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,   ta-da: 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.  Thanks for watching this episode of  Crash Course Biology which was filmed   at our studio in Indianapolis, Indiana and was  made with the help of all these nice people.  If you want to help keep Crash  Course free for everyone,   forever, you can join our community on Patreon.