Discovery Biosynthesis Subgroup
Many extraordinarily useful small molecules are either natural products or can trace their origins to natural products.
Natural product discovery yields drugs and selective probes. The majority of natural products selectively interact with discrete biochemical targets, engendering remarkable phenotypic changes in the biology of treated organisms. Correspondingly, natural products have played a central role as a source of bioactive leads for drug discovery programs and as probes of biological function, leading to new potential therapeutic targets. For example, the ververatrum alkaloid cyclopamine illuminated the hedgehog-signaling pathway, leading to the discovery of the smoothened (SMO) target and providing the basis for the discovery and development of selective SMO target inhibitors such as the synthetic compound vismodegib for the treatment of basal cell carcinoma. Cyclopamine is just one example of the therapeutic potential of natural products; since 1981, 41% of small molecular anticancer drugs were either natural products, natural product derivatives, or natural product mimics.
I. Single cell chemical biology for discovery of small molecules for precision medicine
Immuno-oncology approaches harness the immune system to recognize tumor associated antigens to clear aberrant cells. For example, immune checkpoint blockade therapy, which blocks repression of T-cells to destroy cancer cells, is a powerful and ascendant strategy to activate the immune system to induce remission. However, immunotherapies do not address all types of cancer and are fundamentally limited by the immunogenicity of cancer cells. If cancer cells remain non-immunogenic, no degree of checkpoint blockade will affect their removal. Chemically induced anti-tumor immunity is a general phenomenon by which chemotherapy induced cell death or impairment initiates changes in cells that recruit and stimulate a durable and therapeutic immune response against the tumor (e.g. Immunogenic Cell Death). The VLBS works on the hypothesis that secondary metabolites are capable of inducing anti-tumor immunity in a manner that is dependent upon patient-specific tumor mutations and contexts.
Simultaneously measuring the molecular changes induced by metabolites within heterogeneous tumor cell preparations is challenging. To accomplish this, we have developed a high-throughput flow cytometric platform, Multiplexed Activity Metabolomics (MAM), in which the signaling profiles induced by microbial metabolites in chromatographically arrayed metabolite fractions can be assayed across the range of tumor and immune cell subtypes found in patient biopsies (i.e. primary cell preparations). We have applied MAM to: (1) identify potential secondary metabolites within metabolomes that selectively affect cancerous and/or noncancerous immune cell subtypes, (2) assay multiple diagnostic signaling pathway markers in parallel, and (3) reveal differing cell-type responses between patients.
We propose to transform natural product discovery into a process of precision medicine. Using Multiplexed Activity Metabolomics,1 we will identify bioactive lead compounds from hypogean microorganisms which modulate cellular function in clinically correlated heterogeneous primary tumor samples, prior to compound isolation. As part of the identification process, leads are profiled against cancer and resident immune cells using multiple markers of cellular function diagnostic of cell death and/or immune cell activation.
II. Exploration of novel ecosystems and chemical ecology for the discovery of novel natural product chemistry
The VLBS has pioneered the hypothesis that cave microenvironments create specialized microbial habitats unique to the geology and geochemistry of the region in which they are located, and distinct from their surface counterparts. Furthermore, we hypothesize that the microorganisms living in these hypercompetitive environments will produce a wide variety of cave-specific natural products as defensive, predatory and signaling tools. Our survey of cave microorganism diversity and secondary metabolic fecundity has illuminated the considerable potential of the cave ecosystem for natural product discovery. We established that actinobacteria are abundant and isolable from cave ecosystems and are prolific producers of secondary metabolites. A video outline of this project can be found in a documentary on the Bachmann/McLean project produced by the American Museum of Natural History, which became part of their ‘Hall of Biodiversity’ exhibit in New York in winter 2014. Watch a short video documentary here.