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  • [♩INTRO]

  • When the COVID-19 pandemic began,

  • researchers and public health experts warned us

  • that the earliest possible window for a vaccine would be the end of 2020.

  • They also cautioned us that vaccine development takes time,

  • and that it could be much, much longer than that.

  • But in the closing weeks of the year, two vaccines

  • one from pharma companies Pfizer and BioNTech, one from Moderna

  • began rolling out in some parts of the world.

  • They weren't the first worldwide, but they were, in a sense, the first of their kind.

  • And like Babe Ruth calling his shot,

  • it seems a little like the experts knew how this was going to go.

  • And that's because a technology decades in the making

  • was finally able to rise to the occasion -- just when we needed it most.

  • This is the story of how a new vaccine technology, based on RNA, came to be.

  • And if it continues to prove safe and effective, it won't just be for COVID.

  • It will be a major change in the way we design all vaccines in the future.

  • Now, we're going to cover a lot of research today

  • but none of these papers were published out of the blue.

  • A lot of progress in immunology and biotech had to happen

  • for mRNA vaccines to happen, and a lot of people had to do that research.

  • The job of a vaccine is to safely expose our immune system to an antigen

  • a piece of protein from a pathogen, or infectious agent,

  • that our immune system will remember and recognize.

  • It's like a wanted poster that will teach our immune cells

  • what to seek out and destroy when a real infection happens.

  • Traditionally, we've introduced antigens in a few different ways:

  • using a live weakened pathogen (one that is alive but won't hurt us),

  • a killed pathogen, or just a piece of one.

  • We've also used viruses to deliver instructions to our cells to make an antigen.

  • Whatever method you use, this takes years of work.

  • For example, to make the measles vaccine,

  • scientists had to grow the virus for almost ten years.

  • They needed to weaken the virus enough

  • that it would trigger an immune response without making you sick.

  • But starting around the 1990s, scientists thought that maybe they could

  • cut out the middleman and use messenger RNA, or mRNA,

  • to reprogram our cells so they make those viral antigens by themselves.

  • Instead of us producing them in a laboratory somewhere

  • our cells could do the work.

  • They hoped that such an approach might be safer

  • and more efficient than traditional vaccines, at least for some diseases.

  • After all, the job of RNA is to guide the production of proteins in a cell,

  • and antigens are generally proteins.

  • But mRNA isn't actually the genetic material inside our cellsthat's DNA.

  • You can think of DNA as a giant library containing the blueprints

  • for any kind of protein your body might need to make.

  • But, since it doesn't make sense to schlep the whole library with you

  • each time you need to ask a manufacturing plant to make something,

  • it's easier to just copy out the specific protein blueprints you want.

  • mRNA is that copy.

  • It brings the genetic sequence for a protein

  • transcribed from a cell's DNA to the place where proteins are made.

  • So mRNA vaccines use this feature to safely coax our cells into using their own

  • protein-making machinery to create a viral antigen -- from scratch.

  • And this turns out to be a big advantage when you're dealing with something

  • like a totally new virus causing a sudden pandemic.

  • Because designing one of these vaccines doesn't even require a sample

  • of the virus -- all you need is a digital file with its genetic sequence.

  • That's because as long as you know the sequence of DNA or RNA,

  • you can just make it.

  • It is not nearly that simple with protein-based antigens.

  • Proteins are all foldy and weird.

  • DNA and RNA are just linear strings.

  • Scientists can simply download the genetic sequence of the virus

  • and have a candidate vaccine ready to start testing within weeks or even days.

  • That's what happened with Moderna's vaccine,

  • which was ready for preliminary tests less than a month

  • after the genome of the SARS-CoV-2 virus was published online.

  • Also, this enables a plug-and-play approach.

  • Once you have all the basic pieces to make an mRNA vaccine in place,

  • you don't need a new setup to make a new vaccine for a new virus

  • theoretically, you can just swap in new RNA and go from there.

