Developing Synthetic Biotics for the Treatment of Human Metabolic Disease

The concurrent maturation and convergence of the fields of microbiome research and synthetic biology have made it possible to impact the host’s metabolic processes, immune system, and disease states by engineering bacteria that operate from within the gut. At Synlogic, we aim to use the tools of synthetic biology to program probiotic organisms to perform a pharmacologically predictable and quantifiable function in order to treat metabolic diseases from within the existing host/microbiota communities. We have begun to engineer bacterial strains that absorb and convert toxic metabolites, produce therapeutic compounds, and interact with the immune system. These synthetic biotics have proven effective in genetic mouse models of disease and are exciting prospects for clinical development.

We have designed our synthetic biotics to be non-pathogenic, express a single or series of therapeutic genes, be contained within the gut and survive long enough in the competitive gut ecosystem to be effective. To achieve these design goals, we have had to understand and engineer genetic solutions for metabolic disease pathways, clinically suitable induction mechanisms, dynamics of E. coli transit through and residence within the mammalian gut, and the effects of containment strategies on viability and productivity.

Traditionally, synthetic biology circuits have been characterized on plasmids, in a controlled lab setting, and activated by well-characterized promoters such as tet, lac, and ara. However, plasmid-based synthetic organisms may not perform reliably during scale-up or within the gut, synthetic circuits may face intense selective pressures in competitive environments, and the inducers of the tet, lac, and ara promoters may be not be suitable for human therapeutic use. Therefore, we have developed robust and reusable genomic integration systems, evaluated the genetic stability of our circuits, and identified promoter schemes for reliable induction in a clinical setting. 

Specifically, this approach has proven effective at reducing blood ammonia in genetic mouse models of urea cycle disorders, reducing blood phenylalanine in genetic mouse models of phenylketonuria, and increasing gut short-chain fatty acid concentrations in mouse models of gut dysfunction. Our work demonstrates that the power of synthetic biology can be applied toward generating therapeutic organisms that perform from within the mammalian gut.