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Four new DNA letters double life’s alphabet (nature.com)
277 points by pseudolus on Feb 22, 2019 | hide | past | favorite | 116 comments

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.

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

I liked this comment

Which mountain was it?

Saddle mountain, idaho

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

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.

it was a joke...

I met Steve for dinner once and we had a great chat about how badly the first Mars life-detection experiments were designed.

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.

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.

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

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-...

I see reddish green all the time, although it could be greenish red. Just as often it’s brown.

I’m red-green colorblind.

I think you forgot your link.

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

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 :)


But how do I know you're possible-coloured?

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.

Mantis shrimp pack a really strong punch too. Truly fascinating creatures.


Yup! They're one of the few animals that can see circularly-polarized light, and the quarter-wave retarders in their eyes are really damn good.

As of a few years ago, they had a much wider wavelength range (400-700 nm) than the best man-made ones, which were only achromatic over ~100 nm.

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.

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

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.

"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_

See also: https://en.wikipedia.org/wiki/Tetrachromacy#Humans

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

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.

How do you even know that "everyone else" experiences colors the same as each other? How do you know for example that it is not the case that what I experience as "red" is what, if you experienced it the way I did, you would call "blue"? You can't really get inside another person's experience.

>How do you even know that "everyone else" experiences colors the same as each other?

Generally through measurement. Colors are just differences in electromagnetic wave frequency, change the electromagnetic wave frequency enough and you are out of “visual light rays” and into other types of rays (radio, gamma, x, etc...). Until people start “seeing” those other non visable light rays, we have some indication we are all seeing the same things (light waves).

As to the “colors” of the various frequencies within the visual light wave spectrum, we may receive/interpret them differently (ie color blindness), but the wave frequencies are the same and it is us who work differently.

That’s why we can have other objective factors and measurements (primary colors, mixing of colors, etc...) that suggest for the most part we are all seeing the visual light spectrum waves similarly. In otherwords if you and I saw the visual light wave differently it should be obviously once we start mixing colors to produce new colors (if you saw black and white where I saw blue and yellow, then you couldn’t see green - it would be black). Still your use of “experience” of colors likely is inheriently true we probably all do experience the colors differently (some are my favorites, those don’t need to be your favorites, some may trigger certain emotions in me and not in you) but that doesn’t change the fact that the electromagnetic wave is the same for both observers.

A lot of people consider this to be an interesting question. I don't really. I think the prior of it is exceptionally low both because it's a less simple hypothesis than humans, constructed similarly, having similarly structured internal representations of the world; and because it seems plausible that some well-designed art or optical illusions would reveal such a difference if it weren't trivial.

But more importantly, I think it's like arguing whether all computers are big-endian, or whether some computers stores [R,G,B] values in memory as [G,B,R]. It's not actually mysterious.

Everyone experiences the same colors in the sense that sunlight has a particular emissions spectrum, Earth's atmosphere has a particular absorption spectrum and light-scattering property, and any given viewable object has measurable properties for diffuse reflection, specular reflection, and its own emissions spectrum.

If you point a measurement device at a particular point, you can get a histogram of light intensity over several frequency bands. A histogram with many narrow bands gives a more accurate profile of the measured light.

The human eye usually has only three frequency bands: blue, green, and red. They overlap. They are not always the same width, or centered on the same frequency. The width and center of the red bar is defined on the X chromosome, so some people with two X chromosomes from lineages that see red differently have a fourth histogram bar, and therefore have better ability to distinguish between similar color profiles at the red end of the visible spectrum. Some people with only one X chromosome have a defective copy of the gene encoding for the red histogram bar, and thus only have two bars in their histogram.

So while color is objectively the same, different eyes--connected to different visual cortexes--quantize and encode color information differently. Each brain may interpret the data in the color channels differently to establish an individual's world model.

