arXiv subjects

Emma Lundberg

Publications and source records attributed to Emma Lundberg.

15 recordsLinked to original sources

arXiv2026

PerturbCellRL: Verifier-Guided Reinforcement Learning for Single-Cell Perturbation Prediction

Single-cell perturbation models can reduce costly wet-lab screening by predicting how cells respond transcriptionally to interventions. While recent generative models improve population-level prediction, individual generated cells are not explicitly checked for biological consistency. We introduce PerturbCellRL, a reinforcement learning (RL) framework that post-trains a pretrained single-cell transcriptomic generator using a suite of cell-level verifiers as rewards. These verifiers define four rewards: Pearson top-k similarity, RMSE top-k proximity, DE Spearman, and Pathway activity. The Pathway activity verifier rewards cells whose pathway responses match known perturbation biology. We evaluate PerturbCellRL on multiple genetic and chemical perturbation benchmarks. Across these benchmarks, PerturbCellRL improves over the pretrained flow-matching generator on reward-aligned evaluation metrics and a held-out evaluation metric. Moreover, PerturbCellRL remains competitive with state-of-the-art methods on population-level metrics. Together, these results frame trustworthy single-cell prediction as verifier-guided generative alignment, moving beyond matching expression distributions toward predictions whose single-cell perturbation effects are explicitly checked for biological consistency.

cs.LG↗

arXiv2026

Uncertainty-Aware Distribution-to-Distribution Flow Matching for Scientific Imaging

Distribution-to-distribution generative models support scientific imaging tasks ranging from modeling cellular perturbation responses to translating medical images across conditions. Trustworthy generation requires reliability, or generalization across labs, devices, and experimental conditions, and accountability, or detecting out-of-distribution cases where predictions may be unreliable. We leverage Stochastic Flow Matching (SFM), a marginal-preserving stochastic extension of flow matching for improved generalization under distribution shift. SFM augments deterministic flows with a diffusion term together with a learned score-based drift correction, retaining the learned transport marginals while modeling conditional variability. Building on this SFM framework, we introduce Bayesian Stochastic Flow Matching (BSFM) as a companion uncertainty quantification mechanism and develop AVUQ (Antithetic Variance-reduction Uncertainty Quantification) to approximately estimate epistemic and aleatoric uncertainty via sample-efficient antithetic sampling with approximate posterior inference. We further use AVUQ to yield anomaly scores for unreliable generation detection. Experiments on cellular imaging (BBBC021, JUMP) and brain fMRI (Theory of Mind) across diverse unseen scenarios show that SFM improves generalization while AVUQ provides effective uncertainty-based anomaly scores under practical sampling budgets.

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arXiv2026

CellFluxRL: Biologically-Constrained Virtual Cell Modeling via Reinforcement Learning

Building virtual cells with generative models to simulate cellular behavior in silico is emerging as a promising paradigm for accelerating drug discovery. However, prior image-based generative approaches can produce implausible cell images that violate basic physical and biological constraints. To address this, we propose to post-train virtual cell models with reinforcement learning (RL), leveraging biologically meaningful evaluators as reward functions. We design seven rewards spanning three categories-biological function, structural validity, and morphological correctness-and optimize the state-of-the-art CellFlux model to yield CellFluxRL. CellFluxRL consistently improves over CellFlux across all rewards, with further performance boosts from test-time scaling. Overall, our results present a virtual cell modeling framework that enforces physically-based constraints through RL, advancing beyond "visually realistic" generations towards "biologically meaningful" ones.

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arXiv2026

iSight: Towards expert-AI co-assessment for improved immunohistochemistry staining interpretation

