Cell migration is an integrated mechanochemical process that enables a cell to dynamically crawl through its environment. In doing so, normal immune cells are able to crawl through our tissues on search-and-destroy missions to fight off infections. However, on the darker side, migration also allows cancer cells to spread in our body. Either way, it is important to understand the physical basis of cell migration, so that we can control it for therapeutic purposes. Our current research is focused on the integrated dynamics of F-actin self-assembly, myosin molecular motors, and transmembrane force transmitting molecular clutches. We use computational models to predict the dynamics of cell traction as a function of the chemical and mechanical properties of the environment. We then test these models using live cell microscopy where the cells are transfected with fluorescent proteins fused to key proteins of interest (e.g. actin). A primary focus is on the migration of brain cancer cells (glioblastoma multiforme, GBM), which is responsible for the deadly spreading of the disease throughout the brain over a period of months. By developing computational models tested against in vitro and in vivo migration experiments, we are seeking to identify, in silico, novel therapeutic strategies against the highly conserved motility susbsystems of GBM.
Cell division is a process where the replicated genome is segregated so that each of two daughter cells receives a complete set of chromosomes. To achieve proper segregation, chromosomes physically connect to microtubules via a specialized protein structure known as the kinetochore. The kinetochore is composed of a number of complexes, and has over 60 distinct gene products associated with it. Immediately prior to chromosome separation, the mechanical linkage between the microtubules and the kinetochores is under tension. When chromosomes separate from their sister chromosome, they move apart from each other toward opposite poles. The surprising feature of this nanomechanical system is that the microtubules remain dynamic in their self-assembly, undergoing extended periods of nearly continuous assembly alternately with extended periods of nearly continuous disassembly. The dynamic properties of microtubules are crucial for proper cell division, and interfering with them forms the basis of action of one particular cancer therapeutic, paclitaxel (a.k.a. taxol). Paclitaxel has also proven effective in preventing the cell proliferation that causes restenosis after stent placement.
Our current studies are aimed at quantitatively determining how microtubule assembly dynamics are controlled during cell division, and how those dynamics mediate the forces that move chromosomes. By developing quantitatively predictive, physically-constrained computational models, we hope to develop new therapeutic strategies using simulations as our guide.
As we construct mathematical models of biological processes, we are unlimited by the model’s complexity. With only a few equations and 5-10 parameters, the complexity of the model quickly surpasses our intuition, so that it is difficult to immediately understand why a model behaves in a certain way. Deconstruction of a mathematical/computational model quickly becomes very time-consuming and rate-limiting.
“Body-storming,” or using bodies and minds to construct and deconstruct models, is a concept we developed in the IAS-funded “The Moving Cell Project” collaborative with Dance Professor Carl Flink and the dance company The Black Label Movement. With dancers following the rules of a simulation, we quickly deconstruct models through observation of the simulation in real time and feedback from the dancers. This helps us quickly test opposing hypotheses and decide which to pursue and disregard based on contradictions with experimental results. Overall, “body-storming” provides visual information on why a model works or fails and streamlines the process of selecting a successful model. Watch a video of the project here The Moving Cell Project