What I see as "red" is unique to me. If someone were to bridge my brain to someone else's, my "red" would not match to someone else's "blue". My color channels would be as their octarine, smaudre, and refulgine--three completely different color channels that they have never experienced before. But if our optic nerves were linked, rather than somewhere deeper in the brain, I would see their red as my red, even if their eye reads reds slightly differently because of a minor difference in their X chromosomes. The translation layer between raw visual data and personal worldmodel is not guaranteed, or even likely, to produce similar results.

> How do you know for example that it is not the case that what I experience as "red" is what, if you experienced it the way I did, you would call "blue"?

Because the words "red" and "blue" can be calibrated by reference to external objects. You and I both call stop signs "red" and the sky on a clear sunny day "blue". So if, for example, somebody invented a device that could "translate" your experiences into my brain, and the device "translated" your experience of looking at a stop sign into something that my brain decoded as "blue", I wouldn't conclude that your experience of colors was different from mine: I would conclude that the translator device was broken.

I know that red is red the same way I know that hot is hot, that cold is cold, that pain is pain, that pleasure is pleasure, that loud is loud, etc.

Sure, you can be taught that when you hear a deafening sound to say "wow that's really soft" but that doesn't change the fact that it's a loud sound and you're experiencing a loud sound.

I believe they are raising the point of qualia, or a viewers internal representation of the perception.

You know that red is red, but you don't know that your red is anyone else's - which may be why I like green and you like red, we may have two totally different experiences of the colours.

This has always bothered me, I want everyone to see colors the same way so we can all have the same internal experience.

However, I have rationalized away this theory with a thought experiment. Imagine someone messed with your brain and remixed your colors. So now maybe what you once saw as red you now see as green. However, since your brain has no other reference, you will not even be aware this change has happened.

Now if we put a device in your brain that changes your colors every second or so, you still won’t even know. You’ll never know! Because you have no way to compare a previous representation with a new one.

Imagine looking out now into the world around you, and being told every second your colors are being rewired. Since you can only have one dictionary of colors in your mind, you see nothing change, because that would imply there is an even deeper meta-representation of colors you can compare with.

Ultimately, colors do not exist. This is why my favorite color is black, as it is the only “true” color, and not to mention everything looks good in black.

Don't you think there is a representation of color in memory, that you can compare current visual input to? I can close my eyes and recall the image of a red apple, or are you saying my memory of red would switch to green as well?

"I believe they are raising the point of qualia, or a viewers internal representation of the perception"

So am I.

This doesn't happen for everyone

Some people lack nerve 'analyzers' and do not "feel" pain/heat/cold etc, just pressure: https://en.wikipedia.org/wiki/Congenital_insensitivity_to_pa...

Likewise some people lack emotional analyzers and do not "feel" emotions:


I recall similar thoughts when I was younger (10yo?). It led to "what if everyone's favorite color is the same color, but we all experience colors differently, so it only appears we have different favorite colors!?". That was quickly debunked by those who change their favorite color.

I have a weird thing: out of one eye the world seems slightly redder while out of the other the world seems slightly bluer.

I don't think there's any way for me to tell which (if either!) is the more "correct" perception, eh?

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).

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?

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.

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.

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.

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.

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.

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.

> 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.

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.

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

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:


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.

CIELAB ColorSpace is a better representation:


You're definitely right about that, but projecting the color space onto a cube and then seeing how it distorts everything has a certain visceral feel, like looking at the Mercator projection and seeing huge Greenland and tiny South America. You know all map projections are wrong, but the Mercator is wrong in a way that lays map projection distortion completely bare.

Without seeing the cube viz in my link, I'm likely to look at CIELAB and say, "oh, sure, but you can just take out the brightness and then it's all flat again." The cube makes it clear what happens when you do that.

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.

>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.

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.

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.

Having read that compilation it deserves M for Mature.

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.

> 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)


> 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.

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?

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...

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.

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.

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

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.

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.

Someone could also replace the carbon with silicon.

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.

>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.

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

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

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

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.

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

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.

I always wondered about that incremental optimization. It makes sense in a lot of ways, but then there are cases there big leaps happen, which would require many steps at a severe disadvantage in between.

