Symbiosis and Chemical Diversity Generation

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Project Summary/Abstract Our overall research program aims to understand how chemical diversity arises in living organisms, and to apply that diversity to important biomedical problems. This MIRA project focuses on two related scientific areas: 1) a hypothesis-based approach to discovering new biosynthetic pathways and biomedically important compounds from marine animals; and 2) understanding diversity-generating biosynthesis and applying it to synthetic biology. The program synergizes with our applied biomedical research in drug discovery and development, which is funded elsewhere. Because so much remains to be learned about how nature produces diverse chemical scaffolds, our MIRA program is the key to providing innovative new materials and methods that underlie the biomedical applications. We address two overarching problems: 1) There is a greater variety of animal life in the sea than anywhere else, including millions of diverse animal species. Many marine animals live in highly competitive environments, and therefore they or their symbiotic bacteria synthesize small molecule chemical defenses, which have found value as FDA-approved therapeutics and lead compounds. They contain chemical scaffolds found only in the oceans and nowhere else on Earth. Although many important marine animal natural products have been discovered, the biological and chemical diversity of the oceans has barely been touched. Most marine animals are simply too small, rare, or variable to provide a sufficient supply of compounds for drug discovery and development. In research that will continue through this program, we eliminate the barriers to discovering new potential pharmaceuticals, enzymes, and biochemical pathways from animals. We take a hypothesis-driven approach to determine who makes marine natural products (animal, symbiont, or other) and how the compounds are made biochemically. This activity leads directly to the discovery and development of novel chemicals and potential pharmaceuticals in the applied (non-MIRA) side of our laboratory. 2) Instead of containing a single bioactive natural product, species of animals contain families of compounds, where individual animals harbor variants of a parent structure. Sometimes, thousands of variants arise from a single biochemical scaffold. Underlying this chemical diversity, we have shown that several biosynthetic pathways are diversity generating, capable of synthesizing millions of derivatives. This unusual plasticity has been applied as a tool for synthetic biology. Among other applications, one of the most exciting is the ability to design compounds and then produce them in different kinds of living cells. For example, genetic libraries encoding millions of unnatural natural products have already been created, and we are developing cell-based therapies. Here, using hypothesis testing, we ask how diversity-generating pathways function: what makes a pathway plastic, and how can these features be used in rational synthetic biology approaches. We apply the resulting discoveries to biomedical problems in the non-MIRA, applied biomedical side of our laboratory.