Driessen, Rajwade, Harsanyi, Rapsomaniki and Born published in Nature Machine Intelligence (DOI: 10.1038/s42256-026-01242-8) the Conditional Monge Gap (CMonge), a neural optimal transport method that learns transport maps conditioned on arbitrary covariates — drug, dose, cell type, or combinations thereof — to predict single-cell perturbation responses. The method addresses a recognised limitation: most prior neural optimal transport approaches to single-cell perturbation modelling cannot condition on treatment context, requiring a separate model per condition and failing to generalise to unseen treatments. CMonge instead trains a single global estimator that can be conditioned at inference time on a potentially unseen condition. On the SciPlex3 dataset (three cell lines, 187 compounds, four doses), a single CMonge model reportedly matches the performance of separate condition-specific models and generalises to previously unseen drug–dose combinations, outperforming the conditional baseline chemCPA in out-of-sample prediction using only drug structure (SMILES) as input. Direct relevance to drug discovery: in silico perturbation screening, dose-response simulation, and combination-effect prediction — capabilities that bear on target validation and lead prioritisation. Code released as the open-source cmonge package. Contrary view: single-cell perturbation modelling is a crowded methodological field with competing approaches (chemCPA, scGen, CellOT, diffusion-based methods such as LCD and scPPDM, and flow-matching methods such as PRiMeFlow); CMonge's reported state-of-the-art is benchmark-specific, evaluated principally on SciPlex3 and a 40-plex 4i melanoma imaging dataset, and the out-of-distribution gains are stronger for effect-based (mode-of-action) embeddings than for structure-based ones. The authors themselves note that fine-tuning on giga-scale datasets (e.g. Tahoe-100M) or on patient-derived organoids would be required to unlock the method's full translational potential — meaning the present results are a methodological advance rather than a validated drug-discovery tool. Single-cell perturbation prediction in general remains constrained by the inherent heterogeneity and dropout noise of scRNA-seq, and the absence of prospective wet-lab validation in this study limits direct read-across to real screening campaigns.
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