OREF award winner cracks code on idiopathic scoliosis
Genetic research on familial idiopathic scoliosis, the condition of side-to-side curves in otherwise normal spines, is uncovering the links and opening the possibility of a screening test.
Nancy H. Miller, MS, MD, the 2001 winner of the Orthopaedic Research and Education Foundation’s (OREF) Career Development Award, is among those leading the way to a breakthrough.
In generation after generation, scoliosis brings certain families physical deformity and emotional pain, both of which can be severe. Familial idiopathic scoliosis affects 2 percent to 3 percent of the population; 90 percent of the patients who necessitate surgical intervention are female. There is no cure, and only bracing and surgery are available for treatment.
Dr. Miller, currently professor of orthopaedics at the University of Colorado, Denver, is renowned for her work in deciphering the genetics of scoliosis, a condition she first encountered as a pediatric orthopaedics resident at Boston University.
“When we got down to the scoliosis clinic in the hospital, all these preadolescent females wanted a woman resident,” Dr. Miller recalls. “I was intrigued. But my real interest in scoliosis came from working with Dr. Ponseti.”
As a research fellow under Ignacio V. Ponseti, M.D. at the University of Iowa, Dr. Miller began looking at the pathology of scoliosis, even before the emergence of molecular genetics. She devised a series of experiments to examine the ligaments of the spine. This highly organized network of elastic fibers connects the bones of the spinal column.
“One hypothesis was that the ligaments—that elastic fiber system—had something to do with the development of scoliosis. It could easily be examined, because each of the ligaments in the spine has a significant percentage of elastic fibers,” explains Dr. Miller.
“You could take the ligament to the laboratory and look at it through a microscope. You could look at the cells and how they expressed different aspects of the elastic system. It turned out to be relatively fruitful research.”
From proteins to genes
As Dr. Miller moved into clinical practice, her focus shifted to the individual proteins that make up spinal ligaments—including collagen, elastin, and fibrillin. Her researched focused on how these proteins affect spinal stability. This work was supported in part by a 1991 OREF Research Grant.
With the advent of genetic investigation, Dr. Miller began gathering data and visiting families with a history of scoliosis. Researchers working on the human genome project had already begun to identify some promising genes.
“On one of my family visits,” Dr. Miller remembers, “the grandmother ran out of the room in tears. She has five beautiful granddaughters, and three of them are in braces. I think it hit her that she’s the one with scoliosis; she feels responsible.”
Candidate-gene and later sequencing studies led to Dr. Miller’s receiving the 2001 OREF Career Development Award. The $225,000 OREF Award made it possible for her to assemble a critical mass of data. Those data were the basis for securing critical funding support—in excess of $2 million—from the Center for Inherited Disease Research (CIDR) for a genome-wide scan of the entire population under study. It was one of the largest projects their review board had approved.
“I had identified the disease. I had my population. My population was very well described through highly detailed clinical information. I actually had the genome-wide research in hand with the statistical package behind it,” says Dr. Miller.
“That’s when the National Institutes of Health (through CIDR) said, ‘We’ll fund you,’ at a time when funding for studies of complex disorders was difficult to obtain. I could not have done this without the OREF Career Development Award. It was a big step up,” she says.
Since then, promising pathways have surfaced. By 2005, chromosomes 1, 6, 8, 9, 16, and 17 showed the strongest linkage to idiopathic scoliosis. Now Dr. Miller is about to publish evidence that chromosomes 5, 13, and 19 may also be significant.
Building blocks for a cure are yet to come. Still, Dr. Miller believes her research is a source of hope. Even for families for whom answers will come too late, knowing that the research is continuing brings some comfort.
“One woman called me and wanted to know where we were on our research,” says Dr. Miller. “She and her husband had already decided, due to her scoliosis, not to have children. ‘I couldn’t have children,’ she said. ‘My life is just misery from day to day. I’ve had five back surgeries and I’m not even 40. I couldn’t give this to anybody.’”
Looking forward, Dr. Miller sees the possibility of a screening test and more specific therapeutic options to help larger numbers of families. But more research—and more funding—are needed. Dr. Miller says all orthopaedic surgeons have a vested interest in supporting OREF.
“To be a better clinician, you need to have a fundamental knowledge base in orthopaedic research,” she says. “Patients have become much more knowledgeable regarding their conditions and current research efforts. Patients are going to make treatment choices, influenced by how much their surgeons know.”
Opportunities for giving
Since 1955, OREF has provided more than $59 million in funding for more than 2,500 grants on research subjects ranging from investigations of the process of fracture healing to studies of the capacity of proteins to bind in the tendon—which led to further studies that ultimately resulted in the development of Bone Morphogenetic Protein. To make a contribution to OREF’s 2007 Annual Campaign, or for more information about OREF, please log on to www.oref.org.
Applications for 2008 OREF funding will soon be available. Most applications will be due by October 2007, but please check www.oref.org for updated information. Address any questions to Jean McGuire at firstname.lastname@example.org or (847) 384-4348.