On force and function.

It was a fabric merchant who first opened a window into the cellular world. In the late 1600s, Antoni van Leeuwenhoek used glass he polished into small spheres to create single-lens microscopes that were the most powerful of the day, revealing sights never seen before: pores in a thin slice of cork, swimming bacteria and protozoa, and a pattern of bands in muscle fibers. Optical microscopes are no longer hand held, but they remain critical tools for uncovering the dynamic inner workings of those cells that van Leeuwenhoek first glimpsed. He would no doubt be amazed that the “animalcules” he first reported in his microscope are themselves composed of molecules, intricately organized to coordinate cellular activity. Seeing, however, is only the first step. Dan Fletcher The past 50 years of cell biology research has succeeded in identifying a multitude of genes and gene products, characterizing their biochemical activity, and localizing them within cells. But knowing the identity of each molecule and where it is at this moment in time does not tell us where it will be the next moment, much less how molecules coordinate to pull off the cellular gymnastics of division or motility. For that we must ask questions about the internal and external forces experienced by cells at the molecular level. How are forces transmitted through cells and transduced into biochemical activity? How do forces shape cellular behaviors and guide fate decisions? Answering these questions requires a different way of looking at cells that captures the flow of forces through them. Constructing a complete mechanical map of the cell, which complements the current molecular map, is a central challenge for cell biology over the next 50 years. That force and function mix comes as no surprise, as life at the cellular level is not for the weak. Single-celled organisms must physically fend for themselves in tumultuous environments on land and in water. Cells within multicellular organisms are routinely exposed to a cacophony of forces, such as tension transmitted to adherent cells through deformation of the extracellular matrix or compression encountered by motile cells as they move through tissue. Even cells that wall themselves off from the outside world must deal with the hustle and bustle of internal forces generated by cytoskeletal filaments and motor proteins. Although there is growing appreciation for the mechanochemistry of individual proteins such as molecular motors, it is less clear how multimolecular structures or entire cells are mechanically organized to respond to different matrix rigidities or changes in their external physical environment. Are the compressive and tensile forces experienced by cells important signals or useless background noise? How does a cell know which tap or tug is functionally important? Is there a secret knock? These questions would be easier to answer if only forces were visible. Alas, just the effect of a force—not the force itself—can be seen, acting through the mechanical properties of a molecule or network of molecules and resulting in movement or deformation. Sometimes, forces on cells are local and temporary, whereas other times they are global and sustained. So how can we create this mechanical map of the cell? A key ingredient is cell biologists who understand (and enjoy) physical science, embracing its mathematical foundations and mechanistic insight. In the absence of vitalism, cell behavior must be explainable by the rules of physics and chemistry, and math is a boon companion. A second ingredient is development of experimental methods for capturing and creating cellular forces, together with computational techniques for modeling them. New force microscopy techniques and specialized optical probes can now be used to quantify stresses and strains in live cells, but more are needed. A third ingredient is use of powerful structural, genetic, and bioinformatic tools to test theories of cell mechanics and their implications for development and disease. In the early 1900s, D'Arcy Thompson extolled the power of physics and mathematics to explain biology in his expansive treatise “On Growth and Form.” For him, forces shaped us as they do clay, providing an alternative explanation to heredity for the morphology of organisms. Although modern molecular biology has clearly shown the role that genetics plays in shaping biology, Thompson's desire to ground biology in the fundamentals of molecular mechanics is still to be realized. As the American Society for Cell Biology celebrates its 50th anniversary, it is worth remembering how dependent scientific progress is on new ideas. Researchers who remain interested and open throughout their careers will have the chance to introduce new perspectives and instruments that can change the way we think. Perhaps the next big discovery will come from an unlikely place, maybe even a fabric merchant.