  • And there's also one more reason they're so speedy to put together.

  • Many vaccines require adjuvants.

  • These are substances that enhance the immune system's

  • response to the vaccine and attract the right immune cells.

  • But mRNA, it turns out, is pretty good

  • at bringing in the immune system all by itself.

  • So it avoids the potential need to spend additional months or years

  • testing various types and amounts of adjuvants,

  • and whether they're necessary to make the vaccine work.

  • You can see how all of this could make mRNA vaccines the perfect technology

  • to rely on when we need a defense against a new pandemic, stat.

  • But there's a reason why we're only now hearing about them.

  • They just weren't ready before.

  • You see, for all of its benefits, mRNA also has some drawbacks, which have

  • taken literal decades of research to resolvejust in time for COVID-19.

  • This research got its start around 1971, when UK-based researchers

  • studying protein production put mRNA from a rabbit into frog egg cells.

  • They found that those cells produced the rabbit version of that protein,

  • thanks to the mRNA code.

  • This led to a series of similar experiments, with scientists being able

  • to insert mRNA into more and more complex types of cells.

  • Researchers also kept working on efficient ways to deliver mRNA into a cell.

  • The first experiments in using mRNA as an actual vaccine

  • started taking place in the early 1990s.

  • And that is where researchers ran into huge problems.

  • The major roadblock was that when it's introduced into the body,

  • RNA can be pretty hard to keep in one piece.

  • It turns out that free-floating RNA is often used by tumor cells

  • to make it easier for them to spread around.

  • RNA that hangs around outside of our cells can also be a remnant of a cell

  • that was infected by a virus and then blasted apart by the immune system.

  • And so, to keep us healthy from those two things, our bodies have

  • a lot of ribonucleases, which are enzymes that break up free-floating RNA

  • to get rid of any potential danger.

  • So that's why in early experiments, mRNA would get destroyed

  • before enough of it could get into a cell and start doing its magic.

  • This problem stymied mRNA vaccine research for decades,

  • until scientists found ways to make the mRNA more stable.

  • One solution was adding specific gene sequences to cap the beginning

  • and end of the mRNA strand.

  • That made it look more like mRNA that was generated by our own body.

  • But that wasn't the only quirk of messenger RNA

  • that scientists had to contend with.

  • On top of the ribonuclease problem, free-floating RNA

  • can activate the immune system and attract it to its location.

  • Yeah, sure, like we said before, attracting the immune system can be helpful,

  • because you need that to happen for a vaccine to work anyway.

  • But this was too much of a good thing.

  • In early attempts, the mRNA was activating the immune system so much

  • that it would clear the vaccine away before it could do its job.

  • Like, the goal of using an mRNA vaccine is to teach the immune system

  • to seek out the antigens that the vaccine will program our cells to make.

  • Not to destroy the message before it gets the chance to do anything.

  • And then we reached 2005 when researchers discovered

  • the secret handshake that allows our bodies' RNA to avoid immune destruction.

  • You see, all RNA is composed of four chemical bases,

  • which mirror those used in DNA.

  • But it turns out that in mammals, a lot of those bases are chemically modified

  • until the mRNA strand is needed to guide the creation of a protein.

  • This is not the case in most pathogens.

  • That's why when the immune system notices a strand of unmodified RNA,

  • it's a clear sign that it's dealing with an invader

  • and then, it's time to mount an attack.

  • Figuring this out meant that scientists could now apply

  • those chemical modifications to manufactured RNA.

  • In fact, it actually made mRNA vaccine technology more customizable.

  • Basically, researchers could tweak the percentage of modified bases

  • in the mRNA just enough to call the immune system to the area

  • but not enough to induce an all-out attack

  • and deactivate the vaccine before it can start helping your body.

  • Alright, we have done a lot of work here, from the 1970s to the early 2000s.

  • The final challenge that scientists had to overcome

  • was how to deliver the vaccine into the cell.

