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Your genetic code is neat, but could be better!

Hosted by: Hank Green

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Sources:
Mukai et al. 2017 “Rewriting the Genetic Code” https://www.annualreviews.org/doi/abs/10.1146/annurev-micro-090816-093247
Chin 2014 “Expanding and Reprogramming the Genetic Code of Cells and Animals”
https://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-060713-035737
https://openoregon.pressbooks.pub/mhccbiology112/chapter/the-genetic-code/
Khan Academy “Intro to gene expression (central dogma)” https://www.khanacademy.org/science/high-school-biology/hs-molecular-genetics/hs-rna-and-protein-synthesis/a/intro-to-gene-expression-central-dogma
el-Showk 2014 “The Language of DNA” https://www.nature.com/scitable/blog/accumulating-glitches/the_language_of_dna/
D’Onofrio and Abel 2014 “Redundancy of the genetic code enables translational pausing” https://www.frontiersin.org/articles/10.3389/fgene.2014.00140/full
Spencer and Barral 2012 “Genetic code redundancy and its influence on the encoded polypeptides” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962081/
Duton 1983 “The significance of redundancy in the genetic code” https://www.sciencedirect.com/science/article/abs/pii/0022519383903880
Sleiman et al. 2021 “A third purine biosynthetic pathway encoded by aminoadenine-based viral DNA genomes” https://science.sciencemag.org/content/372/6541/516
Bain et al. 1992 “Ribosome-mediated incorporation of a non-standard amino acid into a peptide through expansion of the genetic code” https://www.semanticscholar.org/paper/Ribosome-mediated-incorporation-of-a-non-standard-a-Bain-Switzer/a011e43038dd85ec8da081e59d73a6f0d8bd5164
Zhang et al. 2017 “A semisynthetic organism engineered for the stable expansion of the genetic alphabet” https://www.pnas.org/content/114/6/1317
Hoshika et al. 2019 “Hachimoji DNA and RNA: A genetic system with eight building blocks” https://science.sciencemag.org/content/363/6429/884
Ernst et al. 2016 “Genetic code expansion in the mouse brain” https://www.nature.com/articles/nchembio.2160
Robertson et al. 2021 “Sense codon reassignment enables viral resistance and encoded polymer synthesis” https://science.sciencemag.org/content/372/6546/1057
Bethencourt 2009 “Virus stalls Genzyme plant” https://www.nature.com/articles/nbt0809-681a
Jason Chin: "Reprogramming the genetic code" https://www.youtube.com/watch?v=9gOImG7I5ek&t=520s
https://groups.molbiosci.northwestern.edu/holmgren/Glossary/Definitions/Def-D/degenerate_code.html#:~:text=Biology%20Glossary%20search%20by%20EverythingBio,by%20more%20than%20one%20codon.
https://www.britannica.com/science/amino-acid

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 Introduction (0:00)



(♪SciShow Intro♪) The genetic code is really neat, with all of its C's and A's and T's and stuff, but under the hood, it's actually extremely redundant. And there are those who look at that redundancy and see a world of potential. Over the last few decades, scientists have been experimenting with ways to take the familiar genetic code and use its redundancies to reprogram and expand it.  But what would you do with a rewritten genetic code? It works fine, right?

Yes, but by rewriting it, scientists are finding new ways for life to build itself from the ground up. And that could help us do all kinds of things, from understanding alien life to using cells as factories to build brand new molecules. So to start off, before we get into anything about redundancy or reprogramming, lets have a quick reminder about how all the stuff in your genome works.

The basic idea is that your genome contains information in the form of DNA. This blueprint comes in the form of the nucleotides, the A's, G's, T's, and C's, as well as the order which they are arranged; T-T-A or C-C-G, for example. When it comes time for your cell to make a new protein, your DNA unzips and a copy of the code made of a molecule called messenger RNA, or mRNA, is made.

IT uses a molecule called uracil, U, instead of T. But it uses the same genetic code as DNA.  This mRNA is then transported to a protein factory called a ribosome. There, the ribosome reads the open-faced mRNA in three-letter chunks called codons.

