DeMixPert: Decomposed Response Modeling with Gaussian Mixtures for OOD Single-Cell Perturbation Prediction

Predicting transcriptome-wide responses to unseen genetic perturbations remains a major computational challenge because accurate prediction requires recovering both perturbation-specific transcriptional shifts and heterogeneous cellular responses. Existing methods often entangle deterministic response structure with stochastic population-level variation, causing dominant shared patterns to mask weaker perturbation-specific signals and impair distributional modeling. To address these challenges, we propose \textbf{DeMixPert}, an approach for Decomposed response Modeling with Gaussian Mixtures for Out-Of-Distribution (OOD) single-cell Perturbation prediction. DeMixPert decomposes perturbation-induced changes into a basal-state-dependent systematic response, a perturbation-specific response, and population-level variation. The systematic component is derived from the basal state encoded from control-cell expression, whereas the perturbation-specific component is inferred from pretrained target embeddings for unseen-target generalization. DeMixPert models population-level variation using a Gaussian prototype Invertible Network and adaptively combines reusable Gaussian prototypes according to the basal state and perturbation condition. The resulting mixture is mapped to a condition-specific variation distribution. Sampled variations are integrated with the systematic and perturbation-specific components, followed by joint decoding with the basal state to reconstruct perturbed-cell gene expression. Experimental results show that DeMixPert effectively captures heterogeneous single-cell perturbation responses and achieves superior performance across unseen-perturbation settings. The source code is made publicly available upon publication.

PertMind: Eliciting Emergent Biological Reasoning in LLM via Reinforcement Learning on Cellular Perturbation Data

Large language models can describe mechanisms, yet scalable post-training still depends on costly, manually curated biological reasoning traces. Here we show that cellular perturbation atlases can instead become reinforcement-learning environments, where measured gene responses provide computable rewards for biological reasoning. We introduce PertMind, which combines trusted-trajectory supervised initialization with gene-, pathway-, and format-level reinforcement signals. Trained only on forward perturbation-response prediction, PertMind improved response inference in unseen cellular contexts while retaining general language capabilities. It also transferred without task-specific post-training to reverse perturbation identification, double-perturbation reasoning, phenotypic-screen prioritization, and biological-process interpretation. PertMind further generated biological profiles that supported competitive gene, cell, and donor representations across multiscale downstream tasks. These results support the hypothesis that reinforcement on experimental endpoints can concentrate reusable biological strategies already accessible to pretrained models. More broadly, perturbation-derived reinforcement learning offers a scalable route for transforming expanding experimental atlases into training environments for general-purpose biological reasoning.

Control-Anchored Residual Flow Matching Conditioned on Gene Geometry for Virtual Cell Perturbation Modeling

A central task in virtual cell modeling is predicting single-cell transcriptional responses to unseen genetic perturbations and drug combinations, and biological networks provide valuable priors on gene relationships. Existing graph-based models commonly use the same network to structure gene representations and mediate intergene interactions, thereby implicitly treating stable associations as perturbation-response pathways. Gene Ontology and control-derived coexpression networks encode relatively stable relationships rather than intervention-specific response directions or magnitudes. We therefore propose GeneGeoFlow, which conditions a control-anchored residual flow on gene-wise geometry derived from biological networks to learn intervention-specific transcriptional responses. GeneGeoFlow derives multi-scale spectral coordinates from Gene Ontology and control-derived coexpression networks. A perturbation-conditioned, gene-wise gating module selects relevant structural scales and network sources, yielding intervention-specific gene geometry. The resulting geometry conditions a control-anchored residual flow without explicitly propagating target-derived signals along the graph. Condition-wise optimal transport couples unpaired control and perturbed populations for training, while a Delta-correlation objective aligns the predicted and observed condition-level expression-shift directions. GeneGeoFlow achieves Pearson Delta scores of 0.8979 on the Norman additive benchmark and 0.9088 on five held-out drug combinations in the fixed ComboSciPlex test split. These results support perturbation-conditioned gene geometry as an effective structural prior for intervention-specific response prediction, without conflating stable gene relationships with response propagation.

