Toward life with a 19–amino acid alphabet through generative artificial intelligence design

Because all known living organisms are made from at least 20 canonical amino acids, the feasibility of life using a more simplified alphabet remains unclear. In this work, we leveraged computational design and synthetic biology to explore building a cell from a 19–amino acid alphabet. Initial analyses suggested that isoleucine (Ile) may be dispensable, which we confirmed by directly replacing Ile residues in essential proteins in Escherichia coli . Critically, protein language models and structure-based models were necessary to redesign functional Ile-less proteins in most cases. We systematically replaced all 382 Ile residues from the ribosome and combined 21 redesigned subunits at a native genomic locus to produce a viable, evolutionarily stable cell. This work provides a roadmap to create the first 19–amino acid organism since early evolution.