When the first COVID-19 vaccines started rolling
out in 2020, most of the world was introduced to a new kind of medicine: the mRNA vaccine.
With traditional vaccines, people are often injected with the
weakened or inactive version of a virus. The idea is to rile up the immune system,
so that the body learns how to fight that virus if it ever shows up again.
If you’ve ever gotten a flu shot, you’ve felt this firsthand.
But mRNA vaccines, like the one for COVID-19, work a little differently.
Instead of containing a virus, these vaccines contain what are basically instruction manuals
for cells to make millions of copies of a protein that mimics part of the virus.
Your immune system gets trained by these proteins so that it's ready
to protect you from the real thing. But before we could even begin to make
these vaccines, researchers had to learn how to write their own cellular instruction manuals,
called messenger RNA, or mRNA. And in the case of COVID-19,
these cellular translation skills have helped save tens of millions of lives.
Hi, I’m Dr. Sammy, your friendly neighborhood entomologist, and this is Crash Course Biology.
Ah, this just in: breaking news—it seems like our theme music has just been indicted on charges of
being too funky fresh…
[THEME MUSIC]
Good news, we’re hearing that the theme music has been acquitted on all charges. Wonderful! A great day for theme music! Now,
back to Biology. We learned in
episode 33 that DNA is a /huge/ collection of instructions that tell cells how to make all
the proteins they need to survive and thrive. And for eukaryotes — life forms like plants,
animals, and fungi — DNA is kept in a special structure inside the cell, called the nucleus.
Generally, this is great, because it protects the DNA.
Which is crucial because if the instructions get damaged, every cell that’s produced moving forward
could potentially be affected. But here’s the catch.
The tiny cellular structures that build proteins are outside the nucleus.
It’s like you’re sitting outside with a pile of wood, all ready to build an
amazing platypus playground … but the how-to guide is chained to a podium in the library.
And your librarian isn’t letting you bring bolt cutters in there – not after you
returned their only copy of “How to Befriend a Platypus” three weeks late and with bite
marks…what? I devour a good book. So, how are you gonna build that
platypus playground of Patti’s dreams? Well, you’re probably going to make a copy
of the pages that you need from the how-to guide. You could take a picture on your phone, or head to
the Xerox machine if you’re feeling old school. Cells do a similar thing.
When they need to build proteins, they copy a few pages of DNA into
a new molecule that can leave the nucleus. That molecule is called messenger RNA, or mRNA.
Yup, just like the instructions that were included in the mRNA COVID vaccine.
Like DNA, mRNA uses its sequence of nucleotides to carry information.
But while DNA uses four bases called A, T, C, and G for short, mRNA uses A, U, C, and G.
It replaces the T thymine with uracil, or U. Most likely because mRNA molecules don’t
stick around for long compared to DNA, and uracil breaks down more easily.
Also, while DNA looks like a ladder, mRNA is only half a ladder, great for sending
messages, not great for cleaning the gutters. It has one strand of material instead of two,
with one nucleic acid base connected to every sugar in that strand.
That’s because, unlike DNA which needs the extra strand to protect itself,
mRNA needs to be quickly and easily read. It’s sort of like how a book is bound with
a nice hardcover, but the copies of pages six through ten you made for class are just bopping
around in your backpack for easy access.
So, cells produce mRNA in a process called transcription.
And the first step in transcription is initiation. Here, an enzyme, or a substance that helps
trigger a biochemical reaction, called RNA polymerase rolls up to a section of DNA.
It swoops in like an airplane approaching a runway.
To know where to land, or where to attach to the DNA, it looks for short stretches of
bases called promoters. Step two: elongation.
Once RNA polymerase has settled in, it unwinds a short section of DNA,
and travels down one of the strands. It forms a chain of nucleic acid bases as it goes,
using one of the strands of DNA as a template. Or, in other words, making a copy.
I guess that makes RNA polymerase more like a tiny, mobile copy machine rather than an airplane.
But stick with me, because there’s one more step here: termination.
Special proteins called termination factors or sequences of nucleic acid bases called termination
sequences terminate, or end the process. Essentially, they tell the RNA
polymerase that its job is done. It should detach from the DNA and
take off for its next one. Safe travels, little buddy!
Meanwhile, the new strand of material that the polymerase just made also separates from the DNA,
and starts making its way out of the nucleus. That new strand of material is called pre-mRNA!
Now, if you compared this pre-mRNA
with the DNA it just copied, you’d notice that they’re not identical.
But it’s not because something went wrong! When it reads a strand of DNA,
RNA polymerase is really making a complementary version of that strand.
But even once pre-mRNA has been transcribed, it’s not ready for
its grand exit out of the nucleus quite yet. Unlike the perfect, oddly warm pages that you
just pulled out of the copy machine to build your platypus playground,
this molecule is a work in progress. If you tossed it out of the nucleus, it would
either get broken down too fast to do anything useful, or the instructions it passed to the rest
of the cell would be impossible to understand, kind of like when you accidentally move the page
that you're copying and the image gets all blurry. So, before it’s ready to leave the nucleus,
it goes through processing. One end of the molecule gets a
little cap, and the other end gets a tail of nucleotides, called the poly-A tail.