E.g. the evolution of flight. Flying is a huge advantage, but evolving towards a body capable of flight without being able to fly, should require millions of years of disadvantages to get the flying advantage. But incrememtal optimization and survival of the fittest contradicts a very slow process over several disadvantaged steps.

I disagree with the millions of years of disadvantages. Imagine if you wiped the world of all fish/mammals/birds. Then populated the planet with a large number of "average" size rats.

Environmental niches filled by squirrels, mice, small dogs, foxes, coyotes, raccoons, hawks, eagles, and numerous others would be left wide open. Those rats would start evolving into any empty niches, that were close enough. Over time/generations the further niches would become available. Smaller rats would take advantage of food sources that the mice used to eat. Better climbers would evolve to take advantages of what squirrels used to eat. Rats that specialize in eating insects would start to specialize.

Some rats would even start to specialize in eating other rats. Other rats would specialize in not getting eaten and fill the niche left by rabbits.

The rats that evolved into squirrel like mammals might specialize in jumping ever further to avoid the ground where the rat-dogs roam looking for rat-squirrels to eat. Said jumping might even evolve into flying squirrel like rats. Given enough time active flight would evolve. Rats would even start to populate the oceans.. much like whales did.

Evolving into a bird requires efficient lungs, light weight (things like hollow bones), and not wasting weight on things like powerful legs, thick skin, etc. But every step of the way would be better for some niches.

> But every step of the way would be better for some niches.

That's what I have trouble with. E.g. the climbing rat would be able to get all these higher food sources on trees. But evolving wings loses the ability to climb. And now it's competing with faster and more sturdy rats on the ground again.

I can only think about the disadvantages being no real disadvantages, because there is abundance of food and no serious competition/predators.

Not necessarily. Bats for instance evolved flight separately from birds, and can still climb.

Evolution will try everything. If there's sturdy carnivorous rats around, the rest of the rats will try their niche. Some will try faster, some will try playing dead, others will dig holes to hide in, or climb trees. Some might grow thicker skin, or looser skin, or venom, or just being poisonous to eat.

These empty niches can be filled pretty quickly. After removing top predators like wolves for instance, the average size of coyotes has been steadily increasing over the last 50 years.

A side note, plants figured (in the evolutionary sense) that birds were great seed spreaders compared to the non-birds. Some evolved impressively strong spices (Capsicum) that birds are impervious to (up to several % by weight) that eliminated non-bird consumption of their berries. So to protect bird feed from squirrels at Capsicum.

Any bird like feature will help with a particular niche. Feathers, beaks, dexterous claws, bird songs, gliding, and of course powered flight. So it's not like you need a huge jump from land based mammal to full flight before you have any evolutionary advantage for a particular niche.

> But evolving wings loses the ability to climb

I think you are skipping steps as you try to imagine the process. Wings are at the extreme, there are intermediate features. Checkout a video of "flying squirrels", you will notice that they are more like "gliding squirrels".

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?

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

Incompatible signals causing destruction.

This is hard to answer. Why are there 20 amino acids in proteins, someone might ask? Which came first? DNA, proteins, or was it RNA? Origins of life research tries to answer these questions, but I am not an expert of that field.

The most common belief is that RNA came first -- it has both the information-carrying capacity and enzymatic activity.

As for why are there 20 encoded amino acids (+ selenocysteine and pyrrolysine)?

I've read that codon similarities hint at an original more compact alphabet of two base codons (allowing for up to 15 distinct amino acids and a stop).

I've also read that the "more recent" amino acids, like cysteine, are more readily oxidized and thus provided some advantage as atmospheric oxygen levels increased.

But all of these are guesses about the world before LUCA, which is really lost to us.

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.

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

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

"[..] 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

"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...

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-...

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.

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.

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

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

6P3 vs 4P3;

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

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

How does it get transcribed if not using polymerases?

More possible states, more possible errors.

What does this mean for DNA based evidence?

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

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

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

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?

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.

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!"

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.

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!"

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.

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.

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

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.

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.

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?

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