mRNA: Persistance Rewarded

We’ve all heard many news stories about the messenger RNA (mRNA) vaccines developed by Pfizer/BioNTech and Moderna. The stories pretty much talk about safety concerns, the new technology behind them, and who gets them first. What they don’t talk about is the work that “tamed” mRNA for the task or the people behind that work. This week is a very good time to address that, as the two major researchers have received their first significant science awards for their work.

On Monday, Brandeis University and the Rosenstiel Foundation awarded the 50th annual Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research to Katalin Karikó and Drew Weissman for their work making mRNA feasible to use as a vaccine. The biggest challenge was that early attempts at man-made mRNA were strongly immunogenic and killed the cells being cultured. Various grant sources saw this as intractable and funding dried up. That led to Dr. Karikó’s demotion at Penn State and removal from her full professorship track.

Katalin Karikó and Drew Weissman

As for the science involved, Khan Academy goes into more detail, but very briefly our DNA is read in our cell’s nucleus and active genes are transcribed into strands of mRNA. These “messages” leave the nucleus and are picked up by ribosomes which read the mRNA three nucleotide base units at a time. Whereas DNA uses nucleotides adenine, guanine, cytosine, and thymine. RNA uses the first three, but instead of thymine, it uses uracil. Each triplet of bases encodes for one amino acid or provides control information about where the protein starts and stops. There are 64 possible triplets, and most of our 20 amino acids can be encoded by multiple triplets.

The big problem is that uracil, I assume outside of a cell, triggers such a strong allergic response that typical mRNA can’t be used. However, Karikó and Weissman first changed triplets that used uracil with triplets that did not, but still encoded for the same amino acid. Typically, this requires replacing uracil with cytosine. A table at Openstax shows the possibilities. However, some amino acids can only be encoded with uracil containing triplets, and this had made other scientists and granting agencies abandon the concept. Karikó’s and Weissman’s main breakthrough came in 2004 when they discovered that uracil could be replaced by a very similar chemical, call it pseudouracil, that works much like uracil but doesn’t trigger an allergic response.

Finally, various fatty chemicals, lipids, are chosen both to protect the mRNA outside of cells and to merge with cell membranes. That releases the mRNA payload into the cell’s cytoplasm where it is picked up by ribosomes to create the the desired protein. In the case of SARS-CoV-2, it’s a spike protein that is exposed on the surface of a virion (individual virus particle).

Dr. Karikó first started working with mRNA and its therapeutic potential in Hungary in 1978, and carried it to University of Pennsylvania in 1985. While there, she met Dr. Weissman at a photocopier where each discovered the other’s interest in mRNA. Replacing uracil not only eliminated the allergenic reaction but created mRNA strands that were longer lived and more productive. While Weissman has stayed at the UPenn, Karikó joined the German company BioNTech in 2014 as Senior Vice President to explore mRNA applications. The pharmaceutical company Pfizer took notice and joined the effort. Their work on treatments for various cancers and pathogens like HIV, malaria, and influenza primed them to jump on the SARS-CoV-2 pandemic and start experiments with mRNA soon after the genetic sequence was published.

The rest of the story has been well covered by the press in all countries, pretty much all the time. It’s time we heard more about the back story and the people who persevered to make this possible. On Feb 5th I received my first dose of the Pfizer/BioNTech vaccine. Thank you, Dr. Katlin Karikó for devoting your career to adding mRNA to our therapeutic arsenal. And thank you, Dr. Weissman for joining that effort.

Further reading:

Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine describes mRNA science in general and then the Pfizer/BioNTech vaccine in particular. The article includes other aspects I didn’t mention above like changes to the SARS-CoV-2 spike protein to stabilize it in the shape seen on the virions. It was bit challenging only because my usual source for keeping up with such science, Science News, has let me down on this subject and have published nothing on Karikó’s and Weissman’s work.

The story of mRNA covers both the work at UPenn and also the creation of Moderna and BioNTech to commercialize mRNA therapies.

The home page for the Rosenstiel Award has information about past recipients, several have gone on to win Lasker and Nobel awards. I watched the new award ceremony online, apparently with 2,000 others, I hope they’ll put it online soon. The acceptance speeches are more about mRNA history and biology than thank you notes.

mRNA technology has an incredibly bright future beyond theraputics. Protein and enzyme synthesis of all sorts has suddenly become easier to do and has promise for agricultural, food, and industrial processes. It will be fun to watch it grow.

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via Watts Up With That?

February 10, 2021 at 09:25PM

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