Understanding Cells Under Pressure

October 25, 2019

Brenton Hoffman's lab explores how mechanical forces can shape and control our cells

Super-resolution microscopy reveals the complex architecture of the actin cytoskeleton in a migrating epithelial cell

Super-resolution microscopy reveals the complex architecture of the actin cytoskeleton in a migrating epithelial cell

Most researchers today understand biology through the principles of chemistry. Cells can communicate through chemical signals, and traditional medicine has long focused on how to treat disease by modifying those signals. But according to Brenton Hoffman, an assistant professor of biomedical engineering at Duke University, this approach is incomplete, as it ignores a major factor in cell biology: physics.

Cells utilize this contractile actin network to probe the mechanical stiffness of their environment, stretching proteins at the interface with their surroundings.“Today, when we get sick we usually get a pill that will affect our chemical system,” says Hoffman. “But if you look diseases that lack a clear chemical treatment option, like cancer, asthma, cardiovascular disease, or muscular dystrophy, they all have a mechanical component that hasn’t previously been looked at.”

Hoffman is pioneering the new field of mechanobiology, which is the study of how physical forces affect cell behavior. His lab explores how the chemical and mechanical aspects of biology interact, and how researchers can use mechanics to study what he calls mechano-sensitive diseases and address problems in biology that can't be solved through chemistry alone. 

When you apply a force on a cell, that pressure can alter and control its structure and behavior. For example, the force generated by blood flow pushes on the cells in blood vessels, helping them grow into the correct shape and behave normally. The same principle, Hoffman says, can be applied to a disease like breast cancer.

“A breast tumor is normally discovered when someone fells a lump, and we know that a lump is a local increase in stiffness, which means it’s a mechanical input to cells,” says Hoffman. “As we learn more about these mechanical inputs, we’re examining whether the physical changes in cells and their local environments that make cancerous tissue stiff may actually be a trigger for cancer to spread, just like if you have a perturbed growth factor or a mutated receptor.”

Until recently, researchers had no way to explore how these processes worked, but the Hoffman lab has circumvented this problem by creating tunable protein sensors capable of measuring forces inside living cells. These tension sensors contain a specially engineered module that emits a fluorescent glow under normal conditions, but dims if it experiences a change in force. The sensor is placed inside specific proteins that physically connect the cell to its surroundings. When these proteins feel a physical force, they stretch, causing the sensor to dim.

“You could argue that we’re making the tools to do basic studies, but that’s necessary, especially in a newer field,” says Hoffman. “If we can understand the pathological mechanics, we can control, or maybe eliminate, the pathological signaling that drives mechano-sensitive disease.”

Hoffman uses fluorescent protein sensors inserted within these proteins to measure forces across them and understand how these mechanical signals are converted into downstream biochemical ones, both in the context of single cells and in multi-cellular constructs that more closely mimic behaviors at the tissue scale.