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Re-Encoded Organisms


KerikBalm

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https://www.newscientist.com/article/2101657-synthetic-supermicrobe-will-be-resistant-to-all-known-viruses/

The concept has been around since at least 2006 (if anyone can find a reference to this concept from 2006 or earlier, I would be *very* interested).

Basically, you modify tRNA anti-codons, and then modify the mRNA anticodons such that the same amino acid is specified by the mRNA.

When a virus comes into the cell to try and hijack its translation machinery... the wrong amino acids are inserted by the tRNAs with altered anti-codons, and nothing works.

The virus would need to be re-encoded too. If the genetic code is different enough, the virus would basically have to change all its base pairs simultaneously... it couldn't evolve around it, as there wouldn't be viable interemediates.

Also, this would make any genetic modification unable to spread to wild populations, as they modified genes would be in the wrong encoding for wild organisms.

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All the virus has to do is carry a bit of tRNA with it and make more in the target cell. That's a fairly trivial adaptation for a virus with a lipid envelope. This certainly improves resistance, at least for a while, but it doesn't make organism completely immune, which means new diseases will evolve around that.

Keep in mind that the main reason viruses aren't perfect at hijacking cells is because once they get too good at it wipe out host population. A dictionary substitution is hardly a game changer.

Edited by K^2
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42 minutes ago, K^2 said:

All the virus has to do is carry a bit of tRNA with it and make more in the target cell. That's a fairly trivial adaptation for a virus with a lipid envelope. This certainly improves resistance, at least for a while, but it doesn't make organism completely immune, which means new diseases will evolve around that.

Keep in mind that the main reason viruses aren't perfect at hijacking cells is because once they get too good at it wipe out host population. A dictionary substitution is hardly a game changer.

#1) name a virus that does that. A few encode some tRNAs iirc, but I don't know of any that carry tRNAs with them.

#2) Even if they did, they rely on host cell ribosomes, which will obviosuly be adapted for the host tRNAs, and host cell tRNA would obviously outnumber the tRNAintroduced by the virus by orders of magnitude. 99% of the time the host cell tRNA would get used, and the synthesized protein is not going to work. Its not trivial like you say.

#3) evolution can only happen if intermediates are viable. A virus isn't going to just mutate half its genome at once in a very specific way to adapt to the new code. Thats about as likely as a dog giving birth to a cat.

#4) as far as I know, there aren't any enveloped bacteriophages.

Quote

Yep, locking viruses out is difficult.

But i think the intendet main application is to keep artificial changes from spreading. Might that work ?

Making the re-encoded genome is the difficult part. Locking out viruses would happen automatically as a consequence.

As to the main intended application... thats difficult to say because both follow as a result of the re-encoding, and at the moment the intent seems to jsut be able to demonstrate re-encoded organisms.

Making bacteria immune to viruses seems to be a dangerous proposition, but making lab strains that can't spread their plasmids/recombine with other bacterial strains would be good.

Worldwide though, trillions of $ are lost every year due to viruses damaging crops, so the big prize here would be GMO crops immune to viruses.

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2 hours ago, KerikBalm said:

#1) name a virus that does that. A few encode some tRNAs iirc, but I don't know of any that carry tRNAs with them.

#2) Even if they did, they rely on host cell ribosomes, which will obviosuly be adapted for the host tRNAs, and host cell tRNA would obviously outnumber the tRNAintroduced by the virus by orders of magnitude. 99% of the time the host cell tRNA would get used, and the synthesized protein is not going to work. Its not trivial like you say.

#3) evolution can only happen if intermediates are viable. A virus isn't going to just mutate half its genome at once in a very specific way to adapt to the new code. Thats about as likely as a dog giving birth to a cat.

#4) as far as I know, there aren't any enveloped bacteriophages.

1) Proteins bound to or contained within envelope change all the time. Mutation to bring a batch of tRNA is trivial.

2) Concentrations will take a while to equalize without an active system to move things around. Viral genetic material will start out swimming in pool of its own tRNA and will quickly make more. It can easily overwhelm cell's own tRNA concentration to the point where error rate in protein expression is going to be acceptable.

3) Intermediate is viable. All it needs is a mutation that makes tRNA stick to the capsid or envelope. As indicated above, these kinds of mutations happen all the time and are the main way in which viruses evolve.

4) I found five families of encapsulated bacteriophages by just opening Wikipedia on "bacteriophage" page.

And this is just a single example of how ability to attack these cells can develop naturally. I can think of a few other ways that would probably not be as likely to evolve quickly, such as having base pairs not compatible with host tRNA at all. And, of course, if we open it up to engineered solutions, defeating the system becomes completely trivial, with engineered virus being free to evolve.

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1) Bringing some tRNA would be trivial... but why would it evolve? the intermediate stage would confer no fitness advantage in normal hosts, and wouldn't be enough to allow infection of reencoded hosts.

