Universal switch

Our project is based on production of biopharmaceuticals by engineered cells and with tight but versatile regulation and safety in mind, we set out to contribute some fundamental advances to synthetic biology.

We considered two options of regulating production of therapeutic proteins in mammalian cells:

• The first would be a prosthetic network where the cells are engineered to sense endogenous signals such as for example blood glucose levels. This signal would control the production of a therapeutic protein (such as insulin), which in turn affects the level of the endogenous signal (i.e. glucose) and is thus regulated by a kind of a feedback loop. This type of system can replace the function of a defective tissue or organ, hence the name prosthetic. Although a very attractive option, such a system would need to be tailor-made for a specific disease.
• For the second option we regarded a cellular genetic network that produces the therapeutic protein of choice, but can be controlled by an external signal such as small molecular drugs or metabolites which can be administered orally or topically. Instead of requiring a continuous presence of an activating or repressing signal, the system should function as a bistable or multistable switch, requiring only a short signal pulse to change into any selected state. This type of a toggle switch has already been implemented in mammalian cells based on prokaryotic transcription factors fused to the eukaryotic transactivator (eg. VP16, VP64) or transrepressor (eg. KRAB) domains (Carlsson et al., 2012).