Our work on a 57-codon E. coli genome is out!

Excited to see our work on constructing and optimizing a genetic-code-engineered Escherichia coli genome published today in Nature Communications. This is a step toward building safer cellular technologies.

Constructing a 57-codon Escherichia coli genome (now in six strains) turned out to be much more challenging than simply redesigning DNA sequences and assembling them.

Throughout the project, we found that genome recoding affected gene expression at multiple levels. We identified and corrected mutations in promoters, ribosome binding sites, overlapping genes, start codons (based on updated genome annotations), and other genomic features. We also removed mobile genetic elements that had inserted into recoded regions and addressed the severe fitness defects that arose as progressively larger portions of the genome were replaced.

To restore growth, we implemented multiple rounds of Adaptive Laboratory Evolution (ALE), Multiplexed Automated Genome Engineering (MAGE), and extensive multi-omics analyses. These analyses also revealed how synonymous codon changes reshape transcription, translation, and ultimately cellular fitness.

This work provides valuable lessons for identifying and overcoming the biological barriers that arise during whole-genome genetic-code engineering, and it represents an important step toward building safer cellular technologies.

For me personally, this was my first major project as a postdoctoral researcher and it marked the transition from computational to experimental biology in the Church lab, where I now combine both approaches. I am especially grateful for everything I learned along the way, particularly about the challenges and engineering strategies involved in translating computational genome designs into living organisms.

I am thankful to lead author Akos Nyerges for bringing this project to completion, to George Church for his mentorship and support, and to the amazing team of colleagues and friends I had the privilege of working with, including Bogdan Budnik, Maximilien Baas-Thomas, Regan Flynn, Shirui Yan, Nili Ostrov, Alexandra Rudolph, and many others who contributed to this work.

Publication: https://www.nature.com/articles/s41467-026-74300-9