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F E B R U A R Y 1 9 9 8
APLAN has always seen patients regularly in his office, but to form a better
idea of their daily lives he began visiting them where they lived. In January
of 1991 he and Randy Cohen, one of the first FOP research fellows, flew to
northern Michigan to see a married couple with FOP: Andy and Nancy (née
Whitmore) Sando.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.
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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.
OP was always assumed to be hereditary, though this belief was based on old,
uncertain, largely anecdotal reports. Proof came when Kaplan learned of two
American families, a father and child in Louisiana who had the disease, and an
afflicted man in Georgia whose three children also had FOP. Another family
turned up overseas. There are so few of these instances, however, because FOP
patients rarely marry and have children. Most cases of the disease result from
a mutation in a sperm or an egg cell which causes FOP only after it has been
passed on to the next generation. Modern techniques of genetic analysis are
powerful tools for identifying genes that cause disease, but they require very
large populations, which do not exist with FOP. So the next step in FOP
research was to study the process by which bone is formed.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.
ATE one evening in May of 1990, as Zasloff, Kaplan, and Tabas worked together
in the lab, Zasloff suggested that they put together a meeting of doctors and
scientists to discuss the work they had done. "Just a small group of people. A
national symposium. No, we'll make it an international symposium." By the time
the meeting actually took place, in late September of 1991, it was a large
gathering of scientists and twenty-five FOP families. During a reception in the
Egyptian Gallery of Penn's University Museum, Zasloff gazed at a stone statue
and remarked that the mystery of FOP was no easier to solve than the riddle of
the Sphinx. Yet at the close of the meeting one scientist was overheard telling
another, "I think we just declared full-scale war on FOP."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.
The online version of this article appears in two parts. Click here to go to part one.
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.
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