
Adding new DNA letters makes novel proteins possible - pseudolus
https://www.economist.com/science-and-technology/2019/01/19/adding-new-dna-letters-make-novel-proteins-possible
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aaavl2821
This is cool scientifically, and also a cool example of how amazing things can
happen with interdisciplinary collaboration in biotech.

When you have a new technology with so many potential applications (adding 152
extra codons on top of the normal 64), it can be overwhelming to figure out
where to start. Getting from "we can add letters to the DNA alphabet" to "we
can build new amino acids into IL-2 to facilitate PEG binding to stop IL-2
binding to the alpha unit of the IL-2 receptor while still binding the beta
and gamma units, which will preserve anti-cancer effects while sparing
vascular damage" seems like a leap that would require a cross-disciplinary
team to make

IL-2 is a molecule that is effective at treating a variety of diseases but has
nasty side effects that make it a poor drug. The article discusses sometimes
fatal side effects of high dose IL-2 in treating cancer; low-dose IL-2 is
actually an effective treatment for autoimmune disease, although it is
difficult to titrate the dose in such a way that you don't accidentally dose
too high and make the autoimmunity worse.

Another startup, Delinia, engineered an agonist selective for the alpha-beta-
gamma subtype of the IL-2 receptor to treat autoimmune disease [0] (where
Synthorx is hitting only the beta-gamma part of the IL-2 receptor to treat
cancer). Delinia was acquired by Celgene last year for $775M, 3 months after
its Series A. Synthorx went public this year and has a $450M market cap. All
of that from making different versions of a single protein

[0] [https://lifescivc.com/2016/09/re-balancing-immunity-via-
regu...](https://lifescivc.com/2016/09/re-balancing-immunity-via-regulatory-t-
cell-potentiation-introducing-delinia/)

~~~
dogma1138
eDNA is one of the more creepy things you can think of in a dystopian future
e.g. you can engineer humans to require a specific synthetic amino acid that
doesn’t appear in nature this is essentially a potential biological DRM.

While applying it to humans directly is unlikely applying it to be some sort
of DRM for drugs to prevent generics from working is quite a realistic
possibility.

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JabavuAdams
I want more life father/fucker.

~~~
jacquesm
Some people have not watched Bladerunner.

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peter303
People speculate there may have been a wider variety of DNA coding in the
past. But natural selection plus perhaps some reaction energetics versus
complexity settled on the current system.

There was probably a simpler two nuclide encoding versus three beforehand.
About half of the amino acids only use the first two nuclides and ignore the
third.

~~~
dnautics
that seems unlikely, because shifting your recognition domain count from 2-3
means that you basically lose all the evolved information from before and have
to rely on chance "correct encodings" everywhere.

~~~
gus_massa
The idea is that the initial tRNA was not specific enough and only care about
the first two letters of each codon and ignored the third. So for example
Proline was determined by the first two letters CC? and was associated the
four codons CCU, CCC, CCA and CCG. Actually, this is the current mapping.

Other blocks of four codons were split for some reason. We can imagine that
originally Isoleucine was determined by AU? so initially AUU, AUC, AUA and AUG
encoded Isoleucine, but now only the first three encode Isoleucine and the
last one encodes Methionine instead.

This is somewhat based in the blocks of four codons that follow this patter
where the first two base determine 16 block that sometimes are split
[https://en.wikipedia.org/wiki/Genetic_code](https://en.wikipedia.org/wiki/Genetic_code)
and because the third base in the tRNA is strange
[https://en.wikipedia.org/wiki/Wobble_base_pair](https://en.wikipedia.org/wiki/Wobble_base_pair)

Anyway, IIRC this is a reasonable speculation but it's not confirmed. So don't
take this explanation too literally.

With this idea, the initial DNA could evolve for a few (zillions) years as
list like

important-important-whatever-important-important-whatever-important-important-
whatever-important-important-whatever-important-important-whatever-important-
important-whatever-important-important-whatever

and then make the whatever letters also important with a almost backward
compatible code, so in most case it still doesn't mater, but in a few cases it
is important.