Even assuming the capsid is littered with tRNA binding proteins, and those bound RNAs are protected long enough for it to enter a cell (RNAses are everywhere), and it can release them at the appropriate time.... the amount of tRNA it can bring in will not be enough when one considered the size difference

2) viral mRNA or DNA won't be doing anything until it reaches a host cell ribosome. Its even worse for DNA viruses which need their DNA to be transcribed and then the resulting RNA to find a ribosome. The cytoplasm is not one homegenous soup. Those ribosomes, when the viral RNA reaches them, will have plenty of the modified tRNAs around to screw things up. We can screw things up even more by modifying the shine delgarno sequence of prokaryotic mRNAs, and the complementary rRNA in a manned similar to the mRNA codon/tRNA anticodon changes. Now that viral mRNA isn't likely to even latch on the the ribosome in the first place. (similar changes for the Kozak sequence of Eukaryotes)

Most viruses are DNA viruses. Even then, the virus is going to have to add a whole bunch of tRNA encoding genes to keep things going. Some viruses encode a few, but this is exceptional. I'm not aware of any virus that comes close to encoding a full set of tRNAs.

3) again, as in #1, that's not going to allow for an infection. The amounts you can fit in/on a virus vs what is in a cell is far too different

4) ok, they exist, but they are very rare. There's also a nomenclature issue. Since Archea are not bacteria (or Eubacteria), the viruses that infect them shouldn't be known as bacteriophages. That lowers those 5 "groups" to just 2: Cystoviridae and Plasmaviridae containing only 2 known species (although the latter has some more tentative species, and I'm sure there are more).
The virus will have to simultaneously develop a system to bring in tons of tRNA, protect that RNA from degredation, acquire dozens of tRNA encoding genes, and develop a system to shut down host cell tRNA synthesis (I'm not aware of any virus that does this, even the ones that do happen to encode a few tRNA of their own)... or simultaneously change nearly every codon in its genome.

If we throw in the Kozak/shine delgarno sequence/rRNA sequence changes at the same time, it gets even worse (although that wasn't discussed in this article/paper). If you now have your own tRNA and your own ribosomes... you're not a virus, you've got a full set of protein translation machinery, and you're a parasitic bacteria/archea/whatever like mycoplasma.

I don't see how an intermediate is going to work to infect the reencoded organisms, and it will be much worse than its competitors at infecting non-encoded cells.

I really really really doubt that it would work.

On the other hand, they started in 2013 with just a single codon change, and that wasn't enough... they were more resistant to infection, but not immune, and if we purposefully made such stepwise changes, then sure, the viruses could probably keep up.

Even conceeding its not strictly impossible, the time frame for sucha  huge evolutionary change is long enough for human purposes that when these new viruses evolve, we can just change the encodings again.... not to mention the proteins involved in packing a ton of tRNA onto the capsid are probably going to be easy for immune systems to spot.

And yes, if we can reencode bacterial or eukaryotic genomes, then it would be trivial to reencode a viral genome to infect the new GROs... and I'm sure someone would do it just like some people make computer viruses..

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Hi KerikBalm,

Not sure if you were looking for pre 2006 references in the scientific literature but if you'll settle for a sci-fi reference, it's mentioned (in a re-encoded human context) on Greg Egan's 'Distress' - published in 1996.

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I don't suppose you could provide any further details, the wikipedia page doesn't suggest anything of that sort being contained within the novel, when I'd think humans that are immune to viruses that the rest of humanity may suffer, and whom can't interbreed with normal humans, would be a major plot point

https://en.wikipedia.org/wiki/Distress_(novel)

Were there specific mentioned of tRNA anticodon-mRNA codons being correspondingly changed? Viral immunity? inability to interbreed?

Edited by KerikBalm
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Sure. I'll dig out my copy and see what I can find. It was kind of a side plot so I'm not terribly surprised that it wasn't on Wikipedia. In the meantime you might have some luck searching for Egan plus junk plus DNA.

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OK, found it.

Spoiler

 

Kind of an extreme version of what you're talking about in that the character (Landers) is in the process of replacing his entire genome with synthetic DNA based on non-natural bases. It's not discussed in much detail but I'm thinking for that to work, he'd also have to do an awful lot of re-engineering for all his DNA replication, transcription and translation enzymes too. Landers has also designed and injected various symbiotes to broaden his metabolism and strengthen his immune system. Basically he could eat old tyres if necessary and can 'shoot up AIDS without batting an eyelid'. 

Sadly, the plotline for all this is fairly predictable if I recall correctly. Ubermenschen survivalist attempts to eradicate the rest of humanity with a virus leaving himself and his minions as the sole survivors.

 

 

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Well, thats not specifically reencoding.

There have been other efforts to make new codes with non natural amino acids and bases, but the idea that just changing the code, without adding any bases, or without changing any of the proteins, would have benefits doesn't seem to be discussed before the 2000's as far as I can tell

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No - I can't think of any better sci-fi references. Dragon's Blood (Todd McCaffrey) gets close, albeit with a fictional genetic code, but that was published in 2005.

Edited by KSK
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