientists in hopes of making some sense of this puzzling
disease. Harry's sister and her husband volunteered to entertain the children
afflicted with FOP and their siblings while their parents attended professional
sessions and swapped experiences. Harry himself played no active role. He had
died in 1973. Yet his silent presence revealed the tragedy and the challenge of
FOP more eloquently than any chart, slide, or clinical description ever could.
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.
RED Kaplan's involvement with FOP began through a combination of accident and his insatiable curiosity. A slight, agile man of forty-six, with the dapper grace of Fred Astaire and a quick, nervous, precise way of speaking, he is a charming example of what doctors should be. He learned about bones early in his life, he says, by breaking a lot of them as an amateur jockey. Later he was drawn to orthopedic surgery because it seemed a vast and open field, full of possibilities. When Kaplan was invited to give an address at the University of Pennsylvania Medical School in 1988, he recalled his own third year of medical school, when he couldn't quite make up his mind and an adviser drew him aside to ask what specialty he planned to choose, saying, "You can't be a student forever, Fred." Kaplan's eyes lit up. What a wonderful ambition, he said to himself. That's exactly what I'll be -- a student forever. Penn medical students, even those with no interest in bones, clamor to do projects under his guidance; word has gotten around that he is humble and curious enough to learn, and generous enough to teach well.
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.
ICHAEL Zasloff saw his first FOP patient at Johns Hopkins, in 1977, while he had a fellowship in medical genetics under Victor McKusick, the father of the field. Zasloff was a pediatrician with a Ph.D. in biochemistry. He worked at the National Institutes of Health pursuing research on basic genetic mechanisms, but he liked to keep one foot in the clinic.
"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.
E tend to think of bone as dead structural material, like the girders of a skyscraper, which we call its skeleton. In reality bone is an active, living organ. Bones become longer and thicker as the body grows, and strengthen or weaken according to the load they bear. Bone marrow produces the red and white blood cells that nourish and protect our tissues, and platelets that stop the bleeding at the site of an injury. Bone has remarkable regenerative capacities: under optimal conditions broken bones heal with no scar, new living material fixing the defect as though it had never been. Ordinarily, growth and repair are the only reasons that new bone appears after birth.
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."
Thomas Maeder is the author of Children of Psychiatrists (1989) -- a portion of which appeared in somewhat different form as "Wounded Healers," the cover article in the January, 1989, Atlantic -- and Adverse Reactions (1994).
Illustrations by Karen Kluglein
Copyright © 1998 by The Atlantic Monthly Company. All rights reserved.
The Atlantic Monthly; February 1998; A Few Hundred People Turned to Bone; Volume 281, No. 2; pages 81 - 89.