Translating Genotype to Chemotype and Extended Phenotype with Synthetic Biology

In his 1982 book, Richard Dawkins introduced the term “extended phenotype” to explain the effects or influence which genes from an organism can exert on its biotic and abiotic environment. Specialised metabolites are one of the major means of how microbes and sessile organisms express such extended phenotype for the selective advantage of the organisms —or, more fundamentally, their genes. A paradigm that has emerged for microbial ecology and natural product discovery in the genomics era is that there are far more biosynthetic genes (or gene clusters) that encode the production of these specialised metabolites than we previously assumed based on the chemical diversity we obtained from microbes growing in the laboratory. The discovery of these cryptic biosynthetic genes in the microbial genomes generated new questions: what chemical diversity do these cryptic biosynthetic genes encode? How do they evolve? Are they responsible for extended phenotypes that confer selective advantage to the organisms or, to the genes themselves? Connecting the biosynthetic genes (genotype) to the specialised metabolites (chemotype) would not only allow us to address some of these fundamental questions but allow us to harness the biosynthetic machineries and their “extended phenotypes” (bioactivities) for potential applications — and this is the central focus of my research program.
My group develops and uses synthetic biology tools to override the genetic controls of specialised metabolic pathways to access the chemical diversity encode by the cryptic biosynthetic genes in fungi and understand how these specialised metabolites are made. One of the main reasons that many of the microbial biosynthetic pathways are cryptic is because they are conditionally expressed in response to varying biotic and abiotic factors in the environment. Inspired by this, we harness microbial biotic interactions and ecological genomics to guide our investigation into the cryptic chemical ecology of fungal plant and human pathogens with the aim to harness the knowledge and molecules for disease management and agrochemical/pharmaceutical applications. We also use molecular taxonomy to guide our genome mining efforts to uncover novel bioactive metabolites from the unique Australian biodiversity (with industrial collaboration) and seek to expand the natural chemical diversity via enzyme and metabolic pathway engineering.