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.
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.
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.
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.
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".
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.
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.
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.
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.
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.
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.
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.
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.
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.
“Project Molecule": a proposed megafund in collision with Epstein, seeded with Gates-foundation capital and JPMorgan clients, with a sinister purpose : controlled pandemics!
Buried in the Epstein files is a 14-page JPMorgan proposal called Project Molecule—a formal partnership with the Bill & Melinda Gates Foundation to transform pandemic preparedness into a permanently governed, privately controlled, transnational system of vaccine procurement, surveillance, and global health finance—developed within the same institutional ecosystem in which the convicted sex offender (Epstein) operated as a connective broker between Wall Street, global health, and political power.
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.
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.
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)
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.
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.
For someone in Software what is a good way to learn the fundamentals of this?
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/
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.
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.
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.
Paper: https://www.nature.com/articles/s41586-025-10006-0
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.
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.
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.
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.
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
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.
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.
Thanks for the heads-up!
Care to enlighten? Google has nothing meaningful.
“Project Molecule": a proposed megafund in collision with Epstein, seeded with Gates-foundation capital and JPMorgan clients, with a sinister purpose : controlled pandemics!
Buried in the Epstein files is a 14-page JPMorgan proposal called Project Molecule—a formal partnership with the Bill & Melinda Gates Foundation to transform pandemic preparedness into a permanently governed, privately controlled, transnational system of vaccine procurement, surveillance, and global health finance—developed within the same institutional ecosystem in which the convicted sex offender (Epstein) operated as a connective broker between Wall Street, global health, and political power.
https://www.nytimes.com/2025/09/08/magazine/jeffrey-epstein-...
https://portside.org/2025-09-15/how-jpmorgan-enabled-crimes-...
https://www.tumlook.com/katiepavlich/post/807627515385561088
https://www.moneycontrol.com/world/how-jpmorgan-enabled-jeff...
LOL, I knew this would be downvoted.
Is there a gene to avoid getting addicted to doomscrolling? ;-)
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.
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.
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.
Human life is meaningless to people without ethics. For them, humans are guinea pigs; or worse - slaves.
Talking of "human life" and "experiment", did you know about this billionaire chap and what he's been really doing in the name of science, experiment and charity? https://m.economictimes.com/industry/healthcare/biotech/heal...
No laws on mars
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)
> 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"