Integrating experimental feedback improves generative models for biological sequences

Abstract

Generative probabilistic models have shown promise in designing artificial RNA and protein sequences but often suffer from high rates of false positives, where sequences predicted as functional fail experimental validation. To address this critical limitation, we explore the impact of reintegrating experimental feedback into the model design process. We propose a likelihood-based reintegration scheme, which we test through extensive computational experiments on both RNA and protein datasets, as well as through wet-lab experiments on the self-splicing ribozyme from the group I intron RNA family where our approach demonstrates particular efficacy. We show that integrating recent experimental data enhances the model's capacity of generating functional sequences (e.g. from 6.7\% to 63.7\% of active designs at 45 mutations). This feedback-driven approach thus provides a significant improvement in the design of biomolecular sequences by directly tackling the false-positive challenge.