Thanks to Trade Coffee for supporting  this episode of SciShow.

You can go  to drinktrade.com/SciShowOffer to get a free  bag of coffee with any subscription purchase. Here’s my pitch for an Oscar-bait  film coming out in 2026.

You ready? An immigrant comes to the United  States, mere pennies in her pocket,   determined to further her career in science. She faces setbacks and resistance  from authority figures, and labors  for decades in obscurity with  barely any funding.

Finally, she’s given an ultimatum: Abandon  her research, or lose her career. She chooses her research, and because she does,  she’s able to save untold millions of lives. Sound like a good movie? ‘Cause it’s  a true story: that of Katalin Karikó,   co-winner of the 2023 Nobel Prize in Physiology  or Medicine and a person who is cooler than you.

Her work made mRNA-based vaccines,  including the ones against COVID-19,   She might have saved your  life, or that of someone you know. And get ready, because her story is  the best movie you will see all year. [Intro music]

In the 1970s, scientists were just beginning to explore the possible uses of messenger RNA in medicine. They knew that mRNA was the means by which the   instructions encoded in DNA  actually got carried out.

The information in a gene gets  copied onto a strand of mRNA,   which travels out into the cell to be  translated into a protein and do stuff. If scientists could write  those instructions instead,   they could direct the cell to do practically  anything. The mRNA vaccines we have today   provide a small snippet of a virus to  teach the immune system what it looks like,   but these early pioneers were picturing everything  up to and including treatments for cancer.

Katalin Karikó first learned about  these ideas as an undergraduate,   and said to herself: Yeah, that’s  how I’m gonna change the world. She started her scientific career in her native  Hungary, but when her funding dried up for the   first time, she moved to the U. S.

You couldn’t  bring money out of the then-communist country,   so she and her husband sold their car and hid  the cash inside their daughter’s teddy bear. Dr. Karikó eventually landed at  the University of Pennsylvania   where she and a collaborator  continued working with mRNA,   including how to get mRNA into cells and make  them express genes they normally wouldn’t.

Then that collaborator bounced for a cushy private  industry job and left Karikó with no funding. There were a couple of reasons there wasn’t a lot  of money for mRNA research in the 80s and 90s. The idea that you could give a cell  instructions to make a vaccine or   treat a disease still held true.  But there were two serious problems.

One was just the difficulty  of manufacturing RNA. That stuff falls apart if you look at it the wrong way. The other was the fact that for some reason, mRNA  made in a lab triggers an immune response if you   try to put it in a living organism.

It was way  too unsafe to even consider putting in a person. Dr. Karikó was working on this  problem when the low point came   in 1995.

Because she had no financial  support, Penn gave her an ultimatum:   Either change the direction of her  research, or take a pay cut and a demotion. Karikó looked at all her work so far,   at the lifesaving potential she was convinced  it held… and like a boss, she chose science. [AIRHORNS] But this is the part of the movie where the  instruments swell, because not long after   this lowest of blows, she met the person  she was going to share a Nobel Prize with. She and immunologist Drew Weissman were  literally fighting over a photocopier   when they struck up a conversation  about science.

And he was like “OK,   but can your RNA make a vaccine for HIV” and  she was like “Yeah, just gimme a minute.” [AIRHORN INTENSIFIES] As it turns out, there are a couple of mRNA vaccines for HIV  in human trials at the time we filmed this. Anyway, Karikó and Weissman started  up a collaboration in 1997. In 2005,   they and a couple others published what’s now  a classic paper containing the key insights   that told the COVID-19 pandemic where to shove it.

Basically, they needed to figure out the  difference between an organism’s native RNA,   which obviously does not make them  sick, and synthetic RNA, which does. The key seemed to be proteins  called Toll-like receptors,   a part of your innate immune system that helps  to recognize foreign substances within the body. Among these foreign substances are RNA and DNA  belonging to invading viruses and bacteria.

