On 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.
Fred 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.