hckrnws

I work in DNA assembly and synthesis. Here is my take:

They don't use oligo pools - "This capacity may be adapted to use large oligo pools to substantially reduce the cost per construct45 but requires further engineering to account for the formation of the unintended Sidewinder heteroduplexes before assembly and the higher truncation rate of pooled oligos"

This absolutely destroys any unit economics when it comes to DNA synthesis. Oligo pool synthesis isn't 10x cheaper, it's 100x to 1000x cheaper than individual oligo synthesis.

So what they really have is a good way to do DNA assembly from synthesized oligos; fair. But we have that: GoldenGate can do 40 part assemblies, hell it can do 52 part assemblies, and you CAN use oligo pools - https://pmc.ncbi.nlm.nih.gov/articles/PMC10949349/ (there are a couple enzymatic properties which allow this, mainly that you can use full doublestranded DNA, which you can make with a PCR. Can't make these overhang guys with a PCR).

We've even found that with some GoldenGate enzymes, the biology somehow breaks the current models of the physics of ligation by being so efficient - https://www.biorxiv.org/content/10.64898/2026.01.31.702778v1

Their gels do look really good, I'll admit. I can imagine circumstances (exception cases) where this would be better. But not only is this kind of thing for 99% of cases has already been available for many years while being orders of magnitude cheaper (plural).

What really blows my mind about this is that they are using off-the-shelf T4 Ligase to ligate the junctions. I figured this was going to be some tour-de-force of enzyme engineering, but nope, all the reagents are pretty much commercially available.

It is super clever and exciting. Note that people have been able to assemble short (<100 bases) DNA oligomer fragments of synthetic DNA into longer fragments using "splint" oligos since forever. But in this case, each splint has to be custom engineered to only bind to the junction of interest (in practice it is pretty tricky and expensive to do this.) These guys figured out a way to use engineered sequences to make the match, and used a clever (but also more or less standard) way to chew up the engineered stuff, leaving behind only the desired long assembly with no scars at the end of the process.

Yes, it's very elegant! It's one of those things you wish you had thought of yourself. Kudos to these guys for being first.

That page numbers in books were only invented 50 years after the printing press is a fun snippet from the article

Sometime after 685 AD, they invented spaces between words. All text - in Latin to that point, mostly - was written in scriptio continua.

All sorts of ambiguity and hilarity would ensue; to be a good writer, you needed to ensure that words didn't bleed together and form incorrect meanings in unintended combinations. If you lost your place when reading, you'd have to know generally where you were in a scroll, and restart from a place you remembered.

Kinda crazy to think how difficult it would be to cross reference things and do collaborative research with no spaces or pages.

Hittite was putting spaces between words in the 17th century BCE. And if we're just interested in Latin, it used the interpunct as a word divider hundreds of years before the use of the space as word divider happened. The use of scriptio continua despite knowledge of word dividers was a choice.

I wonder, how much was gatekeeping, keeping things hard on purpose, how much waas inertia, "that's just the way things are done", and how much was a kind of despairing "holy shit, it'd be so much work to have to go through and recopy everything in the new format, literally decades of effort, and there's other things we want to do with our lives".

The whole context of written words had so much implicit process and knowledge and institutional memory, compared to now when we have petabytes of throwaway logs and trivial scratchpads for software running on a "just in case I might need to figure something out" basis. I'd love to see a written word graph over time, starting ~4k BC to now. And the complexity and diversity of those automated words are going up like crazy since LLMs.

Also probably a bit of "good parchment is expensive, why would we waste it on blank space?"

Also kind of crazy how long “but that’s the way we’ve always done it” can remain the dominant system, despite a revolutionary change being so trivially achievable. This required absolutely no technological advancement, literally just putting a little more space between letters to reduce ambiguity.

English is good example. It has not been fixed for long while. Even if there would be so many better ways to write certain words.

