Linda Sandell, PhD (center), in her lab with summer students Alexis Webber (left) and Celine St. Pierre. “(Linda)’s an innovative, world-class investigator, and her work with cartilage growth and repair will provide much of the foundation for what we’ll do clinically in treating arthritis and cartilage injuries during the next 15 to 20 years,” says Richard H. Gelberman, MD, the Fred C. Reynolds Professor and head of orthopaedic surgery.
When a bone breaks or cartilage tears, an orthopedic surgeon repairs it, and the tissue heals. The patient probably will get some physical therapy to strengthen the area around the injury, and life will go on.
But what happens at the cellular and molecular levels to promote, or to inhibit, that healing? Surgeons and rehabilitation specialists concentrate on the anatomical and mechanical parts, but Linda Sandell, PhD, looks at the biology. She’s the Mildred B. Simon Professor and the director of research in the Department of Orthopaedic Surgery at Washington University in St. Louis School of Medicine.
“There are any number of opportunities to apply biology to orthopedic problems,” Sandell says. “Injuries and arthritis involve more than fractures and tears. There’s an entire backdrop of molecular and cellular events involved.”
DNA and collagen
Sandell always was interested in biology, and that interest became a passion during her last two years of undergraduate work at the University of Denver.
“Our new chairman brought in ‘real’ scientists who quoted scientific papers and who actually did research,” Sandell says. “They also knew about DNA. And when I started to learn about DNA, that was it! It became my favorite topic.”
She earned both bachelor’s and master’s degrees in Denver, and then left Colorado for Cambridge, Mass., to work in a laboratory at Harvard University. That’s where Sandell — now the president of the Osteoarthritis Research Society International and director of the Osteoarthritis Biomarker Global Initiative — began looking at connections between DNA and arthritis.
In the years since, much of her work has focused on a subtle difference that she discovered in the collagen gene, finding new proteins and understanding the regulation of gene expression.
Sandell did her doctoral training at Northwestern University in a laboratory that studied collagen, the fibrous substance that is the main component of connective tissue in the body. Collagen is found in tendons, ligaments, skin, cornea, bone, blood vessels and cartilage. It is the foundation of what is called the extracellular matrix, a complex mixture of nonliving material that surrounds cells.
As she worked with collagen and studied its DNA, Sandell learned that the collagen gene comes in two forms: One promotes growth, and the other kills the cells around it. The only difference is a small change in the gene. Since discovering that change 20 years ago, she has spent considerable time determining how those two forms behave. One of the collagen gene splice forms keeps blood vessels from growing into cartilage. That function is vital to growth.
“We have growth plates at the ends of our bones so that those bones can get longer,” she says. “If blood begins to flow into this cartilaginous component at the ends of the bone, it will calcify and become bone, too, and it won’t grow anymore.”
Collagen is important in preventing blood vessel development near those growth plates. One of the collagen splice forms kills cells that might build those vessels. Meanwhile, the other splice form binds to growth factors and stores them up in the extracellular matrix.
As her laboratory has come to understand how the gene works, the experimental effort has led Sandell from cartilage to tumors. She has been working with other Siteman Cancer Center researchers using the deadly form of the collagen gene to kill breast cancer cells. That research led to a patent application earlier this year, one of six that Sandell’s work has generated in the past two decades.
“That’s how basic science works,” she says. “If you keep looking at the basic science, you’ll eventually find ways to apply it. First, we determined how those two splice forms worked. Now that we’ve pretty well figured it out, we can translate that information into potential treatment strategies, possibly for a number of disorders.”
Sandell also applies her basic science knowledge to osteoarthritis. It’s a complex disease, but between 50 percent and 75 percent of the risk is genetic. As head of a global osteoarthritis biomarker effort, Sandell is looking for genetic markers that might indicate which patients are at risk to ensure a more accurate diagnosis and earlier treatment.
She works with several mouse strains to study what happens to mice after knee surgery, trying to learn how various genetic markers increase arthritis risk or protect against the problem.
“Compare it to osteoporosis,” she says. “We don’t wait until someone is elderly and has a fracture before we treat them, but that’s how it used to be. With arthritis, we tend to diagnose with an X-ray, but our goal is to push diagnosis back into the molecular realm and detect who will get osteoarthritis long before symptoms appear.”
The Center for Musculoskeletal Research
As she continues working with collagen and arthritis biomarkers, Sandell also is interested not only in what happens in her lab but throughout the Department of Orthopaedic Surgery, which ranked first in its discipline in National Institutes of Health (NIH) funding in 2009, receiving $4.9 million in grant funding. She also directs the Center for Musculoskeletal Research, bringing together not only orthopedics researchers but also investigators from 50 other laboratories. The center supports the creation and study of animal models relevant to musculoskeletal biology and disease.
“When I arrived in 1995, there was no NIH funding in orthopedics. Dr. Sandell helped considerably in our rise to national prominence in research effectiveness and in extramural support,” says Richard H. Gelberman, MD, the Fred C. Reynolds Professor and head of orthopaedic surgery. “She’s an innovative, world-class investigator, and her work with cartilage growth and repair will provide much of the foundation for what we’ll do clinically in treating arthritis and cartilage injuries during the next 15 to 20 years.”
Sandell and Jansci on a hike
When she’s not working with cartilage and collagen, Sandell enjoys canvas and glass. She’s an avid art collector. She also loves music. Her house contains both a piano and a harpsichord. And for the last year she also has been a certified yoga instructor.
“I don’t have to figure out art. I don’t have to figure out music. I can just do the emotional part,” Sandell says. “Interpreting genetic data is a lot different than interpreting a painting, and having a love for both helps keep both sides of my brain engaged.”
With no children of her own, Sandell says her niece and nephew get the benefit.
“I just took my niece to Washington, D.C., and my nephew and I have traveled all over the world,” she says. “In the fall, I’ll be installed as president of the Osteoarthritis Research Society at a meeting in Brussels, Belgium, so my nephew is coming with me, and we’re going early for a ‘beer tour.’”
Fast facts about Linda J. Sandell, PhD
Education: BA in zoology, 1969, MS in biological sciences, 1970, University of Denver; PhD in biochemistry, 1980, Northwestern University; Postdoctoral fellowship in molecular biology, 1980-82, University of Chicago.
University positions: The Mildred B. Simon Professor and director of research, Department of Orthopaedic Surgery; professor of cell biology and physiology; member, Siteman Cancer Center.
Family (Bartlett, Ill.): Brother, Mark; sister-in-law, Janet; niece, Katie, 21; nephew, Kevin, 24; mother, Thelma Broeker, 93; dogs, Maxi, 10, and Jansci, 8 months.