Engineering Autophagy: Understanding Cellular Decommissioning Using Synthetic Biology

Autophagy is the natural mechanism that decommissions, through a regulated process, unnecessary or dysfunctional cellular components. Cytoplasmic constituents are transported to the lysosome where they can be degraded. Despite its simplicity, recent research has shown that autophagy plays a wide and complex variety of physiological and pathophysiological roles. Autophagy consists of several sequential steps-sequestration, transport to lysosomes, degradation, and utilization of degradation products-and each step exerts a different function.

Given the central importance of autophagy in regulating cellular health, it is of great significance to deepen fundamental understanding. There are many situations in which this would be of value. For example, the deployment of gene and cell therapies requires knowledge, and control, of autophagy to manage risk. Deploying autophagy to appropriately maintain (e.g. CHO) cells producing therapeutic proteins could have large economic benefit.

This research programme will deploy the tools of synthetic biology to investigate autophagy in mammalian cells. We will seek to use technologies such as synthetic transcription factors that exploit CRISPR-Cas9 to achieve induction and control of signaling pathways important to autophagy. This will be supplemented with novel imaging technologies, such as stimulated Raman scattering microscopy to deliver a unique insight into this fascinating phenomenon.