Single-cell perturbation prediction near experimental reproducibility with GENESIS

Single-cell perturbation atlases now measure cellular responses across millions of cells, but the number of possible combinations of biological contexts, perturbations, doses and other experimental variables make exhaustive measurements infeasible. Here, we present GENESIS (Generative ENErgy-based Single-cell Intervention Simulator), a generative framework that predicts single-cell response distributions directly from the covariates defining an experimental condition. GENESIS uses a lightweight neural network trained with the energy score, a strictly proper scoring rule for distributions. We introduce an experiment-calibrated evaluation framework in which prediction error is interpreted relative to the reproducibility of repeated measurements of the same condition. Across the Tahoe-100M small-molecule atlas and a large PBMC cytokine atlas, GENESIS significantly outperforms existing generative models and statistical baselines and approaches experimental reproducibility on independently repeated conditions. Importantly, GENESIS remains accurate when trained on only a fraction of the available experimental conditions or cells, and generated profiles recover experimentally observed context-dependent transcriptional programs. At comparable training-cell budgets, GENESIS achieves more accurate predictions when measurements span more experimental conditions rather than profiling fewer conditions more deeply. Together, these findings suggest a complementary strategy for perturbation studies: broader, lower-depth measurements can expand experimental coverage, while GENESIS augments sparsely sampled populations and predicts responses in unmeasured conditions.