Bone Deep: How One Man, Three Institutions, and White-Tailed Deer are Fighting Bone Disease
Andersson Dyke was born on Dec. 22, 2000, weighing three pounds and 11 ounces. She had her mother’s bright blue eyes and a wisp of blonde hair. Andersson cried and cooed like the other newborns in the neonatal intensive care unit at Texas Children’s Hospital, but there was something different about her. Unlike the other babies, her bones were as fragile as glass.
When Andersson was just a month old, her mother, Sarah, brought her to the pediatrician for a routine checkup. The pediatrician lifted Andersson onto the examination table and began checking her heart, lungs, eyes and ears. Everything looked normal. He held up her legs to check her hips and make sure there were no problems in her joints. And that’s when he felt it: He had broken her femur.
Flummoxed by the sudden and unexpected break, the doctor ordered a magnetic resonance imaging scan to examine Andersson’s thighbone. She needed an intravenous line first, but when the nurse fastened the blue tourniquet around her upper arm, Andersson’s humerus—the long bone that runs from the shoulder to the elbow—snapped.
“After moving her and doing all of that to get an MRI, she came out with almost all of her long bones broken,” Sarah said.
Doctors soon diagnosed Andersson with a unique case of osteogenesis imperfecta (OI), a lifelong disorder more commonly known as brittle bone disease. The condition is caused by a mutation in a gene that affects bone formation and strength. While healthy bones are made of dense living tissue that is constantly being broken down and regrown, Andersson’s bones have low density and are prone to fracturing. In search of answers, the Dyke family turned to a group of doctors in the Texas Medical Center dedicated to studying the full gamut of bone diseases and translating scientific research into bone-saving therapies.
“By understanding and knowing all the different mutations that can affect bones and then developing targeted therapies, we can much more rapidly and more powerfully treat the conditions,” said Brendan H. Lee, M.D., Ph.D., Baylor College of Medicine human and molecular geneticist and co-director of the Rolanette and Berdon Lawrence Bone Disease Program of Texas.
The team of doctors who treated Andersson, including Lee, prescribed her bisphosphonate drugs, which are clinically proven to prevent bone loss.
“It worked,” Lee said, “but it wasn’t a cure.”
Getting married
The Rolanette and Berdon Lawrence Bone Disease Program of Texas began with one man’s visit to the doctor nearly 15 years ago.
Retired tank barge magnate and philanthropist Berdon Lawrence met with endocrinologist Robert Gagel, M.D., head of internal medicine at The University of Texas MD Anderson Cancer Center, for a spinal problem his internist noticed on a routine chest X-ray. Lawrence had a long family history of severe osteoporosis, which occurs when the creation of new bone in the body cannot keep up with the dissolution of old bone. The condition causes porous and brittle bones that can break from even the slightest movements, including sneezing or coughing.
When Lawrence was diagnosed with severe osteoporosis, he was surprised to learn that there was no concerted effort to study bone disease across Texas Medical Center institutions.
By Lawrence’s second visit to Gagel’s office, the two men agreed that the lack of bone research and treatment in Houston was a serious detriment not only to the growing number of baby boomers entering peak osteoporosis age, but to other patients, like Andersson, who suffer from lesser known bone diseases. Lawrence and Gagel wondered if there was a way to sidestep the competition between TMC institutions and develop, instead, a collaboration.
They approached Baylor College of Medicine, where Gagel had been a faculty member in the division of endocrinology.
“The Texas Medical Center has the thing that other cities don’t have: It’s that we’re all together,” Gagel said. “That’s our strength. We don’t need to build strong collaborations within the institutions. We already have them. We just need to work together.”
But it wasn’t easy.
MD Anderson and Baylor each have a wealth of proprietary information, so the legal agreement to work together in one specialized program meant sharing research, technology and finances. This was new territory for both institutions. They essentially had to agree to a pre-nup.
After a year-long legal tug of war and a sizeable endowment from Lawrence, the bone disease program made its official debut in 2002. As the program grew, Lawrence brought The University of Texas Health Science Center at Houston (UTHealth) into the fold in 2014.
“Putting the three of them together is like having 10 institutions,” Lawrence said. “I see there’s lots of collaboration between all of them now, and I think it will accelerate the technology and the success in solving a lot of these bone diseases.”
Lauded as the first cross-institutional, multidisciplinary effort of the Texas Medical Center, the program is co-directed by Gagel, Lee, and UTHealth cartilage disorders expert Jacqueline T. Hecht, Ph.D. Its mission: to research and treat a kaleidoscope of “silent killers,” including osteoporosis, brittle bone disease, craniofacial disorders and the spread of cancer to the skeleton.
The program has been “a real paradigm for collaboration,” Lee said.
“It builds on the strength of all these institutions and puts a legal agreement to get everyone to work together. It was kind of like getting married at some level.”
The program operates like the hub of a wheel, Lee explained, while the spokes represent various activities occurring within Baylor, MD Anderson and UTHealth.
With financial and technological support from the three participating institutions, researchers involved in the program have made significant scientific discoveries. Gerard Karsenty, M.D., Ph.D., identified gene RUNX2 as the main protein responsible for bone formation. Benoit de Crombrugghe, M.D., discovered that osteoblasts—the cells that make bone—derive from the same lineage as chondrocytes—the cells found in cartilage. And Lee pinpointed CRTAP as the gene responsible for modulating bone collagen and then identified how mutations within it cause osteogenesis imperfecta.
“When we bring all of the patients and all of the institutions together as part of the program,” Lee said, “we are now actually elucidating at a very refined level the function of all the things that control bone health. That’s been the enormous achievement.”
“We all have expertise in different areas,” Hecht added. “By putting us together, we are stronger as a group than we are individually.”
