PREreview del Generative design of novel bacteriophages with genome language models

This manuscript describes very cool molecular biology with careful engineering and a convincing structural and functional assessment of a reconstructed ΦX174-like phage. The build-test workflow is clearly described, and the recovery of infectious particles provides a strong experimental anchor for the computational design story. This is a great demonstration of what is currently feasible for whole-genome phage engineering.

However, it misses a major opportunity to contextualize the generative model performance with explicit baselines. This makes it difficult to assess whether there is a true advance due to the ability of the generative model to move in sequence space with success rates (~16/300) above alternative (lightweight) models. Moreover, the sequence space explored here appears to stay close to known natural sequences, so it is hard to appreciate how the generative model adds novelty beyond proximity to existing genomes. Side-by-side comparisons against simple alternatives (for example a consensus design, frame-preserving randomization under GC and codon constraints, ancestral reconstruction, or family statistical models such as direct coupling analysis) would clarify whether the model improves assembly success or shifts resistance outcomes. Recent studies provide useful templates for such “null model” panels, see OpenCRISPR Figure 3E (https://pmc.ncbi.nlm.nih.gov/articles/PMC12422970/), and ProGen Lysozymes Figure S10 (https://pmc.ncbi.nlm.nih.gov/articles/PMC10400306/) for evaluating LLM-generation of proteins. Including analogous baselines here, with success rates and resistance readouts reported for each, would make the impact of this contribution and generality of this approach unmistakable.

Competing interests

J.S.F. receives consulting fees from and has an equity interest in Profluent Bio, a company using generative AI. J.B.-D. is a scientific advisory board member of SNIPR Biome, Excision Biotherapeutics, LeapFrog Bio, and Acrigen Biosciences and is a co-founder of Acrigen Biosciences and ePhective Therapeutics.