Each of these codons correspond to one of the building blocks of proteins called amino acids. As the ribosome reads the codons, a molecule called a transfer RNA, or tRNA, brings in the matching amino acid. The ribosome brings everybody together and links the amino acids together in a chain in the same order as the codons in the mRNA.

This goes on until the ribosome hits a signal in the mRNA to stop. At which point, it releases the amino acid chain, which is now ready to become a finished protein. And in this way, our cells can turn just 20 amino acids into pretty much all of the stuff we are made of.  But here's where we talk about redundancy.

There are 20 amino acids that our body commonly uses as building blocks. Including the need for a stop signal, there's really only 21 different signals you need for protein synthesis. But there are 64 possible triplets.

That's just math; four options in the first space times four in the second times four in the third equals 64.  64 is a lot more than 21. The end result is that you have extra codons, extra combinations of letters. And rather than leave them blank, the genetic code doubles up and gives some amino acids double codons, or more.

For example, the amino acid tyrosine can be recruited by either the combination U-A-U or the combination U-A-C--it gets two different codons. And the amino acids serine, leucine, and arginine each get six different combinations. Which is what scientists mean when they say the genetic code is redundant.

Actually, the technical term is degenerate. And it's this redundancy that scientists are looking to take advantage of. You might hear terms like redundant or especially degenerate and assume that this is, you know, bad.

So why not reassign codons? Plenty of room to work with, right? But as anyone who's gotten a flat tire and happened to have a spare handy may tell you, there can be benefits to having some redundancy built in.

One of the major benefits to a redundant genetic code may be protection against harmful point mutations. Those are changes to a single letter in the genetic code, such as swapping a 'T' for an 'A'. In a system with no room for error, this would translate into a different amino acid being added to the protein chain, potentially ruining the protein or even making it dangerous to the cell.  But by having a bit of redundancy built in, it means that sometimes those otherwise potentially harmful mutations fizzle out.

To go back to tyrosine for instance, a mutation that changes U-A-U to U-A-C, well, that's still tyrosine so to the cell everything's the same. On top of this, there may be more subtle benefits to this setup as well. It could also steer evolution towards chemically simpler amino acids.  And scientists have suggested that there may indeed be some differences between redundant codons, tweaking things like the speed of protein folding.

Or, how strongly the gene is expressed. Nevertheless, the genetic code being redundant does present scientists with an opportunity for tweaking and filling in some brand new amino acids.  See, those 20 amino acids our DNA codes for have a special place in biology because they are enshrined in the genetic code. They get the fancy name of the "canonical" amino acids, like molecular biology is a TV series or something.

But from a chemical point of view, those 20 aren't especially special. To a chemist, calling something an amino acid just means it's a carbon-based compound with a chemical piece called an amino group on one end and a carboxyl group on the other, with a side chain of something else coming off. Because carbon-based compounds can take all kinds of forms, there are all kinds of things that can make up those side chains.

So technically, there's a virtually indefinite number of amino acids, all of which could be theoretically included in protein synthesis. These extra amino acids are called the "non-canonical" amino acids, which, yes, does make the whole scenario seem a bit like molecular biology fanfiction.  And some of these non-canonical amino acids could be really useful in a bunch of different ways. But before we get to that though, let's talk about how.

Now there are organisms that naturally use something different. There's a yeast that uses C-U-G for serine instead of leucine, for example. But let's start with a nice normal cell and reprogram its entire genetic code to include non-canonical amino acids.

Ideally, somehow without killing it. Now for one thing, to even get this to work you may have to change a bunch of cellular components. Remember that both ribosomes and tRNAs are needed to assemble amino acids.

Those may need to change, for example. You may also need to go even deeper. You might need to change not just tRNAs, but the molecules that pair them with amino acids in the first place.

And you need to get the organism to make your non-canonical amino acid, or you have to keep providing it.  But okay, given that we can do all of that, let's get to the good stuff. We've seen how the genome works, with genes becoming blueprints, becoming proteins. We've talked about how there's some redundancy built in, and we've talked about why changing stuff might be hard. Now, let's talk about how we've done it.

One way to reprogram the code is actually just to go ahead and add in more letters. For example, in 1992, researchers were able to tweak cytosine to create what was essentially a 65th codon, which could then code for a non-canonical amino acid. More recently, we've also been able to make E. coli, a common bacterium, with six base pairs (the original A, C, T and G, as well as two dubbed X and Y). And in 2019, scientist who felt like that wasn't enough created DNA with eight nucleotides.

