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Comment by biophysboy | Hacker News Reader

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.

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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.

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.

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...

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