Abstract
The inside of the cell is full of important, yet invisible species of molecules and proteins that interact weakly but couple together to have huge and important effects in many biological processes. Such "dark matter" inside cells remains mostly hidden, because our tools were developed to investigate strongly interacting species and folded proteins. Example dark-matter species include intrinsically disordered proteins, posttranslational states, ion species, and rare, transient, and weak interactions undetectable by biochemical assays. The dark matter of biology is likely to have multiple, vital roles to regulate signaling, rates of reactions, water structure and viscosity, crowding, and other cellular activities. We need to create new tools to image, detect, and understand these dark-matter species if we are to truly understand fundamental physical principles of biology.