But, there are other options too for reprogramming the genetic code. Like, not just adding new codons but repurposing the existing redundant ones. That is to say, not adding new bases but taking one of the existing 64 combos and getting it to point towards something non-canonical.

This would let us have blueprints that don't just use 20 amino acids, but 21 or maybe even more all within normal DNA. One of the common targets for this kind of tweaking is stop codons. Those are the ones that don't actually tell the ribosome to add any amino acid, instead they are the ones that tell it to stop and let go of the chain.

We have 3 of them. There's UAA, UAG and UGA. As for how this might work, the first step to using, say UAG, for a non-canonical amino acid would be to free it up from its current job.

We can use genetic engineering to change existing UAG sequences to something like UAA. Now there will be way more UAA than normal but the ribosome does not care about that – it's still a stop codon.

Now, this can be tricky because you have to make sure that step happens everywhere in the genome. Otherwise, you might end up completely breaking some other, life-sustaining enzyme somewhere. In which case, you don't end up with a cool new bacterium, you end up with a dead bacterium.

But, if things go right, this means that the cell now has no naturally occurring UAG sequences, but can still make all its necessary proteins. You didn't have to change anything fancy, but you have freed up UAG for our own ends.

We could then say UAG is no longer a stop codon. We're gonna tweak the cell's machinery to now think this is a new, strange amino acid instead. Then a second round of genetic engineering would introduce new DNA sequences that used our upgraded UAG.

This means that this new amino acid could be inserted into existing protein blueprints or even make entirely new ones and this is not just theoretical, we have gotten this to work and not just in bacteria, but in larger animal too, even up to live mice.

We've been able to do this to other codons as well, for example, a 2021 paper in science repurposed three codons, one stop codon and two serine codons. They did this in E. coli and were able to use those three codons to insert three non-canonical amino acids into the genetic code.

Interestingly doing this also made the cells resistant to viruses. They tested this at the point where the'd essentially blanked the codons, but before they assigned the new amino acids.

The viruses would send their genetic codes to the cell's ribosomes for reproduction like normal in the course of an infection. But the viral genomes hadn't been tweaked like the E. coli's had. So, when the bacteria's ribosomes saw a UCA codon, instead of adding a serine it just couldn't. It didn't know what to do.

And that meant that the virus didn't replicate. Presumably, even if they'd tested it later, after they'd reassigned the codons, the virus would still be in trouble, because instead of having the nice virus proteins it would be expecting, they'd be riddled with these random other amino acids. So that's cool. Not what they were trying to do, but cool.

But what where they trying to do. Like what is the point of any of this. Well to go back to the thing we talked about, there are times when we would want bacteria to be safe from viral contamination. There are real-life biotech companies that use bacteria to create drugs or other compounds.

We could also use these reprogrammed organisms to make designer proteins, which might include new medicines or new ways to precisely deliver and control medicines. Like, by adding in certain compounds, we could control protein function with light.

But beyond that, experimenting with reprogramming genomes and non-canonical amino acids, could help us study things in new ways. We could attach amino acids with special tags that are easy to track, helping us watch how cellular machinery actually works for example. And also experimenting with different versions of life's fundamental blueprints might help us think about the different forms life might take in the universe, as well.

So, to recap scientist are able to tweak and reprogram the genetic code, either by adding new letter or tweaking the redundancies inherent to our genomes. And doing this allows us to add new amino acid building blocks to life's arsenal.

And yes, for you, and me, and our dogs, and most of life on earth a little redundancy and sticking to biological cannon is not bad, it can definitely be a good thing. But experimenting with this stuff may one day help us in all kinds of ways, ways we are still discovering as this technology progresses.

Thanks for watching this episode of SciShow. It was a pretty deep dive, and I'm really happy with how this one turned out. So, thanks to everybody who was involved in making it. If you want to get involved, you can consider supporting us on patreon. You'll be able to join our community on discord and you will help us make cool videos that anyone can enjoy for free to get started check out https://www.patreon.com/scishow
(♪Outro♪)