Mechanical Forces in Cell Biology

templateforsympslogoWhen Valerie Weaver brought her first and, at that point, only graduate student to the 2000 ASCB Annual Meeting, her University of Pennsylvania (Penn) bioengineering student wasn’t happy. “She complained that there were hardly any engineers at the meeting,” Weaver recalls with a laugh. “The following year, it was better and now ASCB has a high proportion of bioengineers who attend. It’s fantastic.”

 

Bioengineers of all stripes are one of the fastest growing contingents at the ASCB Annual Meeting as cell biology expands outward and other disciplines from mathematics to tissue engineering flow in. A biochemist by degree, a cell biologist by postdoctoral training, and a cell-centered bioengineer by practice, Weaver is now Director of the Center for Bioengineering and Tissue Regeneration at the University of California, San Francisco (UCSF). She is also a speaker with Matthieu Piel of the Institut Curie in Paris and Jody Rosenblatt of the Huntsman Cancer Institute at the University of Utah, in the Mechanical Forces in Cell Biology Symposium at the 2016 ASCB Annual Meeting this December in San Francisco.

 

The symp organizers are expecting a diverse audience—bioengineers curious about cell biology sitting elbow-to-elbow with cell biologists eager to hear the latest bioengineering technological insights. The research presented should be highly diverse as well, says Weaver, as mechanical force research has exploded in all directions. “In our lab, we’re working on everything from nano scale [interactions] to recruiting of single molecules. We’re looking at how it influences membrane curvature, receptor recycling, nuclear reorganizing—basically the whole nine yards, and, of course, cancer.”

 

This was not the situation at ASCB 2000 when Weaver and her lonely grad student presented. At other meetings and on campus, Weaver herself felt a little isolated scientifically. The year before, Penn had recruited Weaver from a postdoc in the Lawrence Berkeley National Laboratory with Mina Bissell, a pioneer of mechanical force and physical context in breast cancer. (At ASCB 2016, Bissell will receive the E.B.Wilson Medal, the ASCB’s highest honor for her lifetime work on extracellular matrix [ECM] in tumorigenesis.) That Weaver was recruited from a cell biology lab to a research institute for medical engineers was an indication that scientific thinking was already changing. The first years at Penn, though, were tough. Her engineer colleagues, working on large-scale problems such as bone sheer or bioreactor design, were largely baffled by Weaver’s work on the cellular level. She was building 3-D models of the ECM to see if mechanical stiffness alone could disrupt normal breast tissue growth and induce tumor formation. At the same time, Weaver found it difficult to lure potential grad students from cell biology and cancer labs across the Penn campus to join her in a medical engineering building. “They were intimidated by all the heavy machinery in the building,” she recalls. Eventually Weaver snagged a student with an undergraduate background in nuclear engineering and convinced her that mechanical force plays a fundamental role in cells and that this would be a big field one day. “It is such a fundamental regulator of every aspect of how the cell operates and tissue function,” says Weaver. Adding mechanical force to the cellular context changes everything. “The cell seems to be doing something fundamentally different. It’s changing the cell’s physiology. It’s changing gene expression.”

 

These days, bioengineers and cell biologists who study mechanical force at the cellular level are not lonely at ASCB. Weaver couldn’t be more pleased. “It took quite a while and now that it’s a presence, it’s only going to increase.”

 

A look at the work of the other two symposia speakers, Piel and Rosenblatt, shows some of the startling new directions that mechanical force research is taking cell biology. The Curie Institut’s Piel has helped to puncture the myth of the untouchable cell. The Piel lab has shown that mammalian cells migrating through narrow passages can be squeezed so hard that nuclear proteins leak from and cytosolic proteins leak into the cell nucleus, impacting the cell’s behavior and chances for survival. At the Huntsman Center, Rosenblatt has taken a closer look at a seemingly humdrum piece of cellular housekeeping—how epithelial cells get rid of their dying neighbors by extrusion—to reveal a powerful force in morphogenesis and a vulnerable gateway for attacking pathogens. Cells entering apoptosis signal their impending doom to neighboring cells. The neighbors respond by forming actin and myosin contractile rings around the dying cells that pop them out of the tissue like spitting seeds from a watermelon. Rosenblatt has shown that physical extrusion is also a prime defense for epithelial tissue, keeping a tight seal against bacterial pathogens. But when extrusion is defective, pathogenic invaders can coopt the process and use it as a path for infection.

 

With such a diverse mix of disciplines, technologies, and new ideas, Weaver says that physical force cell biology is poised for an explosion in discovery. “We’ve got super tools and exciting concepts. Who knows what we’ll discover? There’s a whole world of exciting cell biology that we can take a look at now.”

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