Scaling an Autoregressive Transformer for Single-Cell Generation

We study a self-supervised generation task for single-cell gene expression vectors: given a set of vectors from a cell type, we aim to generate additional gene expression vectors of that cell type. For this task we characterize both the biological fidelity of the generated gene expression vectors and the scaling behavior of the pretraining loss. The model is a causal transformer paired with a learned quantized VAE tokenizer, trained with a cross-entropy loss. To evaluate the model, we condition it on held-out gene expression vectors of a cell type and generate vectors of gene expression, comparing the resulting distribution over gene expression vectors to the ground truth distribution of that cell type. We study the scaling properties of the proposed architecture by varying the number of trained parameters and the amount of training data. To our knowledge, we find the first jointly-fit two-exponent scaling law and compute-optimal frontier for a single-cell foundation model. Finally, we discuss how this pretrained model could be finetuned for perturbation response prediction.

From Cellular Responses to Pharmacological Domains: Multimodal Zero-Shot Drug Representation Learning

Multimodal drug discovery enables drug representation learning beyond chemical structure by incorporating cellular responses such as gene expression and cell morphology. However, direct fusion and instance-level contrastive alignment may mix mechanism-related signals with modality-specific noise and incorrectly separate structurally dissimilar but biologically related compounds. This limitation can obscure transferable mechanism patterns required for predicting the properties of unseen compounds. We introduce PMRD, a pharmacological response domain-guided framework for multimodal zero-shot drug property prediction. PMRD separates mechanism-consistent factors from modality-specific information and constructs a consensus response domain across three modalities. Mechanism candidate augmentation identifies locally stable factors, while retrieval-geometry attribution dynamically reweights the alignment and augmentation objectives according to whether their updates preserve inter-drug discriminability.This feedback suppresses training signals that conflict with mechanism-discriminative retrieval. PMRD further combines complementary representations through reliability-aware multiview retrieval. Experiments on public datasets show improved zero-shot property prediction and more biologically coherent drug neighborhoods. Hard-negative analysis further indicates fewer conflicts between structurally dissimilar but response-related compounds. These results support PMRD as an effective framework for mechanism-aware multimodal drug representation learning.\footnote{The code will be released upon publication.}

M$^3$-Gen: Interpretable Multimodal Generation of Gene Expression Profiles Using Clinical and Imaging Data

Integrating heterogeneous biomedical data, including clinical metadata, histopathology images, and molecular profiles, is crucial for comprehensive disease understanding. However, gene expression data acquisition remains constrained by high costs and privacy concerns, limiting its use in multimodal research and AI-driven applications. We present MultiModal Molecular Generation (M$^3$-Gen), a novel framework for the generation of gene expression profiles by conditioning a Generative Adversarial Network on histopathology images and clinical metadata. M$^3$-Gen learns a unified latent representation from the clinical variables and the images, leveraging contrastive learning, and exploits the embeddings of the two modalities to guide a generative model in producing biologically coherent gene expression profiles. Evaluations on the TCGA dataset demonstrate that M$^3$-Gen generates realistic and functionally meaningful gene expression data. Importantly, by integrating multiple modalities in an attention-based mechanism, M$^3$-Gen provides intrinsic explainability: it allows the identification of which regions of the histopathology images most strongly influenced the generation of specific gene expression profiles, making the model's decisions interpretable by design.

