(6fu) Accelerating the Speed and Scale of Metabolic Engineering in Challenging Biological Contexts

Biological systems are fantastic platforms for solving myriad societal problems, as they contain a diverse set of highly specific catalysts, operate at mild reaction conditions, self-replicate, and can undergo evolution to improve function.  In order to harness the full potential of living systems, metabolic engineers require detailed models of biological processes to enable rational design as well as high-throughput approaches for generating improved systems where uncertainties remain.  In this poster, I will describe my efforts to fill these critical gaps between metabolic engineering practice and desired biological function in difficult-to-engineer systems.

My graduate research focused on expediting the development cycle of engineered yeast, which is a workhorse organism for the production of diverse chemicals, yet was slow and time-consuming to engineer.  In particular, tuning the rate of biocatalyst synthesis, biocatalyst properties, and the genetic background of the yeast host are each critical to optimizing a bioprocess, yet yeast engineers have been traditionally faced with a choice between working with a handful of suboptimal genetic parts and a time-consuming, iterative process for improving them.  To expedite the optimization of parts related to biocatalyst synthesis, I identified phenomena limiting biocatalyst production and in response developed computational techniques which enable metabolic engineers to quickly refactor these genetic parts and generate novel ones tailored toward their desired application, thus improving biocatalyst production in a single design cycle.  Because the design rules governing biocatalyst properties and host performance remain undiscovered, I further developed experimental techniques for high-throughput optimization of these qualities in yeast.  In each case, my innovative approaches expedited the design cycle by several orders of magnitude over the current state-of-the-art and opened exciting vistas in strain development and biological discovery. 

As an independent researcher, I aim to broaden the scope of metabolic engineering to include the microbial communities that live in the human gut, as this complex ecosystem plays critical roles in the extraction of nutrients, production of vitamins, and the progression of disease, yet whose engineering is currently regarded as a “grand challenge” in human health.  As this organ is, in its simplest sense, a packed bed reactor, chemical engineers are ideally poised to make significant contributions in this area.  In my postdoctoral work, I am currently laying the foundation for engineering this system through the determination of design rules which collectively ensure the stability, robust performance, and safety of engineered probiotics (i.e. the catalysts) in this complex environment.  Looking ahead, these design principles will enable my future lab to engineer “smart” probiotics which monitor the gut environment for signatures of disease and subsequently synthesize and deliver therapeutics in close proximity to affected areas.  Additionally, integration with approaches developed during my graduate work will enable the construction of highly robust therapeutic strains which adjust their genetic content for improved gut function in response to changing environmental conditions.  Third, these engineered strains will enable the elucidation and control of the three-dimensional structure of gut microbiota, enabling further insight into gut disease progression through modeling the currently unknown spatial reaction networks in this environment.  More broadly, the paradigms my lab develops for engineering of the gut community will be applied to other microbial ecosystems in order to address continuing challenges in health, energy, and the environment.