Natural products and compounds derived from or inspired by natural products make up a large fraction of drug molecules. Traditional synthesis strategies based on recovery from the natural source and chemical synthesis approaches present many challenges associated with the purity, scale, and complexity of the compounds, contributing to the raising costs and reduced number of new drug molecules. The development of scalable manufacturing platforms for natural product synthesis will address many challenges faced between natural product drug discovery and therapeutic application. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. However, current approaches in metabolic pathway engineering require a significant investment in time and resources and do not scale with the complexity and breadth represented in natural product biosynthesis pathways. As such, for many natural products of interest, microbial biosynthesis strategies are currently viewed as impossible. The goal of the proposed project is to develop synthetic biology platforms that will dramatically advance the application of cellular biosynthesis strategies to natural product drug discovery, development, and production. The scale and efficiency of manufacturing processes that can be engineered into microbial systems will be transformed through the development of new approaches that will enable the implementation of key biosynthesis process optimization strategies. In particular, the project will pioneer and apply the following approaches: (i) noninvasive and real-time detection of metabolite levels, (ii) closed loop embedded control of biosynthesis system behavior, (iii) active organelle routing supporting biosynthesis specialization and compartmentalization;and (iv) high- throughput screening methods for discovery of new biosynthetic activities within a microbial chassis. The power of these new approaches will be demonst

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1AT007886-01
Application #
8346461
Study Section
Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Hopp, Craig
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$785,000
Indirect Cost
$285,000
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
McKeague, Maureen; Wong, Remus S; Smolke, Christina D (2016) Opportunities in the design and application of RNA for gene expression control. Nucleic Acids Res 44:2987-99
Wang, Yen-Hsiang; McKeague, Maureen; Hsu, Tammy M et al. (2016) Design and Construction of Generalizable RNA-Protein Hybrid Controllers by Level-Matched Genetic Signal Amplification. Cell Syst 3:549-562.e7
Li, Yanran; Smolke, Christina D (2016) Engineering biosynthesis of the anticancer alkaloid noscapine in yeast. Nat Commun 7:12137
McKeague, Maureen; Wang, Yen-Hsiang; Cravens, Aaron et al. (2016) Engineering a microbial platform for de novo biosynthesis of diverse methylxanthines. Metab Eng 38:191-203
Trenchard, Isis J; Smolke, Christina D (2015) Engineering strategies for the fermentative production of plant alkaloids in yeast. Metab Eng 30:96-104
Galanie, Stephanie; Thodey, Kate; Trenchard, Isis J et al. (2015) Complete biosynthesis of opioids in yeast. Science 349:1095-100
Trenchard, Isis J; Siddiqui, Michael S; Thodey, Kate et al. (2015) De novo production of the key branch point benzylisoquinoline alkaloid reticuline in yeast. Metab Eng 31:74-83
Townshend, Brent; Kennedy, Andrew B; Xiang, Joy S et al. (2015) High-throughput cellular RNA device engineering. Nat Methods 12:989-94
McKeague, Maureen; Wang, Yen-Hsiang; Smolke, Christina D (2015) In Vitro Screening and in Silico Modeling of RNA-Based Gene Expression Control. ACS Chem Biol 10:2463-7
Galanie, Stephanie; Smolke, Christina D (2015) Optimization of yeast-based production of medicinal protoberberine alkaloids. Microb Cell Fact 14:144

Showing the most recent 10 out of 20 publications