I feel like Mathematical notation is also a great example (since Math is ultimately a separate language: the language of measurement)

It's been built up over centuries where new innovations and shifts in perspective often create new kinds of notation, but those most frequently just get tacked onto whatever else is already standard and the new notations almost never actually supplant the old.

AFAICT we haven't really had a big shift in fundamental mathematical notation in Europe (and its colonies) since Roman Numerals (CXXIII) gave way to Arabic (123) numerals four hundred years ago. 8I

I think Bourbaki did brought forth a shift (clean-up) in mathematical notation and writing, at least in France.

> AFAICT we haven't really had a big shift in fundamental mathematical notation in Europe (and its colonies) since Roman Numerals (CXXIII) gave way to Arabic (123) numerals four hundred years ago. 8I

Your history is a little confused. Arabic numerals came into use in Europe as early as the 13th century (introduced by Leonardo Fibonacci), but most other mathematical notation like "=" or or "√" didn't show up until the 16th or 17th century.

Imagine if it Turned Out that Capitalizing Various Words made Things more Readable. How Quickly Would That be Adopted?

Do you speak German? A language famous for capitalizing its nouns of course.

i've had lots of Latin, know what you mean, but then thought of the Pantheon, where the word breaks (acronyms included) are indicated (with interstitial dots).

https://commons.wikimedia.org/wiki/File:Pantheon_Rom_1_cropp...

yeah - under certain "the winners write the history" framework, I believe that scribes did not add spaces between "words".. However, the world is a big place; history is long.

Many times obvious things are only obvious once you see them. Like roller suitcases.

See also: the wheel

The early printing press was probably focused on short few page documents (an increasing scale), and it wouldn't be surprising if page numbers were a solution to help printers not mix up pages.

Your hypothesis does not match history, because the early printing was focused on things that had a potentially large market, which at that time meant books like The Bible, with a lot of pages.

The parent article mentions that binding the pages of the first bibles in the correct order, in the absence of page numbers, was an extremely tedious work.

That is why page numbers have invented many years later, exactly as you say, "to help printers not mix up pages".

The Gutenberg Bible was one of the first mass produced books - no page numbers on early copies.

https://en.wikipedia.org/wiki/Gutenberg_Bible#/media/File:Gu...

Hindsight is 20/20 , lol. There are so many obvious, effective constructs and functions in modern English, we kinda miss the absolute janky mess of hacking and tradition and arbitrary rules and facepalm moments that went in to the last 1500+ years of development, let alone the tens of thousands of years prior.

> it wouldn't be surprising if page numbers were a solution to help printers not mix up pages.

It's an interesting idea. Remember they printed large sheets containing many 'pages', I think even in different orientations, which were then folded and the ends cut to produce a nice orderly codex for the reader. They were printing in a different order than the one you read in.

I do think they numbered the large sheets or similar, and you can find old books that retain that number, but I don't recall what it is called.

I can see how it wculd take that long to realize it would be nice to have a way to tell people which page to look at in their exact copy of a book.

Paper: https://www.nature.com/articles/s41586-025-10006-0

For someone in Software what is a good way to learn the fundamentals of this?

If you live near a community bio lab see if you can join up and take some classes to learn some basic lab techniques. And some sort of intro bio class via mooc/textbook/local college class whatever if you can but community lab is honestly a great place to start if you have one.

The main thing to keep in mind is that all the stuff that involves analogies between software and biology is almost universally a bullshit oversimplification that you can safely ignore. It's just that software is so profitable and there's so much vc money in it that there's a ton of pressure to be like "oh we can program biology like we program computers." We can't - we invented computers but didn't invent biology. Biology is the end result of 4 billion years of unchecked entropy - it's a chaos system, non deterministic in the wildest ways, impossibly complicated, and yet something we are getting astonishingly good at understanding and engineering.

Basically, all the biologists that started companies that were like "we can program biology like we can program computers" are bankrupt now.

