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.
Late 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.