Four new DNA letters double life’s alphabet

https://www.nature.com/articles/d41586-019-00650-8

by pseudolus • 7 years ago

277 116 7 years ago

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.

vinceguidry4• 7 years ago

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.

dooglius• 7 years ago

You may be interested in https://en.m.wikipedia.org/wiki/Impossible_color

mattigames• 7 years ago

Every sensory perception is just as subjective, for example sound also "occupies that weird junction between the subjective and objective" in that is how animals interpret the vibration of airwaves despite being thousand of other possible ways to interpret such vibrations; same with touch, smell, etc.

0_gravitas• 7 years ago

I've always akin-ed sensory perception to a language interpreted to bytecode for the animal's OS, were just running a bunch of different OSs so our resulting bytecode is going to be varied.

vinceguidry4• 7 years ago

Base sensory perception is way more subjective than objective. Two people will simply taste differently, and there's only so much you can do to bring legibility and objectivity to the table. The surface area of the physicality with the brain is too large.

Color on the other hand is measurable and regular across humans to a far greater extent, such that we can measure with a fairly high degree of accuracy just how color-blind a person is. That's what's seductive about it.

You don't have that with other aspects of sensory perception.

wittenator• 7 years ago

Just as a sidenote: In Computer Graphics (and according to Grassmann's law) colour is a three dimensional quantity.

vinceguidry4• 7 years ago

I had to dive pretty deep into Wikipedia in order to figure out how that works. I originally wanted to separate out hue from saturation, but all that does is oversimplify color. Here's the page that finally gave me the epiphany:

https://en.wikipedia.org/wiki/YUV

Scroll down a bit and look at the Notes section. Colors seem to have different shapes. Red occupies a corner of the cube. Cyan a whole edge. Trying to flatten the space by removing the lights and darks just doesn't work.

Color is weird.

pmjordan• 7 years ago

Although I have my doubts that this is what the mystics you're referring to are talking about.

whatshisface• 7 years ago

I believe that tetrachromats see the same colors as everyone else, just with higher resolution. This was, at least, the conclusion of the experiment in the linked article that identified a functional tetrachromat.

arketyp• 7 years ago

Some females (due to the XX chromosome setup) are born with red cone receptors that are sensitive to sufficiently different ranges in the wavelength spectrum that they are in effect tetrachromats. I particularly remember reading somewhere that when asked how they experienced the world they had reported to often notice bad color matchings in the way people dress, I suppose much like it can sometimes be apparent that someone is red-green color blind by this same dressing queue.

But a different kind of rod altogether, firing off some completely different signal, who knows what the experience would be like. Psychophysics is a mysterious junction indeed.

groestl• 7 years ago

There is a tetrachromatic painter who tries to visualize her experience for us common trichromatic people: https://concettaantico.com/oil-paintings/

poopchute• 7 years ago

From what I understand, a tetrachromat has (and expresses) the normal green cone, normal red cone, normal blue cone, as well as the cone associated with either protanomaly or deuteranomaly. With that in mind, it seems reasonable that there could exist a pentachromat that expresses all of these cones.

mattkrause2• 7 years ago

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.

hobs• 7 years ago

A great talk about treating lazy eye with VR that discusses creating impossible colors by providing different inputs to different eyes (also just generally cool, discusses multiple methods to have the brain reset the disabling of one eye) - https://www.youtube.com/watch?v=_r1Tj5-F4XI&t=2875s

andyjohnson0• 7 years ago

I lived in Reddish for a while, about 25 years ago. I sometimes used to take a book and sit under the trees on Reddish Green to read. The grass was definitely just regular, visible, non-impossible-coloured grass :)

https://www.google.com/maps/@53.4386822,-2.1639276,3a,62.9y,...

kakarot2• 7 years ago

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-...

tachyonbeam• 7 years ago

Fun aside: your mention of the mantis shrimp led me to google image search them, and it turns out that they are very colorful creatures (http://caradonnajournal.com/wp-content/uploads/2018/04/Peaco...). Their special visual system and bright colors are likely a result of sexual selection.

zepolen2• 7 years ago

Imagine you're looking at wall with 3 colored circles, red green blue - something happens and you can now see a fourth circle that wasn't there before.

You've experienced it already... by shining a black light on ultraviolet pigment.

It's the same principle behind color blind test patterns: https://cdna.allaboutvision.com/i/eye-exam-2017/color-blind-...

A color blind person sees one color - a normal vision person sees two.

ZeroFries• 7 years ago

It's not clear what the relation between sensory input and the experience generated actually is. For a crude analogy, one might think the client sending a certain JSON structure is what leads to a certain database update, but the server can alter that structure in arbitrary ways. You can also get database updates without sending any JSON at all. We should be looking at the server, not the client, to figure out how the database updates work. Similarly, a brain can probably generate arbitrary experiences in qualia-space (although probably dependent on the neural structure to do so).

