Small molecules are a pillar of human health, making up a majority of the drugs we have in our healthcare arsenal. Many of these drugs are obtained by utilizing synthetic chemistry to modify the composition of some small molecule found in nature. Derivatives of tropane alkaloids, for example, alleviate neuromuscular disorders and are derived from a chemical found in nightshade plants. However, sourcing these plants have become exceedingly difficult as climate change, the pandemic, and geopolitics ravage the supply chain. Looking to overcome these challenges, Prashanth recapitualed the biochemical pathway that makes these tropane alkaloids in yeast. In the most complex feat of metabolic engineering to date, Prashanth can make these life-saving drugs in a bioreactor, insulated from the issues that make them expensive and in short-supply.

About the Author

• Prashanth is a graduate student at Stanford University and published this work in the lab of Professor Christina Smolke. Christina and her team are world experts in metabolic engineering and broke multiple records in generating yeast that perform complex biosynthesis.
• Prashanth’s love of science was fostered by his teacher who encouraged him to combine his fascination with biology and his unique perspective on chemistry.

Key Takeaways

• Drugs are often sourced from natural sources like plants that have extremely precarious supply chains.
• The same biosynthetic pathways that makes the drug in plants can be recapitulated in yeast so that the small molecule can be brewed anywhere.
• Moving this biosynthetic pathway from one organism to another is not easy and still requires a ton of novel biology to be discovered in order to succeed.
• Here, Prashant had to hunt for new enzymes, cut-out wasted chemical reactions, and engineer ways to move the molecule and proteins to the specific parts of the cell.

Translation

• Scaling these microbes to make them economically viable first requires maximizing the amount of drug that each yeast can make.
• Directed evolution of useful enzymes, importing new molecular transporters, and optimizing growth conditions will be used to spin-out this microbe.
• The strain will be licensed through Stanford to pharmaceutical companies.

First Author: Prashanth Srinivasan

Paper: 

Biosynthesis of medicinal tropane alkaloids in yeast