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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 common amino acids our body 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 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,