The weak tendons and fragile bones characteristic of osteogenesis imperfecta, or brittle bone disease, stem from a genetic mutation that causes the incorrect substitution of a single amino acid in the chain of thousands of amino acids making up a collagen molecule, the basic building block of bone and tendon.
According to researchers at MIT, that minuscule encoding error creates a defective collagen molecule that, at the site of the amino acid substitution, repels rather than attracts the collagen molecule alongside it. This creates a tiny rift in the tissue, which when repeated in many molecules, leads to brittle tissue, broken bones, deformity and, in the most severe form of the disease, death. For example, if healthy collagen tissue looked like a sheet of paper, diseased collagen tissue would look more like a sheet of paper full of tiny perforations. At each of these perforations, the sheet would be considerably more prone to tearing.
In what may be the first detailed molecular-based multi-scale analysis of the role of a materials' failure in human disease, a paper in the Aug. 4 issue of Biophysical Journal describes exactly how the substituted amino acid repels other amino acids rather than forming chemical bonds with them, creating a radically altered structure at the nanoscale that results in severely compromised tissue at the macroscale. This approach to the study of disease, referred to as "materiomics" by the lead researcher on the project, Professor Markus Buehler of MIT's Department of Civil and Environmental Engineering, could prove valuable in the study of other diseases - particularly collagen- and other protein-based diseases - where a material's behavior and breakdown play a critical role.
"The consideration of how material properties change in diseases could lead to a new paradigm in the study of genetic disorders that expands beyond the biochemical approach," said Buehler.
"We wanted to see how a single-point genetic mutation in a collagen molecule could cause entire tissue to become brittle, soft and even fail. The medical community finds correlations between genetics and patients; our interest is in finding the correlation between genetics and a material's behavior," he said.
Buehler first described the materiomics approach in an article appearing in the March 2009 issue of Nature Materials. He sees the application of this approach to collagen-based diseases as a starting point that could lead to a similar analysis of the mechanical properties of tissue involved in other protein-based diseases. Brittle bone disease affects about one in 16,000 people worldwide, and defective collagen is implicated in many other medical conditions, including Alport syndrome (kidney disease) and Ehlers-Danlos syndrome (overly-flexible skin and joints). The broader category of protein-based diseases contains even neuronal disorders such as Alzheimer's disease.