Similarly to model organisms, which have played an important role in uncovering the operation of conserved mechanisms, synthetic biology has emerged as an unprecedented approach, studying model circuits in vivo to reveal the design principles that constitute the basis of natural cellular networks. We are applying this strategy to understand the functioning, integration and establishment of essential cellular networks, using the cell cycle as a model eukaryotic circuit.
We previously demonstrated the possibility to functionally replace the fission yeast cell cycle control network by a minimal synthetic module bypassing much of the known regulation. Unexpectedly, cells solely operating with this system were virtually identical to wild type. This allowed us to establish a new model of cell cycle control that differs from its classic and complex view, uncovering the unanticipated simplicity and modularity of the core cell cycle engine.
Work in the laboratory uses this synthetic approach to study cellular reproduction in the fission yeast Schizosaccharomyces pombe and focuses on four axes:
CELL CYCLE REPRODUCIBILITY
We are interested in the potential organisation of cell cycle regulation in two separate and interacting layers: a qualitative core that promotes the integrity of cell cycle processes in all cells, and a second layer that prevents cell-to-cell variability in cell cycle progression. We are using a combination of mathematical modelling and in vivo rewiring of the cyclin dependent kinase (CDK) circuit, the main cell cycle effector, to investigate how the architecture of the system ensures population homogeneity.
CELL CYCLE DYNAMICS
Taking advantage of the possibility to finely control CDK activity in our minimal strains by chemical genetics while monitoring their responses at the single-cell level, we are studying the functional relationship between CDK activity dynamics and the different steps in cell cycle progression, both qualitatively and quantitatively.
COMPLEXITY IN CELL CYCLE REGULATION
Our previous results demonstrate that entire branches of the endogenous CDK control circuit are surprisingly dispensable in laboratory conditions. We are therefore investigating the rationale behind the evolution of complexity in eukaryotic cell cycle control, dissecting the selective advantages of the system operating in wild type cells over seemingly functional minimal networks.
EVOLUTION OF MINIMAL NETWORKS
How cellular functions controlled by simple primitive circuits evolve in challenging conditions is a fundamental but difficult question. We are using our minimal CDK control systems as conceptual starting points for laboratory evolution experiments. With this approach, we hope to uncover evolutionary pathways that may provide insights into the shaping of modern cellular processes.
To investigate these questions, we are taking a multidisciplinary approach, ranging from genetics and molecular biology to high resolution microscopy, microfluidics, engineering and mathematical modeling.