
Four new DNA letters double life’s alphabet - pseudolus
https://www.nature.com/articles/d41586-019-00650-8
======
dnautics
Tangentially related story - Steve benner was the researcher whose work
inspired me to go to grad school; during the 2017 eclipse I travelled with a
friend to a remote mountain in the path if totality to observe it; on the way
down I ran into Steve benner (there were about 6-8 people on the mountain that
day), and was left wondering if sometimes serendipitous meetings are instead
the result of similar deductive processes in activity selection and not
serendipity at all.

~~~
jcims
Probably moreso now than ever with the synchronized ideation from Internet
news and social media.

~~~
ionwake
I liked this comment

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vinceguidry
This reminds me a bit of how mystics often claim to have seen colors not seen
in nature. Crazy, weird, sure, but when you actually look at the rod and cone
structure that gives rise to color, there's no reason to think that more of
these might not exist, and indeed some animals have different receptors,
famously, the mantis shrimp has 12. Color occupies that weird junction between
the subjective and objective, so we don't really have a way of working out
what the subjective experience of new colors would actually be.

Why this reminds me of color isn't so much the weird part, but the fact that
color is a continuous surface. What would adding new colors do to the color
space? Does the space remain two-dimensional or do new colors start blending a
third dimension into the topology? I wish those mystics had access to
spectrometers in Heaven.

~~~
mattkrause
More critically, the mantis shrimp doesn’t have opponency.

In humans—-and most other animals—-the visual system represents color[0] using
a relative system: is something redder than it is green? Bluer than it is
yellow? To create this, neurons receive excitatory input from (e.g.) a red
cone and inhibitory input from nearby green cones. This representation makes
sense, given the cones’ spectral sensitivity, but it also makes some colors
“impossible”. Since each color is essentially a point along these two axes,
something can’t be blue and yellow at the same time, reddish green, or even
some shades of “hyper-green”[1,2].

The mantis shrimp, near as we can tell, doesn’t have this sort of
representation. The anatomical pathways don’t seem to be there, and some
behavioral work with trained(!) mantis shrimp also suggests that they have
independent color channels, and, as a result, their color sensitivity is
actually not amazing. Interestingly, they may do something to “fake” color
opponency: different receptor types are in different parts of the eye, and the
shrimp ‘drags’ its eye across the scene to produce a sort of temporal context.

That’s more than you probably wanted to know but...shrimp are neat.

[0] To a first approximation, anyway.

[1] There is a place called Reddish Green, which I assume is not invisible,
but I’ve never been to Stockport, England.

[2] More seriously, there are some tricks you can play to (briefly) perceive
some of these impossible colors. The general approach is that you stare at
something of one color, then quickly switch to looking at something of the
opponent color. This “fatigues” (adapts) cells that signal the first color, so
they provide less inhibitory input in response to the second color.

~~~
kakarot
Here is a blog post which covers some impossible colors and provides a few
techniques to "see" them. [0] Of course reddish green and blueish yellow don't
have any easy visualization techniques.

My personal favorite impossible color is Stygian Blue. Something is so
energizing about seeing a color you know shouldn't exist.

[0] [http://www.luniere.com/2014/03/01/hyperbolic-orange-and-
the-...](http://www.luniere.com/2014/03/01/hyperbolic-orange-and-the-river-to-
hell/)

~~~
Forbo
I think you forgot your link.

~~~
kakarot
Hasn't been a great start to the day. Thank you!

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MatthewWilkes
Greg Egan wrote a good short story with a related premise: a pathologist
investigating evidence discovers the DNA is formed of novel bases. It's called
'The Moat' and is published in the collection 'Axiomatic'.

The whole collection deserves a content warning, but if you enjoy Black Mirror
then you'll enjoy these.

~~~
simias
>The whole collection deserves a content warning

I'm not sure what you mean by that. Who needs to be warned and of what?

Thank you for the recommendation though, there's never too much sci-fi to read
as far as I'm concerned.

~~~
eurg
ETA: Seems this was meant to be a different kind of content warning. Whatever.

\---

I don't know that specific series, but Greg Egan thinks ideas further than
usual in entertainment, usually ends on a note that's neither down nor up, but
nondescript and even nihilistic toward normal-human values, like setting
yourself into an endless loop of trivial emotional experience of no more than
a few seconds content in re. The author often plays with minds like that.
Depending on your make-up, you could interpret the described personas as
tortured people, or free, or ... whatever. Somewhat Camus-like. Just with hard
sci-fi.

------
biophysboy
Really really interesting work. I have so many questions. I wonder if the new
letters change the molecular structure overall. Do these molecules bend and
twist like vanilla DNA does? Will they wrap around histones? Can any of the
new letters be methylated?

