Retrieval-Augmented Generation for Predicting Cellular Responses to Gene Perturbation

Abstract: Predicting how cells respond to genetic perturbations is fundamental to understanding gene function, disease mechanisms, and therapeutic development. While recent deep learning approaches have shown promise in modeling single-cell perturbation responses, they struggle to generalize across cell types and perturbation contexts due to limited contextual information during generation. We introduce PT-RAG (Perturbation-aware Two-stage Retrieval-Augmented Generation), a novel framework that extends Retrieval-Augmented Generation beyond traditional language-model applications to cellular biology. Unlike standard RAG systems designed for text retrieval with pre-trained LLMs, perturbation retrieval lacks established similarity metrics and requires learning what constitutes relevant context, making differentiable retrieval essential. PT-RAG addresses this through a two-stage pipeline: first, retrieving candidate perturbations $K$ using GenePT embeddings, then adaptively refining the selection through Gumbel-Softmax discrete sampling conditioned on both the cell state and the input perturbation. This cell-type-aware differentiable retrieval enables end-to-end optimization of the retrieval objective jointly with generation. On the Replogle-Nadig single-gene perturbation dataset, we demonstrate that PT-RAG outperforms both STATE and vanilla RAG under identical experimental conditions, with the strongest gains in distributional similarity metrics ($W_1$, $W_2$). Notably, vanilla RAG's dramatic failure is itself a key finding: it demonstrates that differentiable, cell-type-aware retrieval is essential in this domain, and that naive retrieval can actively harm performance. Our results establish retrieval-augmented generation as a promising paradigm for modelling cellular responses to gene perturbation. The code to reproduce our experiments is available at https://github.com/difra100/PT-RAG_ICLR.