Immunohistochemistry (IHC) provides information on protein expression in tissue sections and is commonly used to support pathology diagnosis and disease triage. While AI models for H\&E-stained slides show promise, their applicability to IHC is limited due to domain-specific variations. Here we introduce HPA10M, a dataset that contains 10,495,672 IHC images from the Human Protein Atlas with comprehensive metadata included, and encompasses 45 normal tissue types and 20 major cancer types. Based on HPA10M, we trained iSight, a multi-task learning framework for automated IHC staining assessment. iSight combines visual features from whole-slide images with tissue metadata through a token-level attention mechanism, simultaneously predicting staining intensity, location, quantity, tissue type, and malignancy status. On held-out data, iSight achieved 85.5\% accuracy for location, 76.6\% for intensity, and 75.7\% for quantity, outperforming fine-tuned foundation models (PLIP, CONCH) by 2.5--10.2\%. In addition, iSight demonstrates well-calibrated predictions with expected calibration errors of 0.0150-0.0408. Furthermore, in a user study with eight pathologists evaluating 200 images from two datasets, iSight outperformed initial pathologist assessments on the held-out HPA dataset (79\% vs 68\% for location, 70\% vs 57\% for intensity, 68\% vs 52\% for quantity). Inter-pathologist agreement also improved after AI assistance in both held-out HPA (Cohen's $\kappa$ increased from 0.63 to 0.70) and Stanford TMAD datasets (from 0.74 to 0.76), suggesting expert--AI co-assessment can improve IHC interpretation. This work establishes a foundation for AI systems that can improve IHC diagnostic accuracy and highlights the potential for integrating iSight into clinical workflows to enhance the consistency and reliability of IHC assessment.

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arXiv2026

PaperSearchQA: Learning to Search and Reason over Scientific Papers with RLVR

Search agents are language models (LMs) that reason and search knowledge bases (or the web) to answer questions; recent methods supervise only the final answer accuracy using reinforcement learning with verifiable rewards (RLVR). Most RLVR search agents tackle general-domain QA, which limits their relevance to technical AI systems in science, engineering, and medicine. In this work we propose training agents to search and reason over scientific papers -- this tests technical question-answering, it is directly relevant to real scientists, and the capabilities will be crucial to future AI Scientist systems. Concretely, we release a search corpus of 16 million biomedical paper abstracts and construct a challenging factoid QA dataset called PaperSearchQA with 60k samples answerable from the corpus, along with benchmarks. We train search agents in this environment to outperform non-RL retrieval baselines; we also perform further quantitative analysis and observe interesting agent behaviors like planning, reasoning, and self-verification. Our corpus, datasets, and benchmarks are usable with the popular Search-R1 codebase for RLVR training and released on https://huggingface.co/collections/jmhb/papersearchqa. Finally, our data creation methods are scalable and easily extendable to other scientific domains.

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arXiv2025

A path towards AI-scale, interoperable biological data

Biology is at the precipice of a new era where AI accelerates and amplifies the ability to study how cells operate, organize, and work as systems, revealing why disease happens and how to correct it. Organizations globally are prioritizing AI to accelerate basic research, drug discovery, personalized medicine, and synthetic biology. However, despite these opportunities, scientific data have proven a bottleneck, and progress has been slow and fragmented. Unless the scientific community takes a technology-led, community-focused approach to scaling and harnessing data, we will fail to capture this opportunity to drive new insights and biological discovery. The data bottleneck presents a unique paradox. It is increasingly simple to generate huge data volumes, thanks to expanding imaging datasets and plummeting sequencing costs, but scientists lack standards and tooling for large biological datasets, preventing integration into a multimodal foundational dataset that unlocks generalizable models of cellular and tissue function. This contradiction highlights two interrelated problems: abundant data that's difficult to manage, and a lack of data resources with necessary quality and utility to realize AI's potential in biology. Science must forge a collective approach enabling distributed contributions to combine into cohesive, powerful datasets transcending individual purposes. Here, we present a technological and data generation roadmap for scaling scientific impact. We outline AI's opportunity, mechanisms to scale data generation, the need for multi-modal measurements, and means to pool resources, standardize approaches, and collectively build the foundation enabling AI's full potential in biological discovery.

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arXiv2025

Benchmarking and Evaluation of AI Models in Biology: Outcomes and Recommendations from the CZI Virtual Cells Workshop

Artificial intelligence holds immense promise for transforming biology, yet a lack of standardized, cross domain, benchmarks undermines our ability to build robust, trustworthy models. Here, we present insights from a recent workshop that convened machine learning and computational biology experts across imaging, transcriptomics, proteomics, and genomics to tackle this gap. We identify major technical and systemic bottlenecks such as data heterogeneity and noise, reproducibility challenges, biases, and the fragmented ecosystem of publicly available resources and propose a set of recommendations for building benchmarking frameworks that can efficiently compare ML models of biological systems across tasks and data modalities. By promoting high quality data curation, standardized tooling, comprehensive evaluation metrics, and open, collaborative platforms, we aim to accelerate the development of robust benchmarks for AI driven Virtual Cells. These benchmarks are crucial for ensuring rigor, reproducibility, and biological relevance, and will ