Seeing cells as ‘living materials’ provides a new way to understand their behavior
Amy Manley/Syracuse Univ.
Lisa Manning, 38
Physics and biology
Specifically, cells can undergo a jamming transition, a physical role change that was previously known to occur only among foams, sand and other nonliving materials. It’s one of the ways that physicist Lisa Manning has shown how cells get physical with each other — for good and bad.
Manning, age 38, describes cells’ behavior in terms of the mechanical forces they exert on one another. Her approach has led to a new understanding of a whole host of biological processes that involve cells on the move, including embryonic development, wound healing and even asthma and cancer.
“Forces at the cellular scale are important for properties of tissues,” says physicist Jean Carlson of the University of California, Santa Barbara who was Manning’s graduate adviser. “Lisa has been a real leader in thinking that way.”
Manning first blended physics and biology in high school. She was encouraged by her physics teacher in Park Hills, Ky., Sister Mary Ethel Parrott, to try building a biochemical fuel cell, which produces energy from a microbial community. Manning created a mathematical model to figure out the sweet spot: the right amount of sugar to keep the microbes fed and the system running smoothly.
“That feeling of discovery is incredibly addictive,” Manning says. She also realized she could describe important aspects of a complex system using a fairly simple mathematical model. “That’s basically what I do today,” she says. And the benefits were more than inspirational; her efforts won first place in the engineering category at the 1998 Intel International Science and Engineering Fair, a program of Society for Science & the Public, which publishes Science News.
Later as a graduate student in physics, Manning studied the behavior of granular materials, collections of distinct particles. Granular materials can flow like a liquid or jam together like a solid. For example, sand acts like a solid when densely packed, but freed, it pours like a liquid.
Other students in Carlson’s research group were mixing physics with biology, and after attending a conference on embryonic development, Manning thought the physics of granular materials could be applied to biological systems, too. She has proved that early hunch right.
For instance, Manning developed a simulation showing that biological materials can indeed jam. “Lisa gets credit for this whole picture,” says physicist James Sethna of Cornell University. Her work “makes it clear how close the [cellular] behavior is to this jamming transition.”
Manning found that the transition to a jammed state depends on cell shape, which is governed by stickiness and stiffness. Cells have surface proteins to adhere to nearby cells and a kind of internal skeleton that stiffens them.
She predicted a counterintuitive notion: When cells are rounder and stick less to each other, they jam and become more solidlike. When cells are more elongated and stick more to each other, they can unjam and flow.
This theory — that sticky, elongated cells flow — proved to be true in real life and a potential problem in asthma, Manning found in a collaboration with airway epithelial cell biologist Jin-Ah Park at Harvard T.H. Chan School of Public Health and her colleagues. Normally, healthy airway epithelial cells grown in the lab are jammed. “They look like cobblestones,” Park says.
Stop and go
Human airway epithelial cells (stained green) in normal tissue (left) are “jammed,” that is, they act more solidlike. But when mechanically compressed to mimic airway narrowing during an asthma attack, the cells become elongated and can flow (right).
Reconstructing what goes on in the airways of asthma patients, Park and her colleagues had observed that compressing the cells to mimic a bronchospasm, which restricts airways, made the cells elongate and move. Manning’s theory perfectly predicted the cells’ behavior, Park says.
The team also compared the jamming transition in healthy airway epithelial cells with those from patients with asthma, reporting the findings in 2015 in Nature Materials. In asthma, airway epithelial cells don’t respond properly to injuries from viruses, bacteria or pollutants, leading to excess inflammation and narrowed airways. Cells from patients with asthma, grown in a special culture that mimics the airway environment, stayed mobile for up to two weeks before stabilizing and jamming; healthy cells jammed sooner, in about six days.
Park suspects that the excessive motion might correspond to a delay in the ability of airway cells in asthma patients to repair after environmental injury. She and colleagues hope to learn how to manage the forces in airway cells for asthma patients. Helping those cells stabilize could lead to new treatment approaches, Park says.
Manning has also modeled how forces affect cell behavior during embryonic development and cancer. “My hope really is that we are providing a complementary approach to the work in biology,” Manning says, “I think we may be able to identify unexpected targets for therapy.”
M. Merkel and M.L. Manning. Using cell deformation and motion to predict forces and collective behavior in morphogenesis. Seminars in Cell & Developmental Biology. Vol. 67, July 2017, p. 161. doi: 10.1016/j.semcdb.2016.07.029
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J.-A. Park et al. Unjamming and cell shape in the asthmatic airway epithelium. Nature Materials. Vol. 14, October 2015, p. 1040. doi: 10.1038/nmat4357
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