From discovery to design: in conversation with Ali Madani (Profluent)

Over the past few weeks, it’s been hard to keep up with AI in biology. Profluent signed a $2.25B partnership with Eli Lilly on AI-designed gene editors, Verve put out striking base-editing data, CZ Biohub published new scaling results on protein models, and Isomorphic Labs pulled in another large raise.I couldn’t think of anyone better to discuss this with than Ali Madani, the founder and CEO of Profluent. Profluent is an AI lab building frontier models to design proteins, with the goal of taking medicine from discovering molecules nature already made to designing the ones it didn’t. I first read Ali’s ProGen paper back in 2021, DMed him on then Twitter, and wrote the largest first check from Air Street Capital into the company at inception. Last month, Profluent announced a $2.25B deal with Eli Lilly, one of the largest to date between a frontier AI biology lab and big pharma.We discuss the shift from discovery to design, why Profluent bet sequence-first while others went structure-first, the Lilly deal and large-scale DNA editing, fine-scale base editing, whether LLM-style scaling laws hold for proteins, and much more. You can either watch the interview in full here or on YouTube or read the transcript below.Timestamp timeline0:00 – Teaser: AI-designed molecules & the $2.25B Lilly deal0:22 – Intros: Nathan Benaich (Air Street Capital) & Ali Madani (Profluent)2:10 – What is Profluent, and why AI matters5:45 – The landscape: readers vs. writers7:45 – Profluent’s edge: 100B+ sequences and a wet lab9:20 – OpenCRISPR and the exponential curve12:55 – Why sequence beats structure14:50 – The Eli Lilly deal and large gene insertion16:20 – Fine-scale vs. large-scale editing18:00 – Why it’s hard: the pre-AI era and the activity/specificity trade-off20:45 – The Verve news, and scaling beyond one-offs23:45 – Rare vs. common disease26:10 – “What do you know that no one else does?”27:40 – bio × AI is an undersaturated field32:40 – When will a top-10 pharma be AI-first?34:30 – Every molecule will be designed with AITimestamp