"It's the closest thing you'll find in real life to Kafka's Metamorphosis."
No words could describe the ailment that affected Mr. Harry Eastlack any more precisely or eloquently. In a world oft filled with robotic phrases devoid of any context, this touch of prose is welcomed. The language of science is not often conducive to emotion, and as such a disconnect exists between those who research disease from those who have it. To tell your friend you know someone afflicted with " Fibrodysplasia Ossificans Progressiva " is to conceal its harsh reality. For it takes not a scientist, but instead a poet, to truly capture the gravity of FOP.
"I saw a woman today who finally became hard as wood all over," the French physician Guy Patin wrote to a colleague in 1692.
The above account is borrowed from an article published in The Atlantic in 1998. Back then not much was known about Fibrodysplasia Ossificans Progressiva, or FOP for short. While most patients of other diseases would cringe at hearing the emotionless verbiage describing their illness, FOP patients yearned for even a hint of medical jargon to explain just what the heck was turning their muscles into bone. Terms like "stone man's disease" and "a genetic Medusa's gaze" were favorable among the media, but not so much with the patients. The press wouldn't be too keen about an obtuse and abstract medical description of FOP, but for patients it would mean that someone finally knew what genetic wire came undone, and more importantly, be able to start fixing it. It would take just over eight years from the time The Atlantic article was published before researchers would unlock the skeleton key for FOP. While eight years might seem like a lot of time to the non-scientist, considering the initial lack of interest in FOP research, eight years was fast as lightning.
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Though throughout recorded medical history there have been several accounts of FOP, not much was known about the disease until the last 20 years, with a great wealth of knowledge entering the scientific literature since 2006. Despite its striking phenotype, research on FOP was almost nonexistent until the early 1990s. The lack of NIH enthusiasm likely stemmed from two lines of thought. First, early investigations into the disease were mostly of the "trial and error" approach, simply because very little was known about FOP, which limited the ability to construct a hypothesis-driven project. And second, the number of known patients was in the low hundreds (the disease affects approximate 1 in 2 million people), not to mention a wide range of phenotypic severity. It was the classic nightmare scenario for statisticians; and also for patients, whose hopes at living a better life were locked away in the caverns of the unknown, waiting to be explored by those with a dash of adventure and a heart of gold.
Despite the initial apathy from the NIH, two intrepid researchers decided to forge ahead on their own. Physicians Michael Zasloff and Fred Kaplan had seen dozens of FOP patients during the 1980s, and though they were the experts in the field, their advice could be no more than ways to ease the pain for those being imprisoned in a second skeleton. By the early 1990s, advances in both the scientific and patient communities had gained momentum. Just a few years prior researchers had sequenced several Bone Morphogenic Proteins (BMPs) (no small task in 1988), key proteins that initiate bone development in embryos. Separate from the laboratory, the late 1980s was a time of camaraderie and connection for those stricken with the disease, as several small meetings between FOP patients were arranged. Finally, after many years of struggle and hardship by both patients and researchers alike, the 1st Annual International Fibrodysplasia Ossificans Progressiva Symposium was held in 1991.
It was not long after that first symposium that the higher ups at the NIH began to take notice. In 1993, just five years after being rejected for funding, Dr. Kaplan was approved for a large grant to investigate the role of BMP in FOP pathogenesis. The timing was perfect, as Dr. Kaplan had just recruited a junior faculty member from Fox Chase Cancer Center to help co-direct the newly formed Center for FOP Research at the University of Pennsylvania. Dr. Kaplan and his new co-researcher, Dr. Eileen Shore, moved steadfastly to compile a team of post-doctoral fellows, graduate students, and technicians all with one goal in mind - uncover as much as possible about FOP. For over a decade the team trekked along - Dr. Shore focused on biomedical research while Dr. Kaplan continued to see patients. Little by little the team assembled the FOP puzzle piece by piece.
First, they learned that BMP was most certainly involved in the disease pathogenesis, and later they narrowed it down more specifically to BMP4. Clinical observations added even more pieces to the puzzle. Though extra (heterotopic) bone formation was consistent throughout a patient's life, certain events - immunizations, infections, cuts and bruises - all led to the development of rapid lesions called "flare-ups". It was clear the immune system had an impact on the disease, but what or how was unknown.
