Genetic missteps affecting key muscle proteins are known to cause muscular dystrophy, a term that applies broadly to a group of hereditary disorders marked by progressive muscle weakness and degeneration. Using a combination of the latest biochemical, genetic, and physiological techniques, Kevin Campbell has unraveled the molecular mechanisms underlying many forms of muscular dystrophy and discovered new forms of this devastating disease. His discoveries already have helped to improve the diagnosis of muscular dystrophy, as well as suggesting new therapeutic strategies for its treatment.
Early in his career, Campbell set out to answer questions that were not recognized as having any direct relevance to muscular dystrophy; he was interested in the structure and function of calcium channels in skeletal muscle. However, as it became clear that these channels are crucial to many physiological functions, including muscle contraction, Campbell began to wonder whether disruptions in their function also play a role in muscular dystrophy. He set out to investigate this link, and what began as a side project in his laboratory ultimately became the focus of his research.
For Campbell, whose interest in science was ignited by solving complex physics problems, muscular dystrophy is proving to be the ultimate challenge. The most common and severe form of this disease is Duchenne muscular dystrophy, which affects 1 out of every 3,000 newborn boys. This particular syndrome results from an error in the dystrophin-encoding gene—one that leads to the complete absence of the encoded protein in skeletal muscle. While searching for the function of this protein, Campbell identified the dystrophin-glycoprotein complex, a network of proteins important in maintaining the structural integrity of muscle cell membranes and in protecting individual muscle cells from damage as they stretch and contract. Muscle cells that lack dystrophin ultimately degenerate because of the instability of the cell membrane.
The discovery of the dystrophin-glycoprotein complex later enabled Campbell to identify additional forms of muscular dystrophy caused by mutations disrupting proteins that are either central to this complex or associated with it. These dystrophies include several rare forms that not only affect muscles but also cause abnormalities of the brain and eye, including mental retardation. Campbell and his colleagues also have identified the defect that leads to heart damage in some of the most severe forms of muscular dystrophy.
In recent studies, Campbell and his team have demonstrated the ability to restore normal muscle function in mice that model a particular form of muscular dystrophy. This involves expressing a protein called LARGE, which they have shown is important for linking muscle cells to their surrounding matrix. Moreover, the researchers found evidence of similar benefits when they expressed LARGE in cells from patients with related forms of muscular dystrophy that are caused by distinct genes. Their findings suggest that this approach may have clinical benefits for some muscular dystrophy patients.
As the head of a university-based laboratory, Campbell strongly believes his research goes hand in hand with mentoring the next generation of scientists studying muscle diseases. "I don't think there are many things I do that don't involve mentoring," he explains. For his dedication to mentoring students in his laboratory, Campbell has been recognized by the University of Iowa with a Distinguished Mentor Award. He says that he tries to lead by example: "I show them that you have to work hard, and when the health of patients hinges on your work, you must be committed to that work. I don't think there's time to rest on your laurels—there's still a lot of work to be done."