Read the full preprint below 👇 If you're interested in the interface of bioengineering, DNA and virtual cell foundation models, and agentic reasoning, shoot me a note. We're hiring postdocs and ML researchers and starting some crazy new projects
www.biorxiv.org/content/10.1...
Using these enhanced bridge RNAs, we discovered design principles for maximizing the specificity of insertion into the human genome, achieving as high as 82% specificity genome-wide
But unlike other tools, bridge editing is not limited to insertion! We use IS622 for programmable, precise, and scarless genome rearrangements, inverting up to 0.93 Mb and excising up to 0.13 Mb
Bridge recombination systems are elegant molecular tools that utilize a recombinase enzyme and a programmable bridge RNA to "bridge" and recombine two distinct DNA molecules
This is a universal mechanism for insertion, excision, or inversion of any two DNA sequences
Genomes encode biological complexity, which is determined by combinations of DNA mutations across millions of bases
In new work @arcinstitute.org, we report the discovery and engineering of the first programmable DNA recombinases capable of megabase-scale human genome rearrangement
Bridge recombinases can modify the genome from single gene insertions to megabase-sized rearrangements
We're excited about programmable genome design at unprecedented length scales, especially when combined with AI-generated DNA sequences of high complexity (e.g. Evo 2)
In a tour de force of molecular engineering, our team conducted computational ortholog mining, human cell activity screening, and structure-guided bridge RNA engineering to enhance the activity of IS622, a bridge system that showed promising but low activity in human cells
This work was a wonderful collaboration with Silvana Konermann, led by star graduate student Nick Perry with key contributions from the amazing Liam Bartie, Dhruva Katrekar, Gabe Gonzalez, Matt Durrant, James Pai, Alison Fanton, Masa Hiraizumi, Chiara Ricci-Tam, and Hiroshi Nishimasu
Arc is on 🔥
We then performed a systematic deep mutational scan of IS622 and combined a rationally engineered, high activity recombinase mutant with our enhanced bridge RNAs to demonstrate 20% insertion efficiency into the human genome
Most people think of recombinases for payload insertion (e.g. of CARs or corrective genes)
We provide a therapeutic proof-of-concept with bridge-mediated excision of the BCL11A enhancer for sickle cell anemia and of expanded repeat sequences found in Friedreich's ataxia
