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Geometry of cell jamming: New biology, surprising physics, and useful ideas about epithelial layers
Jeffrey J. Fredberg , PhD
Professor of Bioengineering and Physiology, Harvard T.H. Chan School of Public Health
As an injury heals, an embryo develops or a carcinoma spreads, epithelial cells systematically change their shape. In each of these processes cell shape is studied extensively whereas variability of shape from cell to cell is regarded most often as biological noise. But where do cell shape and its variability come from? Here we report that cell shape and shape variability are mutually constrained through a relationship that is purely geometrical. That relationship is shown to govern processes as diverse as maturation of the pseudostratified bronchial epithelial layer cultured from non-asthmatic or asthmatic donors, and formation of the ventral furrow in the Drosophila embryo. Across these and other epithelial systems, shape variability collapses to a family of distributions that is common to all. That distribution, in turn, is accounted for by a mechanistic theory of cell–cell interaction, showing that cell shape becomes progressively less elongated and less variable as the layer becomes progressively more jammed. These findings suggest a connection between jamming and geometry that spans living organisms and inert jammed systems, and thus transcends system details. Although molecular events are needed for any complete theory of cell shape and cell packing, observations point to the hypothesis that jamming behaviour at larger scales of organization sets overriding geometric constraints.
Dr. Jeffrey J. Fredberg has worked to bridge the physical sciences with the life sciences at the levels of organ, tissue, and cell. After earning his Ph.D. in mechanical engineering from MIT, his early investigations addressed asymmetrical branching of the airway tree and its impact on barotrauma and gas exchange during high frequency ventilation; lung impedance and the distribution of ventilation during quiet tidal breathing; and flow-limitation and compensatory lung emptying during maximal forced expiration. These studies led naturally to the longstanding question of a deep inspiration (DI) and why it acts as the most effective of all known bronchodilators during induced bronchospasm but fails to cause bronchodilation just when needed the most – during spontaneous asthmatic bronchospasm. The answer, he found, lies at the level of the physics of the airway smooth muscle (ASM) cell and its cytoskeleton; in response to a DI, the activated ASM cell in some cases can relax and dilate as a result of cytoskeletal fluidization, but in other cases can shorten and freeze as a result of cytoskeletal solidification. These findings and their molecular underpinnings led to still deeper questions concerning basic material properties expressed by every eukaryotic cell, such as deformability, contractility, malleability, and motility. Single-cell methodologies that his laboratory invented, and discoveries resulting therefrom, soon upset the field of cellular biophysics. For example, the cytoskeleton of almost every eukaryotic cells is now understood to fall within the same family as do disordered inert malleable materials including colloidal suspensions, foams, clays, and pastes which, together, are called soft glassy materials. His group then turned attention to collective cellular migration as occurs with bronchial epithelial cells in asthma, with cell invasion in breast cancer, and with embryonic development in Drosophila melanogaster. Using these and other epithelial collectives, his group established that cells can jam much as do coffee beans that become jammed a chute. Or instead, they can unjam and migrate, invade and spread. This body of work, taken together, illuminates poorly understood physical processes that underlie asthma, wound healing, development, and cancer. None of this would have been possible without the generosity of his mentors – Jere Mead, Mary Ellen Wohl, and Joseph R. Rodarte – the openness of his colleagues, and the dedication of more than 50 trainees, many of whom now serve on faculties of physics, engineering, and medicine.