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 the University of Pennsylvania and removal from her full professorship track.
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.
Update:
Brandeis has uploaded the award presentation. Here is a table of contents:
- 0m10s: Ron Liebowitz, President, Brandeis University: Introduction
- 3m40s: James Haber, Director Rosenstiel Basic Medical Sciences Research Center: Summary of RNA science and the research behind the award and the vaccine.
- 10m59s: Derek Rossi, Cofounder of Moderna: More on DNA, RNA, and proteins, why scientists hadn’t used mRNA in their work, and why Karikó’s and Weissman’s work is so important.
- 31m45s: Karikó, Senior Vice President of BioNTech RNA Pharmaceuticals: History and science of her work with mRNA. (The year of the research is in the lower right corner of her presentation.)
- 56m07s: Anthony Fauci, Director, National Institute of Allergy and Infectious Diseases: Prerecorded congratulatory comments.
- 1h00m15s: Drew Weissman, Co-Director, Penn Center for AIDS Research: Various approaches to SARS-CoV-2 vaccines, e.g. Astra Zeneca and Johnson & Johnson’s. Also, how vaccines compare, the time line that allowed them to be developed in ten months, and notes on side effects.
- 1h20m39s: James Haber: Notes on Brandeis’ natural science research and the Rosenstiel Foundation.
- 1h22m37s: Ron Liebowitz: Closing comments.
This is going to get lost in the noise… and it’s not directly relevant to mRNA R&D…
But I feel it needs repeating.
I feel it’s widely acknowledged that the “UK’s minister for virus response” isn’t the sharpest knife in the drawer – but – he announced in August 2020 that he planned to scrap Public Health England (https://metro.co.uk/2020/08/15/matt-hancock-scrap-failing-public-health-england-13134454/) .
Little has been said about that – but it is clear that dim bulb Hancock was incensed that he’d been misled and lied to by bureaucrats from PHE – repeatedly – primarily, but not exclusively about their fraudulent accounting wrt virus mortality – and that that had gone on for some considerable time (months when days mattered).
We should remember that PHE were largely ejected from the NHS at the behest of annoyed clinicians who found them insufferably meddlesome, mendacious and essentially incompetent above the footsoldier grades.
We haven’t really seen anything that sensibly would increase anybody’s confidence in what I call the Public ‘Elf bureaucrat’s competence. The bureaucratic rapacity for swish offices and fat paychecks coupled to and their fresh chair at the top table is still polluting the response to this business – since in the UK their managers figure largely in the SAGE advisory groups feeding policy into government and PR professionals are scampering around on grotesque day rates re-wording their pronouncements to be parroted by a malleable media…. As others here have commented – other proven therapies are being deliberately excluded.
The backlog of routine medical procedures in the UK has simply exploded to what now looks like a several year wait for routine procedures….
I see similar though not identical stuff going on in the USA.
This “pandemic” went political at a very early stage – It’s a miserable shit-show… and I feel that some people are pleased with that outcome.
There is something about Dr Weissman’s lips which makes be feel profoundly uncomfortable.
It would be in his interest to not find himself in a confined space with me.
Very instructive to look at UK “cases” per day. Despite a never ending increase in the number of tests, https://coronavirus.data.gov.uk/details/testing the number of “cases” ( aka positive test results ) peaked on 29th Dec 2020 and has been in freefall ever since.
https://coronavirus.data.gov.uk/details/cases
This is way too soon for any attribution to the level of vaccinations done at that time plus the time needed to develop an immune response to the vaccine.
So far, it has the classic form of any epidemic which has peaked, for natural reasons and is now in decline.
weissman looks like a frkking creep, keep him away from me for his own good.
He makes my skin crawl.
Would you have preferred
Despite a never ending increase in the level of testing: https://coronavirus.data.gov.uk/details/testing , UK number of new “cases” ( aka +ve tests, not clinically ill patients ) has been in freefall since the peak on 29 Dec 2020.
Thus, this has nothing to do with the sociologic placebos they are sticking in your deltoids. The “second wave” is descending as any epidemic does, naturally. It has run its course.
Daily new “cases” is now around 15k compared to 80k at the peak on 29th Dec.
Anyone touting the current situation as a health crisis has a bridge they want to sell you ( or maybe a vaccine ).
You’ve heard the story about how they repaint the Golden Gate bridge and when they have finished, it’s time to start again. Well covid “vaccines” are the same. They are already laying the ground work PR.
For a vaccine that does not stop you from passing on covid , getting covid or dying of covid. It might reduce your symptoms and it might kill you. Strange that it received and award but great for marketing to get idiots to take it.
The claim “a vaccine that does not stop you from passing on covid” is merely due to people weren’t looking at that during testing. They were looking at protection of the immunized.
I’m sure expectations were that lack of infection, or at least a less severe infection would imply reduced transmission. OTOH, people in ICUs don’t have many good opportunities to infect others, if a milder case means they’re out bar hopping, that could be a problem.
https://www.reuters.com/article/health-coronavirus-israel-vaccine-int-idUSKBN2AJ08J says in small part:
Hopefully ongoing court cases will see the end of the fraud- IV. Court Rulings From Portugal And Ecuador