Valuable Genes From Non-Model Plants: Elucidating and Engineering the Biosynthesis of the Cancer Drug Taxol
Event details
| Date | 16.12.2025 |
| Hour | 09:00 › 10:00 |
| Speaker | Conor McClune, Ph.D., Stanford University, CA (USA) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
3-DAY BIOE MINI-SYMPOSIUM on Life Science Engineering
(DAY THREE: talk five / previous talk / next talk)
Abstract:
Humans depend on plants for food and medicine, yet these organisms are surprisingly challenging to study. A classic example is the yew tree, our only viable source for the cancer drug paclitaxel (Taxol®). This plant produces Taxol at extremely low concentrations, yet the full gene set for Taxol biosynthesis has eluded scientists for decades, preventing affordable production of the drug. Enzyme discovery has been hampered by yew’s enormous, enzyme-rich genome anduncertainties about when and where Taxol is synthesized.
We suspected the ~20-enzyme Taxol pathway would be difficult to resolve in this 51,000-gene genome using conventional RNA-seq and co-expression analysis. To identify gene modules with high specificity, we developed a multiplexed perturbation strategy to simultaneously capture gene expression changes across tissues, cell types, developmental stages, and elicitation conditions. These data revealed that paclitaxel biosynthetic genes segregate into multiple expression modules associated with distinct cell states and subsections of the biosynthetic process. Within these modules, we identified eight new enzymes that complete the Taxol pathway, including several surprises. For example, biosynthesis requires a NTF2-like protein, a gene class with no precedent in plant metabolism. Furthermore, the biosynthetic assembly of Taxol requires enzymes that install and later remove temporary modifications absent from the final Taxol product.
Our discoveries enabled us to engineer tobacco to biosynthesize Taxol and baccatin III, the precursor currently harvested by manufacturers. By biosynthesizing baccatin III at levels higher than those found in yew trees, we demonstrate how synthetic biology can provide viable, sustainable routes for accessing complex therapeutic molecules. More broadly, we establish a generalizable approach that scales the power of co-expression studies to match the complexity of large, uncharacterized genomes, enabling discovery of high-value gene sets in non-model species or other biologically intractable systems.
Bio:
Conor McClune is a post-doctoral Damon Runyon / K99 Fellow in the laboratories of Elizabeth Sattely and Polly Fordyce at Stanford. He completed his PhD research with Christopher Voigt and Michael Laub at MIT, where he developed systems and synthetic biology tools to study at scale how proteins evolve new, specific interactions. He leveraged these approaches to design orthogonal sets of synthetic signaling pathways that are insulated from the many, similar pathways already present in cells. As a postdoc, he designed scaled strategies for dissecting plant genomes and studying uncharacterized gene sets, especially those involved in specialized chemistry. He identified the eight missing enzymes in Taxol biosynthesis from the genome of yew trees and engineered the pathway into a model plant for sustainable production of this cancer drug.
Zoom link for attending remotely, if needed: https://epfl.zoom.us/j/69216732793
(DAY THREE: talk five / previous talk / next talk)
Abstract:
Humans depend on plants for food and medicine, yet these organisms are surprisingly challenging to study. A classic example is the yew tree, our only viable source for the cancer drug paclitaxel (Taxol®). This plant produces Taxol at extremely low concentrations, yet the full gene set for Taxol biosynthesis has eluded scientists for decades, preventing affordable production of the drug. Enzyme discovery has been hampered by yew’s enormous, enzyme-rich genome anduncertainties about when and where Taxol is synthesized.
We suspected the ~20-enzyme Taxol pathway would be difficult to resolve in this 51,000-gene genome using conventional RNA-seq and co-expression analysis. To identify gene modules with high specificity, we developed a multiplexed perturbation strategy to simultaneously capture gene expression changes across tissues, cell types, developmental stages, and elicitation conditions. These data revealed that paclitaxel biosynthetic genes segregate into multiple expression modules associated with distinct cell states and subsections of the biosynthetic process. Within these modules, we identified eight new enzymes that complete the Taxol pathway, including several surprises. For example, biosynthesis requires a NTF2-like protein, a gene class with no precedent in plant metabolism. Furthermore, the biosynthetic assembly of Taxol requires enzymes that install and later remove temporary modifications absent from the final Taxol product.
Our discoveries enabled us to engineer tobacco to biosynthesize Taxol and baccatin III, the precursor currently harvested by manufacturers. By biosynthesizing baccatin III at levels higher than those found in yew trees, we demonstrate how synthetic biology can provide viable, sustainable routes for accessing complex therapeutic molecules. More broadly, we establish a generalizable approach that scales the power of co-expression studies to match the complexity of large, uncharacterized genomes, enabling discovery of high-value gene sets in non-model species or other biologically intractable systems.
Bio:
Conor McClune is a post-doctoral Damon Runyon / K99 Fellow in the laboratories of Elizabeth Sattely and Polly Fordyce at Stanford. He completed his PhD research with Christopher Voigt and Michael Laub at MIT, where he developed systems and synthetic biology tools to study at scale how proteins evolve new, specific interactions. He leveraged these approaches to design orthogonal sets of synthetic signaling pathways that are insulated from the many, similar pathways already present in cells. As a postdoc, he designed scaled strategies for dissecting plant genomes and studying uncharacterized gene sets, especially those involved in specialized chemistry. He identified the eight missing enzymes in Taxol biosynthesis from the genome of yew trees and engineered the pathway into a model plant for sustainable production of this cancer drug.
Zoom link for attending remotely, if needed: https://epfl.zoom.us/j/69216732793
Practical information
- Informed public
- Free
Organizer
- Prof. Matteo Dal Peraro, Institute of Bioengineering, School of Engineering, EPFL
Contact
- Institute of Bioengineering (IBI), Dietrich REINHARD