Guest Seminar - Advancing Living Medicines and Microbiome Engineering with Synthetic Biology

After decades of continued research and innovation, synthetic biology is now changing the way how novel medicines, rather than small molecules and protein-based biologics, are developed to fight against human diseases. By implementing synthetic genetic circuits, living cells are able to respond to disease-specific signals and deliver therapeutic payloads to the right location at right time with the controlled dosage in the body. Genetically engineered bacterial cells, including natural members of the human microbiota, thus represent powerful living medicines to improve human health by altering complex microbial communities and restoring human gut homeostasis. Here, we show how to develop smart living medicines with multiple functional modules, such as input, output, and biological containment. We establish high-throughput CRISPR screening systems in human immune cells to elucidate complex host-pathogen interactions and identify host targets for the input module engineering. A synthetic transcription platform is developed as the output module for programmable gene expression in different mammalian cell types. In the dominant human gut commensal Bacteroides thetaiotaomicron, we design and construct a CRISPR-based biocontainment system to prevent unintended spread to the natural environment and an engineered riboregulator to control gene expression.

Our vision is to leverage the power of synthetic biology to probe perplexing questions in digestive diseases and translate our synthetic biology platforms into smart living diagnostic and therapeutic applications, especially for human gut microbiota-related diseases.