Current Research and Scholarly Interests
The knowledge that the mechanical properties of living tissue reflect health or disease dates at least to Hippocrates. However, the underlying cellular and molecular mechanisms have only just begun to be discovered. We now know that mechanical forces at the cellular level guide stem cell differentiation, convey the health benefits of exercise, and underlie our ability to sense touch, sound, and pain. Conversely, faulty cellular responses to mechanical signals contribute to atherosclerosis, aneurism, and cancer metastasis. Understanding how cells sense and respond to their mechanical environment is thus a problem of deep intellectual and practical significance.
Below I describe three projects that together add up to a concerted effort to understand how cells detect and process mechanical signals. I’m happy to discuss any of the following ideas in greater detail, so please feel free to email me with your questions or comments.
Project 1: Understand how motor proteins use chemical energy to generate force and motion. The most familiar motor protein is myosin, which generates the force responsible for muscle contraction. Additional motor proteins are found in every cell in the human body, where they allow the cell to move and divide, transport cargo from one part of the cell to another, and participate in the detection of external mechanical stimuli. We are using sophisticated biophysical techniques to directly observe the motion of single motor proteins in order to better understand the physical principles that allow proteins to convert chemical energy into useful motion. More broadly, recent work suggests that enzymes in general may derive their incredible catalytic ability by coupling protein motion to bond making and breaking. Single-molecule biophysical measurements offer a potentially powerful way to test this idea.
Project 2: Uncovering previously unrecognized functions of mechanical force in extracellular matrix remodeling. The material properties of our own bodies are governed largely by the extracellular matrix, a complex protein and carbohydrate network that gives shape to tissues and organs. Previously, the ECM was dismissed as passive glue that simply held cells together. We now know that failure to maintain the ECM leads not only to aching knees and wrinkles, but also contributes to heart disease and cancer metastasis. We are using techniques ranging from single-molecule assays to live cell imaging to test the hypothesis that mechanical force is an unrecognized regulator of ECM remodeling. We are particularly interested in the possibility that mechanical force may increase the susceptibility of ECM proteins to proteolysis by matrix metalloproteinases, enzymes that are the subject of intense medical interest due to their prominence in cancer biology.
Project 3: Role of intercellular forces in cell and developmental biology. Our goal in this project is to determine how cells generate, detect, and respond to tension at the molecular level. To do so, we are using new microscopy techniques that allow us to measure mechanical forces inside living cells, and even in whole organisms. Questions we hope to answer in the next five years are: 1) Do cells communicate by pulling on each other, and if so, what are the biological consequences? 2) How do cells coordinate their actions over long distances in order to shape organs and tissues? 3) How do stem cells sense the mechanical properties of their environment in order to properly differentiate? Results from this project will be highly relevant to multiple aspects of human disease, to the development of stem-cell-based therapies, and to engineering complex, three-dimensional tissues in the lab.