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.
It's instead a way to stitch together longer sequences of DNA. Still very cool
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.
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.
“ 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.
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?
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.
https://zulko.github.io/bricks_and_scissors/posts/overhangs/
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
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.
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.
I can already see the people protesting against the creation of space marines.
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.
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.
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)
Huh, I kinda assumed we'd already done that part with Dolly the sheep. But I'm not a biologist, I just saw headlines.
https://commons.wikimedia.org/wiki/File:Pantheon_Rom_1_cropp...
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".
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.
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).
https://web.archive.org/web/20260121201045if_/https://www.na...
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-...
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.
I'm wondering if I could find a fun weekend project in alphafold just to see what it's like.
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.
Just tell your car to drive you to the airport. On the way just tell it to play that song you like.
Are they really? Is this just limited to some very specific areas with an active biotech scene?
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.
It's not uncommon that adults do something similar and run a community workshop with whatever the members are interested in.
You're correct that PCR has a limited max length, but it is longer and cheaper than vanilla DNA synthesis.
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.
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
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...
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...
The Polymerase Chain Reaction
https://www.nobelprize.org/prizes/chemistry/1993/mullis/lect...
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...
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...
World’s top 1% own more wealth than 95% of humanity, as “the shadow of global oligarchy hangs over UN General Assembly,” says Oxfam: https://www.oxfam.org/en/press-releases/worlds-top-1-own-mor...
World's richest 10 percent holds more than three quarters of the world's total wealth: https://www.statista.com/statistics/1417996/wealth-held-rich...
Ten richest men double their fortunes in pandemic while incomes of 99 percent of humanity fall: https://www.oxfam.org/en/press-releases/ten-richest-men-doub...
Over the past 30 years the U.S.’s top 1% got richer, and now hold nearly a third of the nation’s wealth: https://fortune.com/2024/10/08/congressional-budget-office-w...
The power of artificial intelligence (AI) and advanced computing has made it possible to design genetic sequences encoding for diverse biological applications, such as proteins that form the building blocks of materials stronger than steel, or personalized cancer treatments. But the act of constructing DNA sequences to realize those designs has been a significant bottleneck. Due to technological limitations, chemical DNA synthesis has been limited only to creating short pieces of DNA. However, DNA molecules on the scale of genes or genomes can be tens to thousands of times longer than current capabilities allow. Without DNA construction, AI-powered biological designs cannot be verified or improved—meaning that the blueprints for futuristic new technologies cannot be realized.
Caltech researchers have invented a new technology to write long sequences of DNA with groundbreaking accuracy. The invention, a method called Sidewinder, utilizes the conceptual equivalent of page numbers for DNA, enabling researchers to stitch together any arbitrary number of short pieces of DNA, called synthetic oligonucleotides, or "oligos," in the correct order to create a much larger piece of DNA—up to the scale of a gene or potentially an entire genome (the entire genetic complement of an organism). Synthetic oligos, which are cheap and widely available, can now be combined into any design using Sidewinder. This innovation clears a major bottleneck for bioengineering new compounds and materials, and it could have a vast array of applications, including agriculture and therapeutics.
The invention and development of Sidewinder was conducted in the laboratory of Kaihang Wang, an assistant professor of biology and biological engineering. A paper describing the technique appears in the journal Nature on January 21.
"DNA is the source code of all earthly life and biological functions," Wang says. "As such, biomedical applications and the future bioeconomy depend on the ability to write DNA. Sidewinder provides a new path to the ancient and persisting desire of humankind to rewrite the very source code of life. We can now make long DNA, regardless of complexity and sequence, and do this faster, more easily, and more cheaply than has been possible."
The diversity of life forms on Earth comes from evolution: As organisms replicate, their DNA is copied into their offspring. Over millions of years, mutations accumulate, giving rise to new organisms with new functions. However, this means that in nature, entirely new DNA sequences are never written from scratch—they are only iteratively copied and edited from a pre-existing template.
Humans have taken advantage of the evolutionary process for millennia; for example, over the course of about 9,000 years, humanity domesticated and selectively bred maize. With the advent of modern biology, researchers began to explore the possibility of synthesizing new DNA sequences from scratch for the first time in human history.
In the 1970s, researchers developed the ability to synthesize short pieces of DNA—the aforementioned oligos. These pieces are around 10 to 100 base pairs long. However, attempts to accurately synthesize oligos longer than a few hundred nucleotides were not successful. Genes that encode for many useful proteins are on the order of thousands to tens of thousands of nucleotides, far too long for current synthesizing methods.
