Biomolecular condensates and the binding problem

Cells engage in a variety of functional behaviors, such as resource reallocation, differentiation, repair, targeted motion, division, growth, or death. While we know much about the many signaling processes on which cells base their actions, we do not know how these processes are woven together, that is, bundled and weighed against each other to elicit a situated response. Given the many signals a cell intercepts, their weaving together is unlikely to be hard-wired, but must depend on the situation and, possibly, past experience. How might a cell do that? 

This question is both of practical import and conceptual interest. The practical significance arises from our need to cure disease by "talking" to cells through chemistry. But for this to be successful beyond picking low-hanging fruit, we need to understand how cells "understand". On the conceptual side, the issue is whether we can meaningfully speak of a cell as generating a representational content of its perception of the environment.

Over the past decade, many conditions have been identified in which molecular components of a cell, in particular scaffold proteins, temporarily aggregate as phase separated "droplets" that behave like tiny compartments held together by internal forces that can be easily regulated. The project will develop and deploy new computational methods and models to study how such droplets might transiently and adaptively "wire" together specific signaling cascades by modulating their interaction. This work includes a nano-technological component that will test whether models qualitatively predict the formation and behavior of droplets using molecular building blocks based on DNA strands synthesized to mimic the interactions specified in the models. Such experiments provide a basic sanity check of the computational approach.

On the technical side, our approach extends the application of prior modeling software that we helped develop. This software is tailored to systems of combinatorially complex interactions and appears useful to a number of other endeavors, such as ecology and organic chemistry proper.  In pursuit of our scientific objective, we will re-engineer the platform in Python and C++ to facilitate community engagement. The conceptual aspect of the scientific objective also calls for a joint exploration with a philosopher, Justin Garson, in a venture that is new territory for us and was instigated by the Agency, Directionality and Function cohort program of the Templeton Foundation.