TaupeRanger• 7 years ago

I think this is a point many people don't appreciate (or don't want to). The nature of "qualia space" or "experience space" is truly mysterious and we really have no clue what its nature is. We can draw increasingly precise correlations between brain states and reported experiences, but the question of why those correlations hold and how the two things interact is very puzzling.

What aspects of reality are off limits to us due to our limited space of possible experiences? A rat will never have the experience of understanding prime numbers. What are we missing?

lostphilosopher• 7 years ago

"It was octarine, the colour of magic. It was alive and glowing and vibrant and it was the undisputed pigment of the imagination, because wherever it appeared it was a sign that mere matter was a servant of the powers of the magical mind. It was enchantment itself. But Rincewind always thought it looked a sort of greenish-purple." - Terry Pratchett, _The Color of Magic_

wes-k• 7 years ago

At a meditation retreat we did some form of “shanmukhi mudra” and I definitely saw some of the most intense colors of my life. I think the combination of sensory deprivation and pressure on the eyelids is what did the trick.

JackFr• 7 years ago

What makes it mystical is that there is color as a physical phenomenon (which relies on rods and cones etc.), and color as a subjective experience which occurs entirely in the thought space of consciousness. Typically the mapping between the two is relatively standard and static, but imagine a situation in which your consciousness registers something which has not correlate in the physical world. That doesn't make it any less real to your consciousness.

BurningFrog• 7 years ago

This reminds me a bit of how mystics often claim to have seen colors not seen in nature.

There is infinitely more wavelength info even in the visible light of nature than the crude three dimensional mapping our eyes can present to our brains.

One simple example: We can't distinguish green light from mixed blue and yellow light.

So my point, which I know I'm annoying slow to get to, is that we're nowhere near seeing "the colors of nature".

For sound we do much better.

c3534l• 7 years ago

To the color thing, I've met more than one person who has taken LSD and seen new colors. Rational and level-headed people otherwise.

mrfusion• 7 years ago

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

archevel• 7 years ago

IIRC RNA is made up mostly of the same nucleic acids as DNA. T (something something) is replaced by Uracil. The main difference is that DNA is double stranded whereas RNA is single stranded. Since mRNA uses three acids to represent one of the amino acids that make up the proteins it encodes, and there is a finite amount of amino acids, this means no new proteins are encoded if you add more "letters" to DNA/RNA.

Possibly the RNA could have some secondary function in the folding of the protein or as a complex inside it...

Edit: spelling

virusduck3• 7 years ago

(Also for RNA, the sugar backbone is ribose, and for DNA it is 2-deoxyribose)

el_cujo2• 7 years ago

Are there new proteins this lets them make?

I think for now we are still a ways off from this being interesting at the protein level. I would think you would need new tRNAs to recognize the new bases in-order to really utilize them at a protein level, and those tRNAs would need to bind to different amino acids than we currently have for there to be any new protein function that we can't already accomplish with ATCG.

That being said, you can still do a lot of interesting stuff with nucleic acids like DNA and RNA, more and more research these days show they can do more than just encode information for proteins.

orthoxerox• 7 years ago

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.

virusduck3• 7 years ago

I don't think you'd need entirely new ribosomes, assuming the new bases are relatively the same size as ATCG. What you'd need more of are aminoacyltransferases, which load amino acids onto tRNAs. You'd also need new tRNA's (probably not super hard), and I imagine you'd want new amino acids. But we don't even know how to predict how existing amino acid chains fold into functional proteins, so I'm not sure what the goal of making new amino acids would further.

More likely, the new bases can be used as a higher-density data storage medium for those folks interested in making biological data stores.

physicsyogi• 7 years ago

Someone could also replace the carbon with silicon.

antirez2• 7 years ago

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

dnhz2• 7 years ago

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.

antirez2• 7 years ago

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

Symmetry• 7 years ago

That number hasn't been subject to evolutionary selection for as long as there have been cells since evolution doesn't have any way to change it. So there's no reason to think it's optimal.

Well, I'm sure that if you evolved life for long enough it might find a way to switch bases. But this looks far harder than the sorts of changes that take a billion years, like photosynthesis or eukaryotes. So I wouldn't expect it to happen before the Sun boils off life on Earth in another billion.

rubatuga2• 7 years ago

There has been enough tine though for it to change to just GC or AT, which it clearly hasn't.

joshuahedlund• 7 years ago

This is essentially one of the arguments made in The Equations of Life: How Physics Shapes Evolution by Charles S. Cockell

beckerdo• 7 years ago

This earlier work discovering nucleotides X and Y might be interesting too (warning paywall): https://www.economist.com/science-and-technology/2019/01/19/...

qwerty456127• 7 years ago

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

Crystalin• 7 years ago

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

rolandog• 7 years ago

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-...