Research continued at a swift pace until finally the team discovered the holy grail 16 long years after the Center for FOP Research was founded. On April 23rd, 2006, Drs. Kaplan and Shore published in Nature Genetics the gene and mutation that caused FOP:
"A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva"
The discovery of the FOP gene brought a lot of sense to past findings. ACVR1, the gene mutated in FOP, is a BMP4 receptor, which fit the previously known importance of BMP4 (as an aside for non-scientists, a receptor is a protein that receives molecular signals from outside a cell and transmits them within a cell).
News of discovery spread fast. On April 23rd, 2006, the same day the original paper was published in Nature Genetics, a story was featured in USA Today. Not long after that, a story about the discovery of the FOP gene made it above-the-fold in the New York Times . In the years to come, more stories would appear, even features in National Geographic and the Discovery Channel. Some would call it exploitation, others would call it awareness, but whatever you called it, the reality was the same; for patients, it finally meant a chance at a normal life. If not for them, then those who would come after. It finally meant that a wordsmith was not needed to describe their disease. It finally meant hope.
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Much can be taken from the journey along the trail of FOP research, some of it novel and some of it expected. We have our classic heroes in Drs. Zasloff, Kaplan, and Shore, whose perseverance in the face of hardship and caring for patients abandoned by the inequities of medicine are an inspiration to all aspiring scientists. We have a lesson repeated in the halls of research. Just two decades before research on FOP started, the cause of familial hypercholestrolemia (elevated cholesterol for non-scientists) was just as hidden as FOP. In order to pinpoint what exactly was malfunctioning biologically, two researchers focused their attention on a family with cholesterol levels in the thousands, way higher than even the danger level for humans. Instead of investigating mild forms of the disease, which often veils the biological problem, Drs. Michael Stuart Brown and Joseph L. Goldstein chose to tackle the most serious form of high cholesterol known to man. It is often said that the true nature of biology is revealed not in its center, but at its edges; for keeping close to this insight, Drs. Brown and Goldstein eventually discovered the Low-Density Lipoprotein (LDL) receptor and characterized its downstream pathway. For this and other contributions to the canon of cholesterol metabolism research, the duo was awarded the 1985 Nobel Prize in Physiology or Medicine. With their success, Drs. Brown and Goldstein accentuated the importance of research on rare diseases, of which FOP certainly is.
This diary is not meant to be overtly political, but as a current graduate student in cell and molecular biology, I cannot broach this subject without emphasizing the political circuitry that can quickly shut the door on future research. Any time conservatives gain power in government, an assault on science is sure to follow. Conservatives might fool the average person when they talk favorably about research and technology, but their rhetoric fools no scientist. As expected, the current Republican-controlled House of Representatives has placed science funding on the chopping block. Proposed cuts to NASA, the National Institutes of Health, and the National Science Foundation total over $1.5 billion just for this year alone. When fewer dollars get pumped into research, fewer labs get funded (or labs receive less funding), which means fewer graduate students and post-docs - all eventually spiraling down to fewer cures and treatments for diseases.
For any aspiring scientist, this death spiral means more competition for positions and more stress as a researcher. As you can imagine, this is not a recipe for success in the lab.
For me specifically, it means that hundreds of FOP patients will spend another day waiting for a treatment to stop the progression of their painful second skeleton. You see, the reason I told you the story above is because I am currently a graduate student at the Center for FOP Research. I have met a teenage boy with FOP, and I can tell you it is the most disabling disease I have ever encountered. But beyond the contorted spine, fused neck, and entrapped arms is hope; if that boy can argue with his parents and text on his cellphone like any other teenager - a semblance of normalcy in the most abnormal world imaginable - then perhaps we can show the world that knowledge is power, and through science comes knowledge.
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A great deal of gratitude is owed to Harry Eastlack, from whose skeleton our lab has gathered an innumerable amount of insight into FOP. It is only fitting that Mr. Eastlack's final resting place is in his hometown of Philadelphia. For him, the old adage "you're never too far from home" rings true. But his presence is also particularly strong for the FOP research community, as we are only a 20 minute walk away from seeing the man whose sacrifice helped lay the foundation for our work. Even to this day we sometimes get a little smarter about FOP by reexamining Mr. Eastlack's skeleton, looking for a replication of any new clinical observation we may encounter.
Perhaps the most comforting aspect of FOP is that even though patients are imprisoned in a panopticon of bone, their mind remains free. It gives us comfort than when we find a treatment for the disease - and believe me, we will find it - our patients will be able to enjoy it with the utmost salience. The tales of this brave Stone Man construct a story about despair and hope, ignorance and knowledge, and they will forever be a part of me.
If you are interested in learning more about FOP, please visit the International Fibrodysplasia Ossificans Progressiva Association website at http://www.ifopa.org