A vision foundation model for single-cell biology via spatial gene cartography

Most single-cell foundation models are adapted from language models, representing each cell as a sequence of gene tokens. This discards the relationships among genes and often the magnitude of their expression. We present scVision, a vision foundation model that instead renders each cell as a continuous image. Using optimal transport, it places genes at fixed positions on a single shared, pan-tissue layout so that co-expressed genes become spatial neighbours, turning a transcriptome into an image in which gene programs appear as local texture. We pretrain a vision transformer by masked image modelling on 72 million human cells and use the frozen encoder with no fine-tuning. In zero-shot evaluations on six independent, held-out studies, scVision is the most accurate cell-type annotator and recovers gene programs without supervision, ahead of existing foundation models and classical baselines; on multi-study integration it matches the strongest token-based model while conserving the most biological structure, without ever seeing a batch label. Permuting the gene layout with the network fixed sharply lowers accuracy, more than removing the vision transformer itself, showing that biologically meaningful position, not the network, carries the signal. By preserving expression magnitude and gene relationships, scVision reframes single-cell representation learning as a vision problem, connecting it to the mature methods of computer vision.

Gene Expression-Informed Jointly Controlled Generative Modeling for Precision Molecular Design

Precision molecular design aims to discover personalized drug candidates through joint control of multiple conditions, such as biological relevance and molecular design strategies. Biological relevance reflects cellular functional states under disease or perturbation conditions, while molecular design strategies provide complementary guidance in terms of structural intentions and property optimization. In this study, we propose JoPMol, a jointly controlled precision molecular generative model that integrates biological states encoded by gene expression profiles with molecular structure information expressed in text, and chemical properties quantified by numerical values within a unified modeling framework. This formulation enables coordinated generation and optimization of candidate molecules under joint condition control. Experimental results show that JoPMol outperforms state-of-the-art methods across multiple evaluation metrics. Moreover, JoPMol demonstrates strong generalization ability in both transfer tasks and biologically grounded simulation scenarios, validating its effectiveness for precision molecular design. The source code is publicly available at https://github.com/hala-yh/JoPMol.

GRAFT: Biological Graph and Hypergraph Benchmarks for Linked Gene Expression and Phenotypic Trait Prediction in Arabidopsis thaliana

Understanding which genes control which traits in an organism remains one of the central challenges in biology. Despite significant advances in data collection technology, our ability to map genes to traits is still limited. This genome-to-phenome (G2P) challenge spans several problem domains, including plant breeding, and requires methods capable of reasoning over high-dimensional, heterogeneous, and biologically structured data. Current datasets and data repositories, however, are not well-equipped for this task. Current studies do not link gene expression and trait data, and most focus on very specific traits, limiting the breadth of possible correlations. To address this gap, we present the novel Gene-Graph Regression for Arabidopsis Functional Traits (GRAFT) dataset, a curated multi-modal dataset linking gene expression profiles with phenotypic trait measurements in Arabidopsis thaliana, a model organism in plant biology. GRAFT supports tasks such as phenotype prediction and interpretable graph learning. In addition, we benchmark conventional regression and explanatory baselines, including a biologically-informed hypergraph baseline, to validate gene-trait associations. To the best of our knowledge, this is the first dataset to provide multimodal gene information and heterogeneous trait or phenotype data for the same Arabidopsis thaliana specimens. With GRAFT, we aim to foster research to accurately understand the relationship between genotypes and phenotypes using gene information, higher-order gene pairings, and trait data from multiple sources.

Modeling Temporal scRNA-seq Data with Latent Gaussian Process and Optimal Transport

Single-cell RNA sequencing provides insights into gene expression at single-cell resolution, yet inferring temporal processes from these static snapshot measurements remains a fundamental challenge. Current approaches utilizing neural differential equations and flows are sensitive to overfitting and lack careful considerations of biological variability. In this work, we propose a generative framework that models population trends using a latent heteroscedastic Gaussian process (GP) approximated by Hilbert space methods. To address the absence of genuine cell trajectories, we leverage an optimal transport (OT) objective that aligns generated and observed population distributions. Our method explicitly captures biological heterogeneity by incorporating cell-specific latent time and cell type conditioning to disentangle temporal asynchrony and trajectories to different cell types. We demonstrate state-of-the-art performance on complex interpolation and extrapolation benchmarks and introduce a novel gradient-based strategy for inferring perturbation trajectories.