Combo: Control-based biodesign of mammalian cell dynamics

Systems Biologists, by combining cell biology with mathematical approaches, have shown that feedback loops in molecular regulatory networks tightly control cellular homeostasis and responses. The interplay between endogenous feedbacks and the extracellular environment results in complex and non-linear cellular dynamics. Mathematical models can help in tackling this complexity, aiding in characterising the links between cellular dynamics and cell-decision making. However, the validity of models relies on modelling assumptions and the quality of data used for parameter fitting: stochasticity and noise limit the power of model predictions across Systems Biology and Systems Pharmacology applications. Conversely, the forward engineering of exogenous gene expression dynamics that recapitulate native cellular behaviours, often used by Synthetic Biologists, is limited by poor robustness to physical parameter variations, diverse modular parts and choice of chassis. To tackle these challenges, this Fellowship proposes to directly and automatically program complex dynamics in mammalian cells, by combining external feedback control to ensure robustness and a microfluidics/microscopy platform to observe and perturb cells in real-time. Exploitation of this technology will allow to: i) Unravel causation in coupled processes and dissect the role that temporal patterns across scales (i.e. gene expression dynamics and cell-cycle) play in stem cell fate, ultimately exploiting such dynamics for the design of superior stem cell culture protocols. ii) Directly track from experiments non-linear biochemical dynamics, without the need of mathematical models, to quantitatively determine causes/robustness of complex native/engineered behaviours, respectively, using experimental and Control-Based Continuation. Direct industrial applications will be explored, including the characterisation of stem cell culture protocols across culture scales, and the use of feedback control to design optimal drug dosing schedules for target cancer cell responses. Our aims are underpinned by two highly synergetic research tracks at the interface of interdisciplinary disciplines. The combination of methodologies from control theory, Synthetic, Systems and Stem cell biology will provide a quantitative framework and highly novel tools to understand, steer and design mammalian cell dynamic phenotypes, with great potential for future therapeutic purposes.