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.