JUMP-lite: Compact, reproducible benchmarking of cell representations

Microscopy images contain rich information about how cells respond to perturbations, making them essential to applications like drug screening. To quantify images, researchers often use representation extraction methods, and recent years have seen a proliferation of deep learning methods. While measuring the quality of these representations is essential, evaluation remains fragmented, with each proposed model evaluated on different tasks and datasets, using custom pipelines and metrics, making it difficult to fairly compare models. Here, we introduce MorphoHELM, a comprehensive open benchmark for evaluating feature extraction methods for Cell Painting, the most widely-used morphological profiling assay. MorphoHELM consolidates evaluation standards in the field, extends and corrects them to be more robust, and evaluates on the widest range of methods to date. A defining feature of the benchmark is that each task is evaluated at different degrees of batch effects (or technical noise), directly quantifying how the ability of methods to detect biological signal degrades as noise increases. Together, these properties enable MorphoHELM to detect trade-offs between methods, and we demonstrate that models that excel at certain kinds of biological signal are weaker at others. We show that no existing model outperforms classic computer vision analytic strategies across all settings, which remain the strongest general use-case representations. All datasets, code, and evaluation tools are publicly available at https://github.com/microsoft/MorphoHELM.

Microscopy-based phenotypic profiling is scalable for drug discovery but lacks the mechanistic depth of transcriptomics, which remains costly and scarce. Existing multimodal approaches either use images to support other modalities or naively align representations by sample identity, ignoring cell-type and dose variations in weakly paired data-limiting generalization to unseen interventions. In this paper, we introduce an intervention-aware distillation framework that leverages perturbational transcriptomics to guide image representation learning. A transcriptome-conditioned teacher integrates gene expression and intervention metadata to produce soft distributions over a chemistry-aware codebook organized by drug similarity. The teacher employs a fine-tuned single-cell foundation model to encode cell-type context and disentangle dose effects. An image-only student learns to predict these distributions from microscopy alone, distilling mechanistic knowledge while operating independently at test time. This design emphasizes intervention semantics rather than identity alignment and explicitly handles dose and cell-type mismatches. We provide theoretical guarantees showing that transcriptomic guidance tightens the risk bound for image-based prediction. On Cell Painting and RxRx datasets paired with L1000, our method significantly improves one-shot transfer to unseen interventions and drug-target gene discovery compared to self-supervised and alignment baselines.

Vision encoders for Cell Painting are typically ranked by a single evaluation, commonly replicate mean average precision (mAP). We introduce CP-BG-Bench, a paired-view evaluation framework that holds the central cell fixed across four matched views (raw crop C, segmented S, and density-augmented variants CD and SD), ablating or augmenting surrounding pixels as a controlled intervention. Instantiating the framework on three datasets (JUMP-CP, RxRx1, RxRx3-core) and three encoders (DINOv3 ViT-B/16, OpenPhenom, SubCell) under four community-standard protocols (replicate mAP, scIB batch integration, CellProfiler feature prediction, cross-batch perturbation recall), we find that the four protocols rank the same encoders systematically differently, with disagreements decomposing along three axes: cell versus background, morphology versus context, and within-study versus across-batch. The largest effect: on RxRx3-core, SubCell with segmented inputs retains 94% of crop replicate mAP but only 32% of crop R@10, so the within-study signal preserved under segmentation is largely non-transferable; density augmentation recovers 84% of the within-study C-to-S gap but only 8% of the cross-batch gap. Segmented views predict CellProfiler features as well as or better than crops on two of three datasets, inverting the replicate-mAP ranking, and the C-to-S gap varies by an order of magnitude across datasets while remaining similar across encoders, indicating that background-driven gain is set by experimental design rather than by the encoder. Single-metric ranking of Cell Painting encoders is therefore sensitive to the protocol used, and protocol disagreements are interpretable as projections onto the three axes the paired-view design exposes. We will release the paired-view datasets, reconstruction pipelines, 36 trained checkpoints, aggregated embeddings, and the full evaluation suite.