On the other hand, the computer scientists that respected the nature of biology and pushed the limits of computing to develop Alphafold - giant models trained on the full complexity of biological data - finally created computer systems that could handle biological systems like protein folding at an extraordinary level of capability. They won a nobel.

Follow up question (Not OP), would alphafold more be used to experiment with an already-defined theory that you have, or could you also make some toy projects (e.g. how people make projects around trading engines).

I'm wondering if I could find a fun weekend project in alphafold just to see what it's like.

TIL community biolabs are a thing ...

Are they really? Is this just limited to some very specific areas with an active biotech scene?

In my part of the world it is a common thing among high schoolers, which form associations and use labs at school or a local university.

It's not uncommon that adults do something similar and run a community workshop with whatever the members are interested in.

That is very cool. Over here we can barely keep the odd makerspace or hacker space afloat, nevermind anything related to biology or chemistry.

Possibly not what you're asking for, but I wrote a generally-accessible intro to why it can be tricky to assemble many DNA fragments with "Golden Gate Assembly", a mainstream method which relies on short sequence overhangs. The Sidewinder method discussed in this thread aims to solve that "short overhang" problem.

https://zulko.github.io/bricks_and_scissors/posts/overhangs/

Chemical modifications of DNA are so amazing, and underpin so much DNA related research and engineering. Illumina and Moderna would not exist without DNA mods. It’s very cool that the set of tools is expanding further!

“ Guided by the removable DNA page numbers, Sidewinder achieves an incredibly high fidelity in DNA construction with a measured misconnection rate of just one in one million, a four to five magnitude improvement over all prior techniques whose misconnection rates range from 1-in-10 to 1-in-30.”

I wonder if this is even a problem, since you could amplify the correct sequence with PCR afterward.

I don’t think PCR is necessarily relevant here. I had the impression that this would be lost useful at linking multi-kb fragments together. If we are looking at sizes much above 2kb, PCR is going to struggle to generate full length fragments efficiently.

I didn’t see this technique as having DNA modification per-se, but a novel way to managing the hybridization process. It’s stock (well engineered) oligos, if I read it correctly.

pcr amplifies all sequences, correct or wrong, no? and as I understand it, it works on short snippets the best.

It amplifies sequences that contain the two primer sequences on each end of the target. So if you had synthesized sequence XYZ with some mistakes like YZX, then you could target X and Z and purify.

You're correct that PCR has a limited max length, but it is longer and cheaper than vanilla DNA synthesis.

Kary B. Mullis Nobel Prize lecture Nobel Lecture, December 8, 1993

The Polymerase Chain Reaction

https://www.nobelprize.org/prizes/chemistry/1993/mullis/lect...

Intuitively I agree some kind of selective amplification should be able to correct for the mistakes. But I think it will be complicated. Because the filtering process needs to be much more complex. It can’t just chemically match to a known subsequence - you won’t know where the mistake might be in a long sequence.

This is a good point. WXYZ and WYXZ are indistinguishable via PCR. And the possibilities accumulate with more segments.

Ok that’s it for me. Selective breeding via BLUP at least had a speed limit, this is going to end with cronenburg brundlefly creations.

Movies that come to mind that involve genetic building at this level are Gremlins 2, The Clone Wars, and some in the Alien franchise.

Yes, someone has attempted in the last to breed or alter for specific traits, we’ve cloned many kinds of life, and if there was extraterrestrial life here, someone probably mixed it with humans and animals.

But the pace of this is not going to increase anytime soon, if history is a judge. CRISPR was scaring people years ago when publicized, but those worries were unfounded and so shall these be. Life is much harder than coding apps.

Pretty cool technique using complementary overhangs and toehold sequences to generate a 3-way heteroduplex, ligate knick, and then remove barcode duplex.

They don't give much details on how the barcode duplex is removed though. I guess ultimately the barcode duplex strands can just be melted off and the ligated strand can be used to template off of.

If this can be made into an easy to use kit, can really make vector generation much easier and hopefully not locked into proprietary systems.