Somehow, Toll-like receptors can tell  the difference between RNA that comes   from a virus, and RNA that comes from you. The team realized that the RNA made by your  cells undergoes specific modifications. The   bases that make up RNA, A, C, G,  and U, can have small chemical   changes made to them without altering the  information content of the RNA itself.

It still codes for the same product, it just has  little “I live here, don’t eat me” bits on it. In the paper, the team showed that the more  modified an RNA strand was, the more Toll-like   receptors would pass it by. Meaning these  tiny little chemical adjustments were the   key to getting a strand of RNA into a mouse – or  a person – without triggering an immune response.

They also established that simply changing the  base U, or uridine, to a slightly different   form called pseudouridine was good enough for  Toll-like receptors to wave the mRNA through. What’s more, mRNA with pseudouridine produced  way more of its product in the cell than mRNA   with uridine did. That’s key when you’re trying  to instruct a cell to make its own medicine.

The discovery should have been  celebrated. It was finally possible   to realize the dream of using mRNA to  write vaccines and other therapies. But the scientific world mostly shrugged.

The 2005   paper was rejected by top journals Nature and  Science, and had to be published elsewhere. A couple of small, obscure biotech  startups did license the idea, though.   Their names were Moderna and BioNTech.  You’ve probably never heard of them. In 2013, Penn made their last mistake.

Dr. Karikó  petitioned to have her position reinstated,   given that she’d, like, solved  the problem preventing a major   therapeutic strategy from being  anything more than a gimmick. They declined, and according to her, they  said she was, “not of faculty quality.” In one interview, she recalled telling  them they should keep her lab how it was,   because it was going to be a museum one day. [AIRHORN FURTHER INTENSIFIES] So she bounced to become a VP at BioNTech – okay, cushy private industry job,  but ya girl has earned it.

And we can kinda hit fast forward  now because you know how this ends. A few kinks still had to be figured out,  like how to get the vaccine into people. And even into the pandemic, scientists were  still debating whether you actually needed   pseudouridine.

A few tried to make  vaccine candidates work without it. Seems like the Nobel committee has let  us know where they stand on that one. But in 2020, when we needed it most,  scientists were able to design vaccine   candidates almost instantly.

And… they worked. A lot of people worked on mRNA vaccines  over the years. A lot of people other   than Karikó and Weissman deserve credit  for bringing the pandemic under control.

But it is fair to say that if one  determined scientist had not chosen   to stand by her research in 1995, a lot of  people who are here today… would not be. We’re pro-science around here, so  whenever a Nobel prize comes out   we’re like “Hey! That’s awesome!

Yay  science!” But even we have to Google   when the prize goes to something like  ‘asymmetric organocatalysis’ because   it’s just not immediately obvious how  that’s going to affect most of our lives. This one feels truly consequential. There’s  not likely to be another Nobel in our   lifetimes that so /viscerally/  connects to our own experience.

Dr. Karikó, if you see this, thank you  for everything. Also did you really  say that to your former boss because holy [bleep].

This SciShow video is supported by Trade Coffee! Trade connects you to over 55 roasters in the  US, so whether you like dark roasts, espresso,   blends, or rare roasts, you can find it at Trade  Coffee. They offer over 450 different coffees!

With so many options, they keep you  from getting overwhelmed by guiding   you through the process and matching you  to coffees uniquely suited to your taste. Once you’ve picked the perfect coffee, it’s  shipped directly to you within 48 hours of   being roasted so you can enjoy the freshest cup  of coffee in your home or office, every time. Fellow SciShow producer, Hiroka, tried their Bark At  the Moon medium-dark roast coffee and said it’s   easy to drink and kept her awake throughout  a busy Wednesday morning.

She loved the rich,   sweet flavor, especially with  its chocolate and caramel notes. To try it for yourself, you can go to  drinktrade.com/SciShowOffer to get a   free bag of coffee with any subscription purchase. Thanks for watching SciShow, and thank you Dr  Karikó, for a truly girl boss-ing into the sun! [Outro music]