  • The mRNA molecule itself is too big to get through a cell's membrane easily.

  • Experiments demonstrated that some can sneak in,

  • but not enough that you could just throw it at cells and hope for the best.

  • Now, there are specialized ways to introduce nucleic acids

  • into cells in a lab setting.

  • But they aren't always suitable for use in a living human body.

  • Things like zapping the cells with electricity to open little holes to let things in.

  • It's not that these methods can't be adapted for use in humans,

  • it's just that there are better options than zapping people.

  • A simple injection is what we want -- something people are used to.

  • Also something we have all of the technology already to administer.

  • Especially if you want to fairly quickly vaccinate billions of people.

  • And that's why scientists eventually turned to lipid nanoparticles,

  • which are the delivery method used

  • in the first two mRNA vaccines to hit the market.

  • Lipid nanoparticles, or LNPs, are tiny balls of layered lipids, or fats,

  • with an mRNA payload tucked safely inside.

  • The LNPs have a positive charge,

  • which makes them stick to the negatively charged cell membranes.

  • In a process called endocytosis, the cell then wraps the LNP

  • in a piece of its membrane and swallows the package.

  • Once inside, our cellular machinery unpacks the whole package,

  • and the mRNA can start making the antigen proteins necessary

  • to train our immune system.

  • And this isn't that new of a technology.

  • As early as 1978, scientists were able to use a basic version

  • of these tiny balls of fat to get the mRNA inside mouse spleen cells

  • and make them synthesize a new protein.

  • Early LNPs had some issues with efficacy,

  • but researchers eventually perfected the technology,

  • just a few years before it turned out to be needed

  • to quickly develop an mRNA vaccine for the COVID-19 pandemic.

  • Building on successful studies in delivering other types of RNA into cells,

  • in the early 2010s, researchers started experimenting with LNPs

  • as ways to make mRNA vaccines easily injectible.

  • And in 2018, the FDA approved the first RNA drug that also used LNPs.

  • Which means the delivery vehicle was ready just in time

  • when researchers started working on mRNA vaccines for COVID-19.

  • So even though the Pfizer-BioNTech and Moderna COVID-19 vaccines

  • were the first mRNA vaccines to be authorized,

  • researchers had been excited about the potential of this technology

  • and had been working on it for decades.

  • It's true we've thrown a lot of money and person-hours at stopping this pandemic,

  • and without that investment,

  • we probably would not be seeing mRNA vaccines just yet.

  • Some efforts to create other mRNA vaccines had already been abandoned,

  • and mRNA vaccines were never considered a sure thing.

  • We had to do the testing, which is why it took until late-2020.

  • But there was an existing body of research to draw from,

  • including into other major coronavirus diseases -- SARS and MERS.

  • What researchers learned allowed them to create

  • these new COVID vaccines even faster.

  • In one sense, these COVID vaccines were an explosive development

  • an incredibly swift global collaboration in the name of human health.

  • Something that feels, to me, on the scale of an Apollo mission.

  • But all science is incremental.

  • It always builds on the dedicated work of generations of researchers.

  • And it never happens in a vacuum.

  • In fact, multiple mRNA vaccines for other viral and bacterial diseases,

  • and even for some cancers, are undergoing human trials.

  • Now that mRNA vaccines are working, it's likely they will keep working.

  • And that is great news for all of us.

  • Thanks for watching this episode of SciShow.

  • We hope it's helped you understand how we got this far.

  • I know that I personally, before I saw this script, didn't know a lot of this history.

  • If you want to help us as we try to make this complicated world

  • a little easier for everyone to understand, consider supporting us on Patreon.

  • Patrons get access to cool perks, like monthly livestreams and bloopers.

  • And we couldn't do this without your support, so thank you.

  • To get involved, check out patreon.com/scishow.

  • [♩OUTRO]

[♩INTRO]

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Why It Actually Took 50 Years to Make COVID mRNA Vaccines

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    joey joey posted on 2021/06/04
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