alt Hacker NewsInvention of DNA "page numbers" opens up possibilities for the bioeconomy
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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.
That page numbers in books were only invented 50 years after the printing press is a fun snippet from the article
For someone in Software what is a good way to learn the fundamentals of this?
The Church lab came up with this in 2006, sadly it never took off: https://patents.google.com/patent/US20060281113A1/en
Here's the paper without the cookies
https://web.archive.org/web/20260121201045if_/https://www.na...
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.
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.
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.
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?
Cool. I wonder how long until we are able to steal anti-cancer genes from whales.
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.
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.
Could we better not?
Such a simple concept took this long to discover? Now we just need a way of packing the DNA strings into blank cells reliably.
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).