[Note: The official letter for whatever is "N" instead of "?"]

~~~
theddman
That's a great explanation! To add a cool point, the wobble position is
frequently modified by highly specific enzymes to make it matter more. It's
like some random protein mutated to do this modification and all of a sudden
the organism got more RAM thus increasing it's fitness.

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pazimzadeh
I might be missing something but I don't see how adding DNA nucleotides can
lead to novel proteins. You have more letters to potentially map to amino
acids, but unless you've also expanded your set of amino acids, how does this
lead to new proteins? And did they also design new t-RNA's (the things that
maps RNA to amino acid)?

~~~
natechols
They have indeed expanded their set of amino acids. I assume they must have
added tRNAs as well but the article didn't go into this detail.

~~~
dnautics
Romesberg got mRNAs up about 3-4 years ago? I presume the tRNAs are made from
processed DNA, not by adding them (adding tRNAs exogenously to bacteria would
be tough, and not economical at all).

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lvs
Floyd does very nice work, but this particular justification -- at least as
expressed in this article -- for a 4-base code is completely flawed. The
article claims that the reason to augment the codon table is because only two
stop codons could possibly be rewired to code for artificial amino acids. But
in fact 43 out of 64 codons could in principle be recoded. That's because of
the extraordinary redundancy built into the codon table of 4^3 = 64 codons:
there are only 20 coded amino acids, plus one necessary stop codon.

So that leaves 43 codons, not 2.

~~~
bhk
It's not that simple. Even when two codons map to the same amino acid, it
doesn't mean they have the same implications.

One factor is that different codons translate at different speeds, and these
can affect how the protein folds.

Another is that base pairs in DNA may have functions or implications apart
from their function as part of a codon in a gene.

Simply remapping a codon to a new amino acid and re-writing all the genes in a
cell's DNA to avoid that codon will cause many things to "break" in a cell's
function. Life is a messy, inter-connected system without the clean modularity
we like to have in software.

~~~
lvs
"can," "may," ...

1) My argument was simply that the limit on recodable codons is much higher
than two, as it was claimed in the article. That's hard to argue with. I
didn't say the result in every case would be neutral mutations.

2) The consequences of recoding the stop codons are also not neutral. For
example, when Isaacs (eventually) did it, there were severe growth phenotypes
in the resulting strain.

So I agree that "it's not that simple," which is frankly why I'm not hugely
optimistic about this class of endeavors. But the point stands that there is
no need in principle for a 4-base code.

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somebodynew
The article talked about directly re-using stop codons like some exotic
organisms do to integrate pyrrolysine, but there is another more nuanced way
which humans use for selenocysteine:
[https://en.wikipedia.org/wiki/SECIS_element](https://en.wikipedia.org/wiki/SECIS_element)

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MarsAscendant
So... like... what happened, exactly?

It sounds astonishing, but I can't make heads or tails of it. Rosemberg and
his team managed to add new letters ("letters") to DNA encoding, and that
allows them to make new proteins... how? Did they make new kinds of acid bases
for these proteins – the kinds that don't exist in nature? Is that not an even
more astonishing achievement?

I'm way out of my depth here, but I'm also intensely curious about anything
related to genetic engineering. Could someone explain this to me?

~~~
eggie
> So... like... what happened, exactly?

A group added a new DNA base pair ("X" and "Y") to a strain of E. coli.

In genes, codons are triplets of DNA letters that transcription and
translation machinery converts into specific amino acids. The mechanisms by
which this happens are complex, but well understood.

The new DNA letters were used to make new codons that could be translated to
particular, novel, amino acids.

~~~
MarsAscendant
So, did they effectively invent scalable natural-mechanism synthetic amino
acid production? Is it at all as cool and biopunk as I imagine?

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strainer
I wonder for curiosity and concerns; how and why the new DNA letters have not
already evolved and do not already feature in the present range of living
species? Should a firm understanding of this, no matter how far off, not be a
prerequisite to aspirations of mass production of novel proteins and new
lifeforms featuring them?

Novel DNA and proteins - after billions of years natural CI... we better be
sure to have a damn good incident response capability! But do we?

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lukas099
> Adding new DNA letters make novel proteins possible

> Adding new DNA letters make

> Adding make

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sctb
OK, updated over here.

