Deep learning techniques have driven significant progress in various analytical tasks within 3D genomics in computational biology. However, a holistic understanding of 3D genomics knowledge remains underexplored. Here, we propose MIX-HIC, the first multimodal foundation model of 3D genome that integrates both Hi-C contact maps and epigenomic tracks, which obtains unified and comprehensive semantics.

We introduce a comprehensive framework for modeling single cell transcriptomic responses to perturbations, aimed at standardizing benchmarking in this rapidly evolving field. Our approach includes a modular and user-friendly model development and evaluation platform, a collection of diverse perturbational datasets, and a set of metrics designed to fairly compare models and dissect their performance. Through extensive evaluation of both published and baseline models across diverse datasets, we highlight the limitations of widely used models, such as mode collapse. We also demonstrate the importance of rank metrics which complement traditional model fit measures, such as RMSE, for validating model effectiveness. Notably, our results show that while no single model architecture clearly outperforms others, simpler architectures are generally competitive and scale well with larger datasets. Overall, this benchmarking exercise sets new standards for model evaluation, supports robust model development, and furthers the use of these models to simulate genetic and chemical screens for therapeutic discovery.

Predicting how different interventions will causally affect a specific individual is important in a variety of domains such as personalized medicine, public policy, and online marketing. There are a large number of methods to predict the effect of an existing intervention based on historical data from individuals who received it. 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. Here, we consider zero-shot causal learning: predicting the personalized effects of a novel intervention. We propose CaML, a causal meta-learning framework which formulates the personalized prediction of each intervention's effect as a task. CaML trains a single meta-model across thousands of tasks, each constructed by sampling an intervention, its recipients, and its nonrecipients. By leveraging both intervention information (e.g., a drug's attributes) and individual features (e.g., a patient's history), CaML is able to predict the personalized effects of novel interventions that do not exist at the time of training. Experimental results on real world datasets in large-scale medical claims and cell-line perturbations demonstrate the effectiveness of our approach. Most strikingly, CaML's zero-shot predictions outperform even strong baselines trained directly on data from the test interventions.

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.