I’m also glad the article stressed the importance of polymerase. For the
uninitiated, if this molecule cannot be replicated with polymerase, then it
severely constrains its applicability. Most research labs do not synthesize
their own DNA - they replicate it in cells or with PCR.

~~~
twic
> I wonder if the new letters change the molecular structure overall. Do these
> molecules bend and twist like vanilla DNA does?

 _Expanded genetic systems are most likely to work with natural enzymes if the
added nucleotides pair with geometries that are similar to those displayed by
standard duplex DNA. Here, we present crystal structures of 16-mer duplexes
showing this to be the case with two nonstandard nucleobases (Z and P)_

[https://www.ncbi.nlm.nih.gov/pubmed/25961938](https://www.ncbi.nlm.nih.gov/pubmed/25961938)

> Can any of the new letters be methylated?

Z has an amine group where the methylation would go on cytosine, and P has a
ketone group instead of the amine group where the methylation would go on
adenine, so presumably not, or at least not in the same way.

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foobarbecue
Before I knew much about transistors etc, I used to wonder why only 2 logic
levels (0 and 1) are generally used in computers. I know there are some
exceptions but it turns out binary works best with the hardware we have
available. I'm guessing that four logic levels works best with ribosomes and
all the other cellular machinery. Or maybe it's hard to have codons longer
than 3, so the number of DNA bases is set by the number of required amino
acids to sustain life?

~~~
naasking
IIRC, optimal information density is achieved by an alphabet the size of
Euler's number [1]. So trinary might actually be theoretically optimal since
we have to be discrete.

But there are pragmatic considerations to consider that make trinary
difficult. Since most of computation currently happens with voltage, that's a
one-dimensional quantity that we would have to divide into 3 levels to
discriminate "bits". This requires more sensitivity and precision than merely
two levels. (Edit: although maybe not, some historical computers were
trinaryband reportedly more efficient; time will tell I suppose).

It would be easier to achieve trinary if we had _two_ axes with which to
encode, but that intrinsically yields quaternary; maybe that's how DNA
operates.

[1] It is via radix economy:
[https://en.wikipedia.org/wiki/Radix_economy#Radix_economy_of...](https://en.wikipedia.org/wiki/Radix_economy#Radix_economy_of_different_bases)

------
logfromblammo
This is a perennially recurring article. Seems like every few years someone is
adding base pairs to DNA. The first one I can recall used the Greek letters
kappa and chi for the novel base pair. I thought it was cool and exciting at
the time, which was probably around 1992. They keep coming up with new ones,
and reviving the "6 letter DNA alphabet" articles.

2-amino-8-(2-thienyl)purine and pyridine-2-one

7-(2-thienyl)imidazo[4,5-b]pyridine and pyrrole-2-carbaldehyde

7-(2-thienyl)imidazo[4,5-b]pyridine and
4-[3-(6-aminohexanamido)-1-propynyl]-2-nitropyrrole

2-(2-Deoxy-β-D-erythro-pentofuranosyl)-6-methyl-1(2H)-isoquinolinethione and
(1R)-1,4-Anhydro-2-deoxy-1-(3-methoxy-2-naphthyl)-D-erythro-pentitol

These all work fine when copying DNA sequences using existing cellular
mechanisms and PCR. As far as I know, it remains to be seen whether they can
encode for proteins.

RNA transcription is complicated by "wobble pairs" with uracil, inosine, and
uridine variants, occurring in RNA, with the four bases present in DNA, and
with each other. There isn't a 1-to-1 correspondence from DNA base to RNA
base. It may be that our DNA uses only the four specific bases guanine,
cytosine, adenine, and thymine because wobble pairings provided additional
mutation resistance, or offered additional structural options for transcribed
proteins.

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mrfusion
Are there new proteins this lets them make? How does this translate to rna?
The cell’s messenger molecule.

~~~
orthoxerox
To make new proteins, you have to create new ribosomes, as it's they who
interpret the RNA codons to stitch amino acids together. Bootstrapping a new
ribosome is several magnitudes harder than constructing a synthetic DNA/RNA.

Actually, you don't even need new DNA letter to do that. DNA codons can encode
64 different amino acids (63, as one codon must encode the end of sequence),
but only 20 amino acids are actually used.

Adding another amino acid is theoretically possible, but this would require
rewriting the whole DNA to reencode, say leucine from CTG to another codon to
assign CTG to some other acid.

~~~
physicsyogi
Someone could also replace the carbon with silicon.

~~~
anticensor
Silicon/Bismuth biochemistry is way more limited than Carbon/Hydrogen Oxide
biochemistry in terms of temperature range and stable compounds.
Silicon/Hydrogen Sulfide biochemistry does not work at all because hydrogen
sulfide does not have the point of least volume.

 _biochemistries listed here are denoted as bonding atom /solvent pairs._

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antirez
Maybe 4 is a trade-off between stability and information density.

~~~
dnhz
DNA does more than code for proteins, but in terms of proteins, 3-letter DNA
codons already provide for 64 possibilities, and there are only 20 amino
acids.

~~~
antirez
So you mean, it did not evolve differently for lack of need?

~~~
nabla9
Genetic evolution is path dependent. Starting point of evolution severely
limits where evolution can go.