Both of these structures have various jobs, but ultimately, they work to keep
the final mRNA stable once it’s ready to go. But something is still off about this molecule.
It’s like you copied a chapter about how to build a diving board for your platypus,
but you also got pages about how to fold laundry, and… beginner beekeeping?
Y'all I got that down already. You see, during transcription, it’s like
RNA polymerase copies a whole chapter of DNA. But not every page in that chapter is
useful for making proteins. That’s why we need splicing.
Splicing is where all the parts of mRNA that don’t tell the cell how to make proteins get removed.
It’s like recycling all the pages that don’t tell you how to build
a platypus playground for Patti here. Once processing and splicing are over,
tada: We officially have a finished mRNA molecule! From here, the molecule can leave the nucleus, and
travel to cellular structures called ribosomes. These ribosomes read mRNA’s code and use that
information to build proteins.
We’ll get more into how that works next time. But overall, this process — information going from
DNA, to RNA, to proteins — is essential for life. In fact, it’s so important that it’s usually
taught with a very fancy-sounding nickname: the Central Dogma.
Often, the Central Dogma is communicated as this: “DNA makes RNA, and RNA makes proteins.”
And generally, this is true! But it’s actually a bit more
complicated than that. Let me explain.
In 1957, Francis Crick gave one of the biggest lectures in biology.
Crick was a researcher who helped discover that DNA looks like a twisted ladder.
And emphasis on “helped” given that Rosalind Franklin produced the DNA image that allowed
him and his collaborator to figure it out. His research led him to develop an idea,
a hunch really, about how information moves inside of a cell.
He believed that information in cells could only travel in certain directions, like chess pieces.
It could go from nucleic acids to nucleic acids — so, information stored in DNA could
be used to make either DNA or RNA. Or, information could go from nucleic
acids to proteins — like when mRNA brings instructions to ribosomes.
But that was it. Crick’s very specific hunch
was that the information in proteins can’t be used to make DNA, RNA, or more proteins.
And with no direct evidence, this was kind of a wild hypothesis at the time.
And what he said about how information flows, that’s the Central Dogma.
He summarized it as, “Once information has gotten into a protein, it can’t get out again.”
Now, because science is a process driven
by evidence, the Central Dogma didn’t get into your textbook just because an
educated guess was made at a conference. Generations of scientists since have
rigorously explored and tested this idea to confirm that this really is how life works.
And along the way, they’ve discovered new things about this process like alternative splicing.
This is where the cell does more than just cut out fluff, like in regular splicing:
It picks and chooses which parts of its message to keep, in order to make multiple,
different proteins from the same, original code. For instance, imagine the DNA codes for a
message that says “Mix together red, yellow, and blue paint.”
Which would be weird for DNA, but hey. By default, mRNA copies that whole sentence.
And none of it is fluff: Every word is an important instruction.
But check out what happens next. With alternative splicing, this one message
can get spliced into three different messages. Like, if your cells needed orange proteins
right now, they might cut out the last part of the sentence to say
“Mix together red and yellow paint.” Or if they needed purple proteins,
they might cut out the middle part, so that it reads: “Mix together red and blue paint.”
They’re cutting useful parts of the message to change its meaning in another useful way.
Alternative splicing means that one stretch of DNA can code for a whole rainbow of proteins.
So, scientists think it may be a way your DNA is extra-efficient and saves space.
Instead of having three sets of instructions, the DNA carries one message that can get sliced
and diced into three different versions. Alternative splicing is so complex it’s
still being studied, including by researchers like Dr. Tracy Johnson.
In her research on brewer’s yeast — the stuff that makes beer alcoholic — she and
her collaborators learned that temperature is one thing that affects how mRNA gets spliced.
Turns out, our buddy Yeasty the 99th likes it hot. So, the way we understand the world isn’t just
thanks to one scientist, or even a few of them. It’s a team effort that’s
been unfolding for centuries. And that brings us back to where we began: 2020.
That year, scientists were able to create mRNA
vaccines for COVID-19 because of generations of knowledge about how mRNA and transcription works.
They looked at the RNA in the COVID-19 virus, and found the instructions to make a protein that
serves as an identifying feature for the virus. Then, using RNA polymerase, they transcribed
that information into a piece of mRNA. Many, many tests later, the mRNA became part
of a life-saving vaccine that allows our bodies to recognize an invader that it’s never seen before!
So, without transcription, life on Earth wouldn’t have gotten very far.
And without understanding transcription… a vaccine for COVID-19 might have taken
a lot longer to produce. Now, teams of scientists
are trying to learn just how many more diseases can be fought with this strategy.
Next week, we’re going to dive a little deeper into what happens after mRNA delivers its message.
I’ll see you then. Peace!
This series was produced in collaboration with HHMI BioInteractive.
If you’re an educator, visit BioInteractive.org/CrashCourse for
classroom resources and professional development related to the topics covered in this course.
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