Simulating 500 million years of evolution with a language model
More than 3 billion years of evolution have produced an image of biology encoded into the space of natural proteins. Here, we show that language models trained at scale on evolutionary data can generate functional proteins that are far away from known proteins. We present ESM3, a frontier multimodal generative language model that reasons over the sequence, structure, and function of proteins. ESM3 can follow complex prompts combining its modalities and is highly responsive to alignment to improve its fidelity. We have prompted ESM3 to generate fluorescent proteins. Among the generations that we synthesized, we found a bright fluorescent protein at a far distance (58% sequence identity) from known fluorescent proteins, which we estimate is equivalent to simulating 500 million years of evolution.
Authors
- Halil Akin (ORCID: https://orcid.org/0000-0003-1666-3223)
- Neil Thomas (ORCID: https://orcid.org/0000-0002-9089-1921)
- Tom Sercu (ORCID: https://orcid.org/0000-0003-2947-6064)
- Carolyn Kim
- Nicholas Sofroniew (ORCID: https://orcid.org/0000-0002-3426-0914)
- Alexander Rives (ORCID: https://orcid.org/0000-0003-2208-0796)
- Roshan Rao (ORCID: https://orcid.org/0000-0003-4412-3742)
- Yousuf A. Khan (ORCID: https://orcid.org/0000-0003-0201-2796)
- Deniz Oktay (ORCID: https://orcid.org/0000-0001-7104-0104)
- Jun Gong (ORCID: https://orcid.org/0000-0002-4402-1263)
- Jonathan Deaton (ORCID: https://orcid.org/0000-0002-1852-3112)
- Patrick D. Hsu (ORCID: https://orcid.org/0000-0002-9380-2648)
- Rohil Badkundri (ORCID: https://orcid.org/0000-0003-3338-383X)
- Alexander Derry (ORCID: https://orcid.org/0000-0003-2076-1184)
- Salvatore Candido (ORCID: https://orcid.org/0000-0002-5847-0617)
- Robert Verkuil (ORCID: https://orcid.org/0000-0001-9533-7623)
- Thomas Hayes (ORCID: https://orcid.org/0000-0002-7631-495X)
- Marius Wiggert
- Irhum Shafkat
- Liam J. Bartie
- Matthew Nemeth (ORCID: https://orcid.org/0009-0001-1224-9116)
- Vincent Q. Tran
- Zeming Lin (ORCID: https://orcid.org/0000-0002-0883-1373)
- R. Molina
- Chetan Mishra
Institutions
- Palo Alto Institute (US)
- New York Consortium in Evolutionary Primatology (US)
- Arc Research Institute
- University of California, Berkeley (US)
Publication Details
- Journal
- Science
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1126/science.ads0018
- Citations
- 482
- Primary Topic
- Genomics and Phylogenetic Studies
- Type
- article
- Field-Weighted Citation Impact
- 379.64