RobertoG• 7 years ago

"[..] 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_cujo2• 7 years ago

"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, which cites https://www.nasa.gov/content/nasa-ames-reproduces-the-buildi...

MatthewWilkes2• 7 years ago

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• 7 years ago

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.

baq• 7 years ago

Having read that compilation it deserves M for Mature.

eurg• 7 years ago

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.

MatthewWilkes2• 7 years ago

Like Black Mirror, many of the plot lines are distressing. As it's a collection of short stories, being specific about what the particular things are ruins plot devices.

It's not a book to read to cheer yourself up. It's interesting and clever, but I don't feel comfortable unreservedly recommending it to people I don't know. Hence the warning, it's so people who know that they're sensitive to difficult topics, either in general or right now, don't go ploughing in unawares.

biophysboy• 7 years ago

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• 7 years ago

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

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.

astazangasta4• 7 years ago

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?

swamp402• 7 years ago

Mankind has always striven to understand his universe. You don't really understand something until you can tear it down and rebuild it in a hundred different ways.

astazangasta4• 7 years ago

This is like suggesting we need to rebuild computing to use ternary, and somehow it will help us.

virusduck3• 7 years ago

There is productive research into using DNA as a data storage medium. I could see this being used to either increase data density or as an error-correction mechanism.

astazangasta4• 7 years ago

DNA gets its fidelity from the machinery that maintains it, i.e. chromatin, repair enzymes, polymerases, topoisomerases. All of these evolved around the idosyncracies of the genetic code and have perfected themselves over billions of years - more if you count all of the lives of individual organisms put together. Now you want to break that basis and somehow think you will improve things?

As for increasing data density, again, do you suggest converting computers to ternary to do the same?

twanvl• 7 years ago

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.

astazangasta4• 7 years ago

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/ 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!"

koeng• 7 years ago

There are lots of reasons. For one, expanding the genetic code would allow new and interesting structures in RNAs, would allow massive expansion of amino acid coding sets, different evolution paths based on codon usage, etc. Generally in synthetic biology we want to build new systems from scratch, and these base pairs are a wonderful step in humanity defining life instead of life defining humanity.

swamp402• 7 years ago

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

pavlov• 7 years ago

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

dnautics3• 7 years ago

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.

dekhn2• 7 years ago

are you sure it wasn't Steven Brenner or Syndey Brenner? Or maybe Seymore Benzer? I always get them confused.

dnautics3• 7 years ago

100% sure, since I asked him. Actually I identified him because he gave me and my buddy a lift out of a canyon, and there was someone who looked like he could be his son sitting in the front seat, who was wearing a shirt with the seal of my alma mater; several years prior, Steve Benner gave a talk and afterwards he mentioned that his son was thinking about my alma mater. I've also met Sydney Brenner, and I'm pretty sure Sydney Brenner would not have been able to ascend the mountain we were on.

socketnaut• 7 years ago

Which mountain was it?

dnautics3• 7 years ago

Saddle mountain, idaho

jcims• 7 years ago

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

ionwake• 7 years ago

I liked this comment

foobarbecue• 7 years ago

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• 7 years ago

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...

gus_massa• 7 years ago

There are 20 aminoacids encoded in the DNA, and you need an "stop" code (the "start" code is reused when it is in the middle).

There are some tricks to transform the 20 aminoacids in other aminoacids after they are in the proteins, so that increase the number of used aminoacids a little https://en.wikipedia.org/wiki/Non-proteinogenic_amino_acids And there are small variations of the genetic code that include other aminoacids https://en.wikipedia.org/wiki/Genetic_code#Alternative_genet.... So the total number of aminoacids used in the wild is approximately 30.

With 4 bases and 3 bases per codon, you can encode up to 64, so there is some redundancy and room for a few new aminoacids.

You don't want too much redundancy, because you have to synthetize the tRNA. And in principle you need a tRNA for each possible codon, so you want to minimize the number of codons. (Actually, the genetic code has some patters and instead of 63 tRNA the cells have at most 41 tRNA. https://en.wikipedia.org/wiki/Transfer_RNA

I guess that increasing the number of bases makes it more easy to make mistakes, and more difficult for the enzymes to distinguish them.

pytyper2• 7 years ago

What does this mean for DNA based evidence?

logfromblammo2• 7 years ago

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.

pvaldes• 7 years ago

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.

hoseja• 7 years ago

More possible states, more possible errors.

vkaku• 7 years ago

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

6P3 vs 4P3;

RocketSyntax• 7 years ago

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

yread• 7 years ago

How does it get transcribed if not using polymerases?

Four new DNA letters double life’s alphabet

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