Joerg Stelling

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  Multi-Objective and Multi-Scale Design of Synthetic Gene Circuits
  Joerg Stelling

  Synthetic gene circuits have to operate in natural systems such as cells or organisms, with corresponding load on and cross-talk with them. These aspects are of particular relevance for biomedical applications where multiple design objectives with trade-offs (e.g., efficiency and robustness) and multiple scales (e.g., organism-wide impact of cell-based therapeutics) need to be considered. The first part of the talk will describe a Bayesian circuit design method that identifies circuit topologies whose behavior is robust to variations in parameters; it enables to reliably assess trade-offs between performance, robustness, and experimental feasibility, thus increasing the probability of success of circuit implementation. The second part will discuss a biomedical application of synthetic gene circuit design for in vivo closed-loop control, specifically for the treatment of type 1 and 2 diabetes; we achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. The examples help to argue that novel systems analysis methods are needed to enable efficient computational design of synthetic circuits, and how the design of synthetic systems allows us to refine our understanding of natural biological systems.