New paper demonstrates most advanced example of engineering integrated systems for biosynthesis

MENLO PARK, Calif., Sept. 2, 2020 /PRNewswire/ -- A new paper published today in the journal Nature describes the first successful microbial biosynthesis of the tropane alkaloids hyoscyamine and scopolamine, a class of neuromuscular blockers naturally found in plants in the nightshade family. Describing a first-in-class fermentation-based approach for producing complex molecules, the paper lays the foundation for a controlled, flexible, cell-based manufacturing platform for essential medicines that currently rely on crop farming. The research was led by Dr. Christina Smolke, professor of bioengineering at Stanford University and CEO and co-founder of Antheia, a synthetic biology company making next-generation plant-inspired medicines.

The tropane alkaloids hyoscyamine and scopolamine are neurotransmitter inhibitors and are classified as essential medicines by the World Health Organization for their use in treating neuromuscular disorders such as Parkinson's, intestinal disorders, and other issues caused by muscle spasms. Currently, global supply of these medicinal tropane alkaloids relies on intensive cultivation of nightshade plants, as direct chemical synthesis of these medical agents is not commercially viable. As a result, this class of drugs is subject to global supply risks, including environmental disasters, such as the 2019-20 Australian wildfires, or global crises leading to sudden spikes in demand, such as the ongoing COVID-19 pandemic. The current agricultural-based supply chain coupled with increasing demand have resulted in recurring shortages of tropane alkaloid-based medicines – such as atropine, an antimuscarinic agent used to reduce salivation before surgery, and transdermal scopolamine patches used to prevent nausea and vomiting.

"This paper is an exciting breakthrough for the pharmaceutical industry and a positive signal for the next phase of growth in synthetic biology," said Dr. Smolke. "Publishing our efforts to produce complex molecules like tropane alkaloids is a critical proof point for realizing an advanced manufacturing model that offers greater efficiency, consistency, and quality in global medicine production. Beyond the potential impact on pharma, the ability to functionally express, integrate, and orchestrate genetic and biochemical functions across kingdoms and species will help realize synthetic biology's promise across several industries and applications."

Since the inception of synthetic biology, efforts have abounded to use microbial hosts like yeast to produce a diversity of chemicals, with most successful demonstrations applied to compounds that require the introduction of limited numbers of non-native genes. To date, microbial biosynthesis has been demonstrated for a limited number of relatively simple medicinal compounds, including antimalarials and cannabinoids. One of the key challenges in reconstructing more complex plant-based biosyntheses in microbes is that plants have evolved extensive strategies for spatially distributing enzymes (and associated chemistries) across cellular compartments, cell types, and even tissues, strategies that cannot be readily recapitulated in single-cell yeast.

The full reconstruction of tropane alkaloid biosynthesis in yeast presented in this paper is the most advanced example of a microbial cell factory to date, requiring the functional expression and integration of 26 genes from 10 different organisms (across 4 kingdoms) and 8 gene deletions. The resulting whole-cell system expresses enzymes and transporters across every yeast organelle to truly re-envision the cell as a factory for efficiently assembling the most complex molecules known to humankind.

The tropane alkaloids are the latest category of highly complex plant-based medicinal compounds Dr. Smolke's lab has produced via yeast fermentation. Dr. Smolke's earlier pioneering work demonstrated the biosynthesis of another class of plant-based medicines (benzylisoquinoline alkaloids), and this paper further highlights the flexibility and power of brewer's yeast as a platform for synthesizing the most valuable and complex molecules. This unique whole-cell bioengineering approach to biosynthesis underlies Dr. Smolke's work both in her Stanford lab and at Antheia, which brings together functional genomics, protein engineering and strain optimization to enable on-demand and at-scale production of plant-inspired medicines, and to dramatically expand the possibilities for discovering new medicines.

"This study is setting new standards for how yeast can be recruited for production of complex plant natural products," said Professor Jens Nielsen, Chalmers University of Technology, Sweden. "Assembly of a pathway consisting of more than 30 plant enzymes in yeast is truly impressive, and the learnings from this study will enable a far wider application of yeast based production of complex plant natural products that can be used as pharmaceuticals and nutraceuticals."

To read the full paper, please visit https://www.nature.com/articles/s41586-020-2650-9.

About Antheia
Antheia is unlocking the medicinal power of nature with synthetic biology. Through a novel whole-cell engineering approach to reconstruct complex molecules in yeast, Antheia's platform enables the discovery and manufacturing of plant-inspired drugs of unprecedented complexity and diversity. Antheia's team of scientists and technologists is headquartered in Menlo Park, California. For more information, visit www.antheia.bio.

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