Episode Summary: 

When COVID-19 hit and society decided to use mRNA vaccines for the first time, many questions remained about whether RNA itself was ready for the challenge. But three scientists at Stanford University who had barely worked with each other before the pandemic realized that RNA’s limitations were merely a design challenge and not an issue with the substrate itself. Through emails and zooms, Kathrin, Gun, and Hannah built a tool to massively test RNA designs. With it, they screened for RNA with better functionality, increasing the stability and expression of the protein they encode and ultimately creating a platform to improve these life-saving vaccines. 

Episode Notes:

About the Authors

• Hannah, Gun, and Kathrin had all been separately researching various aspects of genetics and RNA before the pandemic.
• When COVID hit and RNA vaccines were being built, the three realized they had newly complementary skill sets.
• They set aside their individual projects, leveraged their unique backgrounds, and worked in shifts to abide by social distance rules in order to solve multiple issues facing RNA as a substrate for vaccines.

Key Takeaways

• RNA holds great potential for therapies and vaccines as they are highly programmable, extremely flexible, and are much easier to scale than other options.
• But RNA is hard to deploy for vaccines because it is extremely unstable both in the body and on the shelf.
• Enhancing the expression and stability of RNA allows us to reduce the amount needed to give a person, increasing the number of people that can be vaccinated.
• The three designed PERSIST-seq to test a multitude of RNA designs in one-pot by leveraging synthetic biology and next generation sequencing.
• They also leveraged citizen science through a “game” called Eterna in order to optimize sequences using the collective brain power of humanity.
• With it in they found synonymous mutations and alterations to the untranslated regions that changed RNA folding and improved stability and translation.

Translation

• PERSIST-seq must still be validated in animal models to fully connect how improvements on stability and expression alter vaccine efficacy.
• The team is ready to leverage their approach through licensing to help RNA vaccine companies improve their designs.
• The design rules and method to discover them can be used to enhance any RNA therapeutic that will undoubtedly be coming through the pipeline soon.

First Authors: Kathrin Leppek, Gun Woo Byeon, and Hannah Wayment-Steele

Paper: Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics