Synthetic biology aims to assemble unrelated biomolecular parts (genes, proteins) into artificial networks with well-defined dynamic behaviour. This would help elucidating the working principles of complex biological systems but could later also lead to the design of self-organising, interoperating, intelligent bionanotechnological devices. The field has so far mainly focussed on the engineering of transcriptional regulatory networks, which are slow and represent only a fraction of cellular control systems. I plan to implement synthetic protein network motifs (feedback loops, toggle switches) operating in human cell lines. Special emphasis will be put on the design of swappable interfaces that allow the exchange and rewiring of the different components. Raw building blocks will derive from modular proteins that transduct signals via auto-inhibition or spatial proximity between individual domains.
Molecular engineering will be assisted by computational protein design. Individual domains will be labelled with genetically targeted small molecule fluorescence markers to follow and verify their status and interaction in vivo. This will yield parameters for the design and simulation of different networks, which can then be tested in vivo.
The synthetic systems will hence be controlled on two levels of complexity:
(1) The careful labelling of interacting players will reveal deviations from reaction network simulations.
(2) Iterations of protein design, molecular simulation and network implementation will correlate perturbations of protein structure and dynamics with network-level effects and may show whether and how the complex dynamics of single proteins affects the functioning of cellular networks.
Through this work, I hope to complement my mainly computational background with a portfolio of experimental techniques, systems biology know-how and strong collaborations that allow for independent research at the cross roads of molecular and cellular complexity.
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