Dan Fletcher: A recipe for cooking up cellular machines

G rowing up on a big piece of land in Texas, Dan Fletcher explored how things in both the natural and mechanical realms were put together. But in his early school days a particularly traumatic dissection of a bloated fetal pig sent him in the direction of " hard, clean " sciences. By the end of his doctoral work developing new instruments that combined optical and atomic force microscopy (AFM), he realized that such technology could help in the study of cells, in all their messiness. As a postdoc, he studied the physics of cell motility with Julie Theriot at Stanford University, including measuring the nanon-ewton-scale forces generated by actin comet tails propelling lipid vesicles (1). Now a professor of bioengineering and biophyics at the Fletcher investigates how cells transduce mechanical signals into biochemical signals and vice versa. His group's advances in AFM have allowed biophysical studies to jump from single molecules to cells and subcellular assemblies (2), letting them twist, compress, or pull on membranes, ves-icles, and cytoskeletal networks to see how they respond. In 2007, his lab showed that branched actin networks exhibit a unique mechanical property—revers-ible stress softening—that arises from their branched architecture and allows the network to be both stiff and soft under different forces (3). A big fan of recreating simple cellular structures in the lab, Fletcher and collaborators have used reconstitution to show how protein crowding can curve membranes (4), how spindle assembly depends on compartment volume (5), and how membranes can bundle actin (6). We recently chatted with Fletcher about his feats in the lab and forays into public service. Why do we care how much force organelles or cytoskeletal components generate? That's a question I have gotten not too infrequently from reviewers. If we can understand where and when forces are generated by cells, and how individual molecules respond to those forces, then we can pull the covers back on what I would argue is a hidden set of signals. In cells, forces are simply another way to communicate. We know that if you pull on a motor protein , such as myosin, its catalytic activity slows down. What's less clear is how that happens on the collective, multimolecular scale where cellular behavior emerges. The challenge of understanding that mechanical language got me interested in cell motility, membranes, and actin networks—the transmission lines for mechanical signals. How did your technical improvements to …