In other words, evolution never does whole system redesign. It's all legacy
code from the beginning with incremental optimization steps in response to
selection pressure at the moment.

Genes and amino acids are very close to the starting point, it's unlikely that
they are optimal outside the starting environment. 4 amino acids was enough to
get things going, inserting new amino asides later would require redesigning
all the machinery starting from scratch. Evolution can't do that, but humans
might be able to insert news stuff.

~~~
cft
That's assuming that life originated only once. If there were multiple
independent origins of life, then why couldn't they have had different base
pairs and compete with each other in the evolutionary manner?

~~~
samirm
They could, but if they originated in the same environment then the likelihood
of that goes way down.

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RobertoG
"[..] there is nothing particularly “magic” or special about those four
chemicals that evolved on Earth[..]"

An interesting corollary would be that, if we find them outside Earth, then,
probably, they didn't evolve on Earth

~~~
el_cujo
"In March 2015, NASA scientists reported that, for the first time, complex
organic compounds found in DNA and RNA, including uracil, cytosine and
thymine, have been formed in the laboratory under outer space conditions,
using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine
and polycyclic aromatic hydrocarbons (PAHs) may have been formed in red giants
or in interstellar dust and gas clouds, according to the scientists."

[https://en.wikipedia.org/wiki/Meteorite#Meteorite_chemistry](https://en.wikipedia.org/wiki/Meteorite#Meteorite_chemistry),
which cites [https://www.nasa.gov/content/nasa-ames-reproduces-the-
buildi...](https://www.nasa.gov/content/nasa-ames-reproduces-the-building-
blocks-of-life-in-laboratory)

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rolandog
Pretty interesting. I wonder if bio-hackers from the future will tinker for
fun and exchange very large steganographic 'files' that, if read in a certain
order, produced the complementary DNA (cDNA) [0] of a patented organism.

[0] [http://sitn.hms.harvard.edu/flash/2015/the-patent-
landscape-...](http://sitn.hms.harvard.edu/flash/2015/the-patent-landscape-of-
genetically-modified-organisms/)

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pvaldes
That opens the door to a genetic signature for man made and modified creatures
in a not much far away future. Would be important to clear biological
invasions or "tainted" species if you can check for it.

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duncan-donuts
This is pretty cool! I wonder if there is so some limit in how many pairs can
be added. I’d imagine as we try to store more information in a system like
this we’ll keep adding synthetic pairs.

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pavlov
There's a startup in this space called Synthorx which recently did an IPO:
[https://synthorx.com/](https://synthorx.com/)

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vkaku
Aren't just a set of complementary two letters / acids enough to double it?

6P3 vs 4P3;

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qwerty456127
I want genetically modified children with 12-"letter" DNA!

~~~
Crystalin
Start by getting one with a 12-"letter" name and see how that works !!

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yread
How does it get transcribed if not using polymerases?

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hoseja
More possible states, more possible errors.

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pytyper2
What does this mean for DNA based evidence?

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swamp40
I predict this will become the basis for many sci-fi/horror books and movies
coming up in the future.

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beckerdo
This earlier work discovering nucleotides X and Y might be interesting too
(warning paywall): [https://www.economist.com/science-and-
technology/2019/01/19/...](https://www.economist.com/science-and-
technology/2019/01/19/adding-new-dna-letters-make-novel-proteins-possible)

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RocketSyntax
hasnt S been around for a while? what about M?

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astazangasta
Seriously what is the point of this other than novelty? Why would you throw
out billions of years of biochemistry and evolution? Is the expressive power
evidenced in all of life not good enough?

~~~
twanvl
No one is talking about "throwing out billions of years of biochemistry".
Rather, by changing a small part of biochemistry we will be better able to
understand it. Not all research is about making something better.

Artificial bases might help us understand why live evolved the way it did.
Maybe there is an interaction between the bases and the way DNA folds? Or were
ACTG just an accident?

Artificial bases might be useful as part of other techniques, perhaps for
tagging DNA sequences. Maybe they can one day be used to disrupt or alter
certain biological processes.

I am not a biologists, so I have no idea if that makes any sense, but the
research is interesting.

~~~
astazangasta
I am a biologist. We already know many of the things you asked. For example,
the stacking energy between bases:
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360284/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360284/)
All this can be studied with some chemistry. These people are engineering new
organisms with a new genetic code and new amino acids. It goes far beyond mere
study. It's as if someone suddenly said, "Yes, but imagine if pianos had 99
keys!"

~~~
Pfhreak
This seems analogous to:

"No one will ever need a 100 megabyte drive!" "No one could ever use a 1
megabit network connection!" "No one will ever use more than 256 megabytes of
RAM!"

But I don't know enough biology to understand if that's the case.

~~~
falsedan
This is more like: "no one will need gold audio cables!" "No one could ever
tell the display refresh rate was 1kHz!" "No one will ever use a mineral oil
bath to cool their PC!"

~~~
drilldrive
Gold audio cables are useless, yes? I assume the other two are just as such
then, if that is the analogy you are shooting for.