A little earthquake
Andersson Dyke’s spine follows an S-shaped curve that limits the space in her chest and weakens her lungs. Without her walker or wheelchair, she can only amble around a short distance before she runs out of breath and her bones begin to ache.
At a young age, she endured an extensive surgery in which doctors placed metal rods in her arms and legs to splint her long bones. But her bones still break. They’ve broken “up to a 100” times in Andersson’s 15 years, her mother said, though it’s hard to keep track because of how frequently it happens.
“When she was a baby, she would break a bone about once a week,” Sarah said. “It’s still physically and emotionally painful.”
But with the bisphosphonate treatments, Andersson’s fractures have become less frequent, giving her the chance to lead a more ambulatory and independent life.
Between 20,000 and 50,000 cases of osteogenesis imperfecta exist in the United States, according to estimates from the National Institutes of Health. With more than 800 different mutations currently known to cause OI, biochemical and DNA testing can often help patients and doctors identify the type and severity of the disease, as well as potential therapies. Because Andersson did not exhibit the typical forms of the disease, she confounded doctors, who were unable to genetically determine her condition. Ultimately, she was clinically diagnosed with type 3 OI, considered the most severe of the eight known types of brittle bone disease in children who live past their first few months.
Eventually, Andersson adapted to her constantly fracturing bones and learned to become ambidextrous amid a never-ending cycle of pain and necessity. When she broke her left arm, she’d use her right arm to write, eat, draw and perform other activities. When the right arm broke, she’d switch back to the left and start the process all over again.
“People think I’m crazy because we wouldn’t go to the doctor every single time,” Sarah said. “We would be there all the time.”
It’s true. Given the rarity of Andersson’s condition, most doctors would waste time scratching their heads, while Andersson already knew the protocol: Wrap the site of the fracture to support it without completely immobilizing it, get comfortable on the living room sofa, turn on the television to Nickelodeon, and try not to move until the fracture becomes less painful. It usually takes Andersson’s body a week or two to heal from a hairline fracture. But when a bone breaks all the way through, it can take up to two months to heal.
“I know my body really well,” Andersson said. “Every time I break a bone, I can accurately tell what happened to it. If it’s just a pop, then I know it’s a little pop. But if it’s a break, then I can hear the bones.
This March, Andersson was walking around her house when she suddenly felt an excruciatingly sharp, cracking pain in her leg, like “a little earthquake in my bones,” she said.
Her femur had snapped, out of the blue. The metal rod was the only thing keeping her leg straight.
“The hardest part about OI is that you never know when it’s going to happen,” Sarah said.
There are currently six classes of drugs—including bisphosphonates that block osteoclasts from dissolving bone—and at least three new therapies pending Food and Drug Administration approval designed to treat bone loss. But there is still more to be done for patients.
“Our goal is to take a situation in which people lose bone, and reverse it,” Gagel said. “We have gotten reasonably good at that.”
While there is currently no cure for OI, osteoporosis and many other bone diseases, doctors at the Rolanette and Berdon Lawrence Bone Disease Program of Texas see new hope on the horizon—for Andersson and millions of others—in the antlers of white-tailed deer.
Antlers
“Berdon, I’d like you to bring me a deer antler home,” Lee told Lawrence on the phone about two years ago. Lawrence, who owns a 14,000-acre ranch in South Texas, knows a thing or two about deer. But what Lee wanted with an antler was a puzzler.
“Okay, well, I can do that,” Lawrence responded. “But what do you need a deer antler for? You want something mounted to put in your house?”
No, Lee didn’t want a rack to hang above his mantel. Instead, he wanted to analyze the antler as part of a new study for the bone disease program. Deer antlers have fascinated those in the bone field for a long time because bucks are able to grow them back every year, in pattern, over three or four months. Additionally, deer antlers share many properties with human bone and serve as excellent models for bone growth in humans.
“It’s the fastest regenerating organ in the animal world,” Lee said. “We thought, ‘Wow, wouldn’t it be amazing to understand how that works?’”
Lawrence never did bring Lee a deer antler. Instead, Lawrence took him to the Caesar Kleberg Wildlife Research Institute at Texas A&M University-Kingsville on King Ranch, where he was able to collect blood samples from white-tailed deer for his research. Lee and his team became the first to sequence the whitetailed deer’s genome, a sequence with more than three billion nucleotides. The process took nine months.
Lee said he believes analyzing the complete deer genome will open a whole new frontier in bone disease research. Understanding which genes regulate antler growth and provide blueprints for their structure could lead to novel bone regeneration therapies to help patients with a range of bone diseases—everyone from 15-year-old Andersson Dyke to 74-year-old Berdon Lawrence.
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All about bones
In literature and the arts, the human skeleton is often a memento mori associated with the macabre and death. But bones give us life. Bones provide our bodies with shape, support and movement, while protecting our vital organs from external damage. Bone marrow contains stem cells that develop important oxygen-carrying red blood cells and infection-fighting white blood cells. Bones also release osteocalcin, a protein that helps regulate the body’s blood sugar and fat, and store essential minerals.
Bones are primarily made up of three components: Type 1 collagen, the same type of molecule found in the skin; calcium phosphate; and calcium carbonate. The collagen is a long protein that weaves together with two other strands of collagen to create a flexible rope-like structure with grooves along the sides. Crystals of calcium phosphate and calcium carbonate attach within these grooves to provide rigidity and strength.
When a bone fractures, blood clots around the site of the break and specialized immune cells, called phagocytes, devour bacteria, foreign particles and dead cells to protect the bone from infection. Cartilage cells, called chondroblasts, then produce the collagen matrix around the fracture to connect the bones, allowing osteoblasts—cells that synthesize bones—to begin calcifying and building new bone.
