Engineering microbial diagnostics and therapeutics with smart control

Abstract

Microbes have become an increasingly powerful chassis for developing diagnostic and therapeutic technologies. While many of the earlier engineering efforts used microbes that expressed relevant proteins constitutively, more microbes are being engineered to express them with region-selectivity and disease-responsiveness through biosensors. Such 'smart' microbes have been developed to diagnose and treat a wide range of disorders and diseases, including bacterial infections, cancers, inflammatory disorders, and metabolic disorders. In this review, we discuss synthetic biology technologies that have been applied to engineer microbes for biomedical applications, focusing on recent reports that demonstrate microbial sensing by using animal models or clinical samples. Advances in synthetic biology will enable engineered microbes to significantly improve the medical field.

Figure 1.. Microbes have been engineered to diagnose and treat many diseases and conditions.

A) Microbes have been engineered to sense pathogen-associated chemical signals. After recognizing these signals, the engineered microbes can report on the presence of the pathogens or produce proteins that induce lysis of the pathogens. B) Tumors create microenvironments with low oxygen content and low pH. Various microbes can natively sense and colonize these microenvironments with high selectivity. Colonization in this microenvironment is accompanied by the production of proteins that recruit tumor-killing immune cells, directly inhibit tumor growth, or cooperate with systemically administered anti-cancer drugs to kill the tumor cells. C) Toxins and microbes are able to pass through leaky epithelial barriers in the intestines and enter the blood stream. This passage leads to the recruitment of a variety of immune cells that induce inflammation. Microbes can be engineered to sense the gut microenvironment and inflammation-specific metabolites to diagnose this inflammatory response. These microbes can also be engineered to produce cytokines that inhibit the inflammatory response of the immune system. D) Metabolites are transported across the epithelial barrier between the blood stream and gut lumen. As such, engineered microbes in the gut can sense and interact with dysregulated metabolites. In addition, these microbes can be engineered to sense environmental signals in the gut microenvironment and to respond by producing a variety of enzymes that can help maintain healthy levels of specific metabolites.