The next gene editor will be designed: Profluent + Lilly, $2.25B

Profluent just announced a multi-program strategic partnership with Eli Lilly to develop AI-designed recombinases for genetic medicine — worth up to $2.25 billion in milestones, plus tiered royalties on net sales.In this episode, Nathan unpacks why this deal matters far beyond the headline number. CRISPR taught us how to fix typos in the genome. The harder problem — and arguably the larger one — is editing at the kilobase scale: replacing whole paragraphs of DNA at a chosen genomic address. That's the route to therapies for the long tail of genetic disease driven by patient-level mutational heterogeneity, from cystic fibrosis to inherited hearing loss to retinal dystrophy.Recombinases have always been the right class of enzyme for this job. They've also been stuck for decades because their targeting specificity is encoded directly in the protein structure, with no equivalent of CRISPR's modular guide RNA. That makes recombinases a near-perfect problem for foundation-model protein design — and it's exactly the bet Profluent has been building toward since their 2024 work designing novel Cas enzymes from scratch.We cover: why kilobase-scale editing is the next frontier of genetic medicine; why recombinases were intractable until AI; how Profluent's foundation-model platform changes the picture; why Lilly is the right partner; and what the world looks like if you can name a genomic address and get a designed editor back.