1. Elucidating Core Design Principles to Explore the World of Nonconventional Yeasts

Saccharomyces cerevisiae is far from being the only yeast of potential scientific and economic importance. Many of the 1800 other known yeast species have highly unusual metabolic, biosynthetic, physiological, and fermentative capacities. As outcomes of long-term natural evolution in particular environments, these high-performance characteristics are conferred by a network of genes via a hierarchy of regulations that are intrinsically complex, making the horizontal transfer of these functions into model hosts very challenging. However, significant technology hurdles lay in front of the world of high-potential nonconventional microorganisms. This research theme will provide the main avenues to enable rapid functional modifications of challenging nonconventional species and genome-scale genotype-phenotype profiling.

Currently we are (1) establishing in silico principles to predict genetic elements vital for the creation of stable plasmids; (2) building low-copy, high-copy, and integration expression platforms for convenient gene and pathway manipulations; (3) developing a high throughput pipeline for transcriptome engineering and reprogramming genome-scale regulatory network to enhance the desired cellular function. Our research is geared towards elucidating systematic rules and enabling generalizable platform technologies that can be effectively applied from one species to another.

2. Building Novel Microbial Biomanufacturing Platforms for the Synthesis of High-value Compounds

To design well-suited microbial factories, Shao group emphasizes on tailoring host selection according to need. For example, Scheffersomyces stipitis is being explored to produce plants-sourced flavonoids and alkaloids because its highly active pentose phosphate pathway renders higher precursor availability for the upstream shikimate pathway; Yarrowia lipolytica is chosen as the producer to synthesize wax esters, based on its exceptional oleaginous nature to provide sufficient acetyl-CoA; Issatchenkia orientalis is being exploited to produce dicarboxylic acids owing to its superior acid tolerance.

Through collaboration with Professor Jean-Philippe Tessonnier group, we are also striving for identifying bioprivileged molecules and integrating biocatalysis and chemical catalysis to create a diversity of chemical products including drop-in chemicals and novel species with desired functional replacements.

3. Exploring Microbial Consortia to Perform Complex Tasks

Microbial consortia, composed of multiple interacting microbial populations, can carry out complicated tasks that are more difficult for individual populations to perform. The existence of cooperation and division of labor is common in nature, where organisms have established all kinds of relationships. We can easily find such examples, e.g., between bacteria for anaerobic methane oxidation, between plants and bacteria for global nitrogen fixation, and in higher animals where gut microbes facilitate food utilization and metabolite transfer. Microbial consortia have also been utilized in industrial processes, such as food processing and waste degradation.

Currently, we are exploiting a yeast consortium to produce compounds with nutraceutical and pharmaceutical values. In a collaborative project with Professor Laura Jarboe, we are also engineering an isogenic self-tuning bacterial consortium for converting mixed substrates and producing mixed products. In another collaborative project led by Professor Emily Smith, we are applying microbial consortium strategy to study plant cell wall degradation.

4. Developing Synthetic Biology Strategies for High Throughput Strain Optimization

Shao group is interested in applying various protein, pathway, and genome engineering strategies to optimize strain performance systematically. One example project is to develop a high-throughput sensing platform to report the chain length of fatty acid products. Another project aims to explore genetic context dependency as a tool to fine-tune pathway behavior.