I can imagine a company that bioinformatically generates libraries of common long oligos with corresponding barcode and allow end-users to select oligos to modularly ligate together in a one pot reaction. Cool stuff.

We’ve been able to do this type of nucleotide 3D engineering for a while. I used to use large DNA branched complexed fluorophores to label cDNA back when I was in grad school. They were more or less mixed of DNA that self assembled into larger hairballs.

But branched DNA is really interesting. It’s a bit hard to get my head around. We spend so much time thinking about DNA in the 2D sequence sense, it’s easy to forget that it exists in 3D space.

I’m honestly not sure how different this really is to the traditional ways of doing this (with custom oligos). The common set of large self-hybridizing oligos is definitely easier, but you still have to have compatible tag overhangs between your two fragments. Meaning, it isn’t quite as universal and you’ll still need work to pair the fragments together. But where I think it might be useful is if you have a set of common hybridizing pairs that can be easily located onto the custom flanking oligos. You’ll still need some sequence analysis to get your custom oligos, but it would make the process more “standardized”.

I think the main bonus here is the self correcting selection… that you only end up with matching pairs linking together, so you could really have a mix in a one tube reaction that links many kilobase fragments together. That’s quite nice. And useful. And still cool.

One thing that is interesting is that this is another step towards getting the “writing” step of DNA analysis better. For the past 50+ years, we’ve developed all sorts of tools for reading DNA. It’s only really been the past 20-ish or so that we’ve had tools for writing. And now we can write longer chunks. That’s all a good thing.

Not sure I think it’s revolutionary (yet), but that’s a university PR release for you! I’m still thinking about the paper.

> using complementary overhangs and toehold sequences to generate a 3-way heteroduplex, ligate knick, and then remove barcode duplex

At first I thought this was about olympic figure skating, but after a bit of googling I think:

Complementary overhang - https://en.wikipedia.org/wiki/Sticky_and_blunt_ends

Toehold sequences: https://en.wikipedia.org/wiki/Toehold_mediated_strand_displa...

Ligate (ligase?) knick (nick?) - https://en.wikipedia.org/wiki/Nick_(DNA)

Barcode - https://en.wikipedia.org/wiki/DNA_barcoding

Heteroduplex - https://en.wikipedia.org/wiki/Heteroduplex

The article mentions AI multiple times even though the invention appears to have nothing to do with AI. I guess it’s important to have it as a marketing buzzword.

Sidewinder itself sounds neat.

Has anyone dabbled in hobbyist genome editing and DNA synthesis or is this something that requires a huge pile of capital?

Probably AI in the sense of what Google DeepMind has been up to with the protein folding and other biological simulations, instead of the LLM variant of AI.

Here's the paper without the cookies

https://web.archive.org/web/20260121201045if_/https://www.na...

The Church lab came up with this in 2006, sadly it never took off: https://patents.google.com/patent/US20060281113A1/en

Saw the headline and thought we were coming full circle on GEB -- a discovery of page number mechanisms in DNA functioning like GOTOs in code.

It's instead a way to stitch together longer sequences of DNA. Still very cool

Cool. I wonder how long until we are able to steal anti-cancer genes from whales.

This is probably the only way "humans" are going to colonize any planets other than Earth. And probably lots of new places on Earth too.

Just include the genes for extreme-cold or extreme-arid climates. Or the genes for low oxygen environments, or even for metabolizing useful things from eating rocks. Or from spending 24 hours a day in salt water.

The ease of this "just" is the most concerning thing in the context of humankind's survival.

>The ease of this "just" is the most concerning thing in the context of humankind's survival.

Right? I wouldn't expect genes for heat/cold tolerance in other organisms to necessarily be useful in humans. They work by mechanisms that are useful for that organism, but humans have our own set of problems.

It's like saying you can strap a jet engine on to a tractor and expect farm work to massively speed up. No: the machinery doesn't translate for a clean swap like that.

