Niels Bohr Lecture by Alexander Dunn, Stanford University

Physical principles of cellular self-organization in cardiovascular health and disease

ABSTRACT

The remarkable capabilities of living tissues reflect the self-assembly of biological macromolecules into structures far larger and more complex than their individual components. My laboratory seeks to understand the physical principles that allow molecular interactions to produce organized, functional tissues. In this talk, I will focus on cardiomyocytes (heart muscle cells), whose contractile machinery, built from repeating units called sarcomeres, provides a striking example of biological self-assembly.

Using measurements that apply controlled forces to single protein molecules, we find that α-actinin-2, a core component of muscle fibers, binds actin filaments with a strength that depends sharply on both the magnitude and the direction of the applied force. This behavior suggests how the forces generated during contraction can help organize and stabilize the architecture of the muscle as a whole. In parallel, we are investigating how mutations that cause inherited cardiomyopathies (diseases of the heart muscle) perturb sarcomere mechanics and organization. In particular, we are using cryo-electron tomography to directly visualize the structure of heart muscle fibers at the molecular scale. These and other data suggest that changes in sarcomere organization may be closely linked to the development of cardiomyopathies.

Finally, I will describe new single-molecule approaches that move beyond measuring one interaction at a time to systematically surveying hundreds of molecular variants. These approaches now make it possible to study mechanobiology at scale and to design and characterize new proteins that sense and produce force.

BIOGRAPHY

Alexander Dunn is a Professor of Chemical Engineering at Stanford University whose laboratory studies how molecular interactions within the cytoskeleton and at cell adhesion complexes drive the assembly and self-organization of cells and tissues. Recently, his lab has expanded into cryo-electron tomography to investigate the molecular-scale organization of complex subcellular structures. Dunn’s honors include the Hertz Fellowship, the Burroughs Wellcome Career Award at the Scientific Interface, the NIH Director’s New Innovator Award, and the HHMI Faculty Scholar Award.