Duchenne muscular dystrophy is a devastating progressive genetic disease. Affecting one in 3,500 boys, the genetic basis for the disease is known. Unfortunately, however, the manifestations of the disease in muscle are far more complicated and multifaceted, and symptoms always worsen as patients age. There is no cure for Duchenne muscular dystrophy; nearly all afflicted patients die before age 30.
Two UVA Biomedical Engineering faculty members, Silvia Salinas Blemker and Shayn Peirce-Cottler, have been awarded a highly prestigious $2.5 million National Institutes of Health grant to build a computer model that reconstructs the complex cascade of events that causes the muscles of DMD patients to degenerate. Once developed, the model would serve as a platform for testing new treatments.
“Our goal is to develop an in silico model that replicates the DMD disease process, incorporating all the complex mechanisms involved in the disease, and providing an entirely new framework for identifying new treatments that will stop the disease progression,” Blemker said.
Manipulating the Dynamics of Degeneration
DMD is caused by a mutation in a gene that encodes for dystrophin, a protein that helps keep muscle cells intact. Muscle cells that lack dystrophin are fragile and easily damaged. Between the ages of 3 and 5, boys with DMD start experiencing muscle weakness. By 7 or 8, their movements are noticeably impaired, and by their early teens they are wheelchair bound and their heart and respiratory muscles continue to fail. The boys rarely survive past their late twenties.
DMD results from the interplay of biomechanical and biochemical responses. Muscle cells sense physical, biomechanical stresses in their environment, which trigger biochemical changes that in turn affect their physical properties. In healthy muscle tissue, the small contraction-induced injuries produced by exercise generate intersecting biomechanical and biochemical responses that make muscles stronger. In DMD, these same stresses generate an alternate set of responses that cause muscles to degenerate over time.
Developing a computer model of this disease process is unprecedented. The cascade of responses changes over time as the disease progresses and muscles atrophy. DMD also affects different kinds of muscles in different ways. Some muscles waste away more quickly than others. And the course of the disease varies from person to person. Computer modeling provides a unique ability to explain these observations and potentially leverage that knowledge to suggest new treatments.
“It is almost impossible when using experimental tools in the lab to determine cause and effect when dealing with large numbers of intertwined biomechanical and biochemical signals,” Peirce-Cottler said. “With a computer model you can simulate how manipulating one signal will affect all the others, and in this way you can predict how new interventions, or therapies, will work for a particular patient.”
Merging Two Approaches to Modeling Muscles
To bridge the gap between biomechanical and biochemical, Blemker and Peirce-Cottler are connecting two very different kinds of models. Finite element models, Blemker’s specialty, are used to characterize the physical properties of muscle cells as well as the forces applied to them. Agent-based models, Peirce-Cottler’s area of expertise, are used to describe the biochemical exchanges between muscle cells and all the other cell types and proteins that interact with them. “We are developing computer algorithms and code that will allows us to link these models in a seamless way,” Blemker said. “The linked model will be first of its kind.”
In order to replicate the disease, the model incorporates phenomena across multiple length scales. “We are creating multi-scale models because we need to understand how changes at the cell and molecular level affect muscle function,” Blemker said. “We also need to understand how loads we put on an entire muscle affect the disease process on the cellular level.”
Building a Platform for Discovery
Peirce-Cottler and Blemker have unique expertise at all the relevant length scales. At the smallest scale, they have developed a coarse-grained representation of dystrophin and are modeling cells and subcellular processes that muscle cells enact as they are exposed to different forces and biochemical signals. The model also includes immune cells that cause the characteristic inflammation in DMD, fat cells that infiltrate muscle during advanced stages of DMD, fibroblast cells, which cause scarring, and satellite stem cells, which allow muscles to regenerate after they are damaged.
“These models are highly innovative because they incorporate so many different cell types,” Peirce-Cottler said. “As we strive to develop new treatments for DMD, we must have the ability to predict how interventions affect all the different cell types that are implicated in disease – and computer modeling gives us that ability.”
The researchers will include data from DMD patients to provide data for their model as well as to help validate its predictive abilities. They will also do laboratory experiments to confirm their results.
Blemker and Peirce-Cottler are committed to creating a model that researchers can use to find drugs that will be effective in treating the disease as well as create exercise regimens that might forestall muscle damage from DMD.
“Our focus is to use the models to generate new predictions that will lead to novel, more effective treatments and ultimately improve the lives of boys with DMD and their families,” Blemker said. “This new perspective and approach can really make a difference.”