Then I recommend you don't find out what "Project Molecule" intends to do.

Care to enlighten? Google has nothing meaningful.

[flagged]

These files are a never ending quell of evilness. It’s really fascinating. One day people are going to realise the upper 1% are just that—very few….

[flagged]

For the most part, they only have the power others give them.

Slight correction: the power others gave them a long time ago, and now nothing can help those others take it back without uprooting the whole civilization in the process. Current power is a malignant formation too advanced to heal without destroying the whole organism.

Or so it seems, I'd really like to be wrong here.

It's not a slight correction, those claims are the exact problem - the propaganda of the powerful: Give up, there is nothing you can do.

People in democracies can easily vote to change where power lies (that is, power lies ultimately with the citizens), if that's what they want, and it's not hard to see how: The current situation is highly unusual for democracies; there is a long history of what to do and how to do it.

A major reason they don't do it is that they keep reading and believing they are powerless.

*collusion

[flagged]

Thanks for the heads-up!

There is no way it is just "just". And we should start from simpler stuff like vitamin B12, C and D.

Everything is “just” eventually.

Just tell your car to drive you to the airport. On the way just tell it to play that song you like.

Alas, one's happiness (as in genuine inner wellbeing, as opposed to the consumption-based external one) is no "just" matter, and never will be.

Is there a gene to avoid getting addicted to doomscrolling? ;-)

Relevant and topical..

TikTok's 'Addictive Design' Found to Be Illegal in Europe: https://news.ycombinator.com/item?id=46911869

Gen Z less intelligent than millennials: How skipping books and doomscrolling are taking a toll on cognitive abilities: says Dr. Jared Cooney Horvath: https://www.msn.com/en-in/news/India/gen-z-less-intelligent-...

Imagine if we could turn our bodies into perfect spheres, and then adjust genetic beauty preferences to match it.

Seems like a heat dissipation problem

Oh if only science was not constrained by ethics.

I can already see the people protesting against the creation of space marines.

No laws on mars

Science has never been constrained by ethics.

The same scientists who cry about ethics, have happily experimented on mice and guinea pigs in their labs, even if it causes the deaths or distress of those little sentient beings.

Mutations/mutatives like Halo's Master Chief and Marvel's Super Soldier serum won't remain sci-fi for much longer, methinks.

former practicing scientist at an institute whose name you would recognize.

The field may not be fully constrained by ethics, which is just a way of saying that the work is done by people and people have varying ethical bounds, but from what I saw many of my colleagues were highly ethics driven.

I remember one Russian colleague who smuggled blood products out of Russia so they could be tested for HIV. Because the Russian government refused to help these patients. The man risked his life to help HIV sufferers.

Ethics is best when matched with courage, if a person is willing to put their life on the line for their beliefs.

Also noting that in the western world, experiments generally need approval of an ethics board before proceeding. That board's sense of ethics might make different judgments than you on, for example, mice experiments, but there is a big difference between "not constrained" and "some of the constraints are different than what I would choose".

where in this case, the ethics boards decided that provided a certain risk/reward barrier is crossed, and that the animals are otherwise treated well, sacrificing mice to improve human health is just fine.

That is an ethics based decision that was debated for a long time. And maybe should continue to be debated, there is real value in your stance that all beings are sentient and this demands a level of care.

@a_better_world: (apt username for this conversation!)

I do understand what you mean, and I do comprehend that animal testing cannot be avoided for scientific advancements to help and progress humanity.

But I have a simple motto I want to adhere to (it is very hard though, to practice it in principle and action daily): Ethics is best when it is for the good of humanity, without being bad for Earth.

In recent years, I am starting to feel humanity is sharply veering away from its basic ethics (and the first ethic must be to not shit where one eats - but hey, we are actively aggressively destroying the only beautiful bountiful planet we know of, that can support humanity), and doing whatever the top richest most-powerful elites want.

