[♩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 cells – that’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 resolve – just 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].