Biology will not become truly programmable until DNA synthesis stops being the limiting step. Writing long, complex DNA, especially sequences rich in repeats or extreme GC content, remains slow, inaccurate, and expensive.
“Half the human genome is complex, repetitive, or GC-rich, and those regions are almost impossible to build,” explains Woolfson. “In plants, it’s closer to 85 percent. It’s a huge region of sequence space that you simply can’t navigate it, because you can’t construct it.”
The issue comes from how DNA is traditionally assembled. Most methods rely on complementary overlaps at fragment ends to stitch sequences together. Those overlaps serve two roles at once: they guide assembly, and they become part of the final DNA sequence. That coupling, Professor Kaihang Wang argues, is the root of the field’s long-standing accuracy ceiling.
“I have been suffering from the pain of DNA construction for decades,” Professor Kaihang Wang says. “When assembly instructions are coupled to the sequence itself through two-strand overlaps, you fundamentally cap specificity at about 90 to 97 percent, meaning misconnection rates as high as one in ten to one in thirty.”
In the lab’s new Nature paper, their Sidewinder method breaks that coupling between sequence and assembly instructions1. In Sidewinder, fragments locate their correct neighbors using barcodes that ligate at a three-way junction. After assembly, those barcodes are removed or displaced. The barcodes can be thought of as page numbers in a book, and the fragments as the information in the pages. The result is a seamless DNA sequence assembled with orders of magnitude higher accuracy than conventional approaches.
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