And this unbridled greed and apathy is going to sow the seeds for the downfall of humanity, I'm afraid. At the cost of our precious Earth and its other denizens who share this planet with us humans.

There has been a catastrophic 73% decline in the average size of monitored wildlife populations* in just 50 years (1970-2020), according to World Wildlife Fund‘s (WWF) Living Planet Report 2024.

https://www.worldwildlife.org/news/press-releases/catastroph...

https://www.bbc.com/news/articles/c5y3j0vzpl3o

Forests around the world disappeared at a rate of 18 soccer fields every minute, a global survey found.

https://www.nytimes.com/2025/05/22/climate/deforestation-wri...

Our generation is the last one that can still save the wild forests of the Earth, which help us cope with the climate crisis and preserve the biodiversity of the planet. A new study by Greenpeace Russia and the University of Maryland has shown that if urgent and effective measures are not taken to preserve wild forests, most of them will disappear in the next 20 years.

https://www.greenpeace.org/international/story/51810/wild-fo...

And save human life at the same time? Experiments are not just about torturing animals; people spend a lot of time optimizing for experiment design.

Hey, did you hear about the Volkswagen Monkeys?

Volkswagen (the same megacorp that did the infamous Dieselgate/Emissionsgate scams) forced monkeys to inhale exhaust from its automobiles, to try to show that fumes from current models (the cars, not the monkeys) were less noxious than previous models.

https://www.msn.com/en-us/science/sociology/20-of-the-most-u...

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

I guess this cannot be termed as "torturing animals" in the "name of science".

We humans also inhale vehicular exhaust fumes, don't we?

Oh wait, I forgot. Monkeys don't drive cars.

Or do they? https://m.youtube.com/watch?v=XW5NLeGEo94

[flagged]

Very cool, but may have some unexpected consequences. E.g., someone can probably use this to synthesize a bacterial genome containing every known drug resistance gene, and this is just the first thing that comes to mind. Possibilities for bioeconomy indeed.

You don't need to synthesize an entire bacterial genome from scratch to do this. You can just insert them one at a time into existing bacteria. Or just give them plasmids. Anyway, the ability to achieve the outcome you're describing has existed for decades.

Such a simple concept took this long to discover? Now we just need a way of packing the DNA strings into blank cells reliably.

It's a lot like TikTok, right? It's a very simple concept: immediately produce customized video recommendations taking into account even the most recent interactions.

You just need a way to pack the TikToks into blank data centers.

(Note: blank data centers is a concept that kind of sorta makes sense. A blank cell doesn't make any sense at all)

It was known in 2006 but rediscovered recently: https://patents.google.com/patent/US20060281113A1/en

> Now we just need a way of packing the DNA strings into blank cells reliably.

Huh, I kinda assumed we'd already done that part with Dolly the sheep. But I'm not a biologist, I just saw headlines.

They have a nice simple explanation. But the biochemistry of it I’m guessing is anything but simple. I’ve never heard of three way junctions in DNA before. I wonder how new those are. And designing the molecules to do the matching and splicing must have taken a long time.

"just"

Could we better not?

[flagged]

What's the source of the text? It seems to be either a copypasta from a journal article or LLM-generated (and not your own text).

I briefly scanned the paper. The above summary is garbage.

For a biologist, a summary might be like this: pcr fragments are generated with short reverse complementary sequences added to the end of one fragment that match that at the begining of the next to-be-joined fragment.

These will anneal to create a cross-shaped DNA molecule. The short arms of the cross being the complementary sequences. Like so:

  ======∥=====

So do the complementary sequences naturally bind to their neighbors? So you just mix the “pages” in a soup for a while until they all find their friends. And then the custom enzyme (or what is it) just slices off the three way junctions?

Really clever.

That's right.

It's one of those elegant solutions that just seem so obvious once they're presented. But this lot did it first.

LLM–generated summary. A human summary wouldn't specify the temperature used because it's irrelevant.