[âŠINTRO] 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 werenât 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 thatâs 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 wonât just be for COVID. It will be a major change in the way we design
all vaccines in the future. Now, weâre 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. Itâs like a wanted poster that will teach
our immune cells what to seek out and destroy when a real infection
happens. Traditionally, weâve introduced antigens
in a few different ways: using a live weakened pathogen (one that is
alive but wonât hurt us), a killed pathogen, or just a piece of one. Weâve 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 isnât actually the genetic material
inside our cells â thatâs 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 doesnât make sense to schlep
the whole library with you each time you need to ask a manufacturing
plant to make something, itâs 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 cellâs 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
youâre dealing with something like a totally new virus causing a sudden
pandemic. Because designing one of these vaccines doesnât
even require a sample of the virus -- all you need is a digital
file with its genetic sequence. Thatâs 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. Thatâs what happened with Modernaâs 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 donât 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 thereâs also one more reason theyâre
so speedy to put together. Many vaccines require adjuvants. These are substances that enhance the immune
systemâs 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 theyâre 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 thereâs a reason why weâre only now
hearing about them. They just werenât ready before. You see, for all of its benefits, mRNA also
has some drawbacks, which have taken literal decades of research to resolve
â 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 itâs 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 thatâs 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 wasnât 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 bodiesâ
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. Thatâs why when the immune system notices
a strand of unmodified RNA, itâs a clear sign that itâs dealing with
an invader and then, itâs 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 cellâs 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 arenât always suitable for use
in a living human body. Things like zapping the cells with electricity
to open little holes to let things in. Itâs not that these methods canât be adapted
for use in humans, itâs 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 thatâs 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 isnât 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, itâs
likely they will keep working. And that is great news for all of us. Thanks for watching this episode of SciShow. We hope itâs helped you understand how we
got this far. I know that I personally, before I saw this
script, didnât 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 couldnât do this without your support,
so thank you. To get involved, check out patreon.com/scishow. [âŠOUTRO]
i like the part where you just know the virologists are cracking jokes, pranking IT saying that they're intentionally downloading a virus
So theyâre the 3D printer of vaccine types.
This fucking rules