CellDuality: Unlocking Biological Reasoning in LLMs with Self-Supervised RLVR.

Abstract

Developing generalist large language models (LLMs) capable of complex biological reasoning is a central challenge in computational biology. While existing LLMs excel at predictive tasks like cell type annotation and logically-constrained problems, enabling open-ended and mechanistic reasoning remains a challenge. A promising direction is Reinforcement Learning from Verifiable Rewards (RLVR), which has been shown to significantly enhance complex reasoning in general domains like mathematics and code synthesis. However, its application in biology is hindered, as most biological outcomes are non-verifiable. For example, verifying a generated gene sequence is usually infeasible. In this paper, we introduce CellDuality, a self-supervised framework that enables LLM agents for robust reasoning in single-cell biology. Our framework is built on the principle of complementary task duality, a self-verification process that leverages a bidirectional reasoning loop. First, the model performs a forward reasoning task by predicting a biological outcome (e.g., a cell's response to a drug). Then, in a complementary inverse task, it must reason backward from its own prediction to reconstruct the initial conditions (e.g., the original drug perturbation). The fidelity of this reconstruction serves as an intrinsic reward signal, creating a feedback loop that enforces logical and biological consistency. We use these intrinsic rewards to align the base LLM via reinforcement learning, without requiring ground-truth verification labels. We demonstrate that CellDuality achieves state-of-the-art performance and provides coherent biological explanations across a diverse suite of single-cell reasoning tasks. Critically, on the challenging out-of-distribution perturbation prediction benchmark, our self-supervised approach significantly outperforms the standard fine-tuning baseline and narrows the performance gap to a supervised RLVR baseline. Our work showcases a new path toward scalable training of biological foundation models.