OCellus: A Language-Model Framework for Single-Cell, Spatial, and Perturbation Biology with Natural-Language Reasoning

Abstract

Computational modeling of cellular behavior--the virtual cell--has emerged as a stated grand challenge at the intersection of artificial intelligence and biology, yet existing foundation models remain specialized: single-cell models process dissociated transcriptomes only, spatial models require dedicated spatial-aware architectures, and perturbation predictors depend on manually curated knowledge bases that cap generalization. Here we introduce OCellus, a single nine-billion-parameter language model (Qwen3.5-9B) fine-tuned on twenty-two biological tasks that simultaneously addresses all three limitations through three coordinated technical contributions on a shared backbone. First, EvenClock encodes two-dimensional spatial coordinates as eighteen clockface sectors of text, enabling spatial reasoning on a vanilla language model without architectural modification; on ten spatial transcriptomics tasks OCellus attains 77 percent spatial-neighborhood accuracy, 96 percent spatial-cellchat accuracy, and 0.70 proportion-cosine similarity on spatial deconvolution, all without any spatial-aware architectural components. Second, per-gene language-model embeddings replace the Gene Ontology annotations that GEARS depends on, achieving Pearson correlation 0.945 on the Replogle 2022 perturbation benchmark versus 0.84 for GEARS across 457 completely unseen knockout genes. Third, OCellus-Agent provides a Planner-Router-Verifier natural-language interface that achieves 75 percent pipeline accuracy on eighty multi-task queries. Removing language-model embeddings collapses perturbation Pearson to 0.06, confirming that learned functional representations--not graph topology--drive the gain. As a cell-type encoder, OCellus ranks first among fourteen foundation models in linear-probe accuracy at 95.1 percent across four benchmark datasets, and reaches 72.6 percent average across twenty-two evaluated biological tasks--a 57-percentage-point absolute gain over the strongest baseline configuration. As a language model, OCellus uniquely generates natural-language explanations of its predictions, a capability absent from all competing methods. Code, pre-trained model weights, the graph-neural-network module, and the agent system will be made available upon publication.