In the past four decades, short synthetic oligos have been produced at scale to enable biotech advances, such as the recent messenger RNA (mRNA) vaccines targeting COVID-19. But in order to create entire genes, and thus enable biotechnologies such as personalized cancer vaccines, these short oligos would need to be stitched together with perfect accuracy into longer, complex DNA sequences.
Enter Kaihang Wang's Sidewinder. With Sidewinder, synthetic biologists can write new genes and entire genomes within just a few days, if not hours.
To explain Sidewinder's mechanism, Kaihang uses the analogy of assembling printed pages into books in the West. "In 1441, Johannes Gutenberg invented the printing press, enabling the creation of individual printed pages," he says. "But Gutenberg's bibles never contained any page numbers. These books were painstakingly assembled by aligning the contexts at the beginning and end of each page, for hundreds of pages. Thus, the eventual invention of page numbers, which took about 50 years, was revolutionary. The seemingly simple concept of page numbers was actually non-trivial. We are fortunate to learn from this history, because we are facing a surprisingly identical challenge: how to guide the construction of long sequences from individually synthesized pieces. In this case, they are DNA oligos instead of printed pages. It has been 40 years since the invention of oligo synthesis, the equivalent of a Gutenberg press for DNA, and now it is high time that we invent the equivalent of 'DNA page numbers' to guide the assembly of these short oligos to construct long and functional DNA—the equivalent of books—for genes, gene clusters, and all the way to genomes to complete the book of life."
The Sidewinder process attaches DNA "page numbers" to each oligo, enabling each piece to match up with the right neighbors in the sequence—piece number 4, for example, follows piece number 3 and precedes piece number 5. It works by using a technique called a 3 Way Junction (3WJ), which causes the page number pieces to stick out of the side of the assembled DNA construct like little tags. In this way, the information guiding the construction of the DNA sequence can be separated from the information encoded in the DNA sequence. These little tags extending from the 3WJ are then smoothly removed, resulting in a perfectly assembled, uninterrupted DNA double helix for any desired applications. The ability to remove the third helices from the 3WJs in a single, seamless step after using them as "page numbers" to guide the DNA construction is a critical part of the Sidewinder invention. 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.
"Sidewinder is wonderfully creative, and a powerful step toward the goal of writing DNA of any complexity," says Caltech's Frances Arnold, the Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry, director of the Donna and Benjamin M. Rosen Bioengineering Center, and winner of the 2018 Nobel Prize in Chemistry. Arnold invented a method called directed evolution—a technology to mimic natural selection in the laboratory—and is now using AI to facilitate protein design. "Sidewinder addresses a key bottleneck in translating computational design into reality, with applications across health and sustainability."
"A cell is a complex computer, one we want to be able to engineer for our own applications," says the study's first author, Noah Robinson (PhD '25), who completed his graduate studies in Kaihang Wang's laboratory and is now continuing the work as a postdoctoral scholar. "To do that, we need to be able to design and construct in the language of life, DNA. With Sidewinder, our lab is developing tools to make this a reality."
The team now plans to address additional bottlenecks in scaling up construction of sequences. Additionally, Kaihang emphasizes the importance of interfacing Sidewinder with AI.
"Interfacing with AI will give us the freedom both to design and to construct," Kaihang says. "Whatever can be designed by AI as a biological function can be constructed through Sidewinder. The convergence of design through AI and construction through next-generation DNA writing technologies such as Sidewinder may enable an alternative to how life can come around, in addition to evolution. Now maybe it can be designed and made."
A paper describing the research is titled "Construction of complex and diverse DNA sequences using DNA 3-Way Junctions." In addition to Robinson and Wang, Caltech co-authors are graduate students Weilin Zhang, Bryan Gerber, Hanqiao Zhang, and Sixiang Wang; and research scientist Charles Sanfiorenzo (PhD '24). Additional co-authors are Rajesh Ghosh and Dino Di Carlo of UCLA. Funding was provided by the National Science Foundation, the Shurl and Kay Curci Foundation, the National Institutes of Health, and Caltech's Center for Environmental Microbial Interactions. Genyro, a biotechnology company co-founded by Kaihang Wang, has entered into an exclusive licensing agreement for Sidewinder to advance next-generation DNA construction.
