Glioblastoma (GBM) remains the most aggressive tumor, urgently requiring novel therapeutic strategies. Here, we present a dry-to-wet framework combining generative modeling and experimental validation to optimize peptides targeting ATP5A, a potential peptide-binding protein for GBM. Our framework introduces the first lead-conditioned generative model, which focuses exploration on geometrically relevant regions around lead peptides and mitigates the combinatorial complexity of de novo methods. Specifically, we propose POTFlow, a \underline{P}rior and \underline{O}ptimal \underline{T}ransport-based \underline{Flow}-matching model for peptide optimization. POTFlow employs secondary structure information (e.g., helix, sheet, loop) as geometric constraints, which are further refined by optimal transport to produce shorter flow paths. With this design, our method achieves state-of-the-art performance compared with five popular approaches. When applied to GBM, our method generates peptides that selectively inhibit cell viability and significantly prolong survival in a patient-derived xenograft (PDX) model. As the first lead peptide-conditioned flow matching model, POTFlow holds strong potential as a generalizable framework for therapeutic peptide design.

Virtual cell modeling aims to predict cellular responses to perturbations. Existing virtual cell models rely heavily on large-scale single-cell datasets, learning explicit mappings between gene expression and perturbations. Although recent models attempt to incorporate multi-source biological information, their generalization remains constrained by data quality, coverage, and batch effects. More critically, these models often function as black boxes, offering predictions without interpretability or consistency with biological principles, which undermines their credibility in scientific research. To address these challenges, we present VCWorld, a cell-level white-box simulator that integrates structured biological knowledge with the iterative reasoning capabilities of large language models to instantiate a biological world model. VCWorld operates in a data-efficient manner to reproduce perturbation-induced signaling cascades and generates interpretable, stepwise predictions alongside explicit mechanistic hypotheses. In drug perturbation benchmarks, VCWorld achieves state-of-the-art predictive performance, and the inferred mechanistic pathways are consistent with publicly available biological evidence.

However, designing adequate and insightful models for such data is difficult because the response of a cell to perturbations essentially depends on its biological context (e.g., genetic background or cell type). For example, while discovering therapeutic targets, one may want to enrich for drugs that specifically target a certain cell type. This challenge emphasizes the need for methods that explicitly take into account potential interactions between drugs and contexts. Towards this goal, we propose a novel Factorized Causal Representation (FCR) learning method that reveals causal structure in single-cell perturbation data from several cell lines.

Model-based optimization (MBO) has emerged as an effective method to design biological sequences in an automated manner, and has recently been used in promoter design methods.

Agentic AI "scientists" now use language models to search the literature, run analyses, and generate hypotheses. We evaluate KOSMOS, an autonomous AI scientist, on three problems in radiation biology using simple random-gene null benchmarks. Hypothesis 1: baseline DNA damage response (DDR) capacity across cell lines predicts the p53 transcriptional response after irradiation (GSE30240). Hypothesis 2: baseline expression of OGT and CDO1 predicts the strength of repressed and induced radiation-response modules in breast cancer cells (GSE59732). Hypothesis 3: a 12-gene expression signature predicts biochemical recurrence-free survival after prostate radiotherapy plus androgen deprivation therapy (GSE116918). The DDR-p53 hypothesis was not supported: DDR score and p53 response were weakly negatively correlated (Spearman rho = -0.40, p = 0.76), indistinguishable from random five-gene scores. OGT showed only a weak association (r = 0.23, p = 0.34), whereas CDO1 was a clear outlier (r = 0.70, empirical p = 0.0039). The 12-gene signature achieved a concordance index of 0.61 (p = 0.017) but a non-unique effect size. Overall, KOSMOS produced one well-supported discovery, one plausible but uncertain result, and one false hypothesis, illustrating that AI scientists can generate useful ideas but require rigorous auditing against appropriate null models.

Better generalisation reduces the need for extensive and costly screens at single-cell resolution.

However, there are many settings where the number of channels may vary, such as microscopy images where the number of channels changes depending on instruments and experimental goals.

However, in many settings it is important to predict the effects of novel interventions (e.g., a newly invented drug), which these methods do not address.

Drug synergy prediction is a critical task in the development of effective combination therapies for complex diseases, including cancer . Although existing methods have shown promising results, they often operate as black-box predictors that rely predominantly on statistical correlations between drug characteristics and results. T o address this limitation, we propose CausalDDS, a novel framework that disentangles drug molecules into causal and spurious substructures, utilizing the causal substructure representations for predicting drug synergy. By focusing on causal sub-structures, CausalDDS effectively mitigates the impact of redundant features introduced by spurious substructures, enhancing the accuracy and interpretability of the model. In addition, CausalDDS employs a conditional intervention mechanism, where interventions are conditioned on paired molecular structures, and introduces a novel optimization objective guided by the principles of sufficiency and independence. Extensive experiments demonstrate that our method outperforms baseline models, particularly in cold start and out-of-distribution settings. Besides, CausalDDS effectively identifies key substructures underlying drug synergy, providing clear insights into how drug combinations work at the molecular level. These results underscore the potential of CausalDDS as a practical tool for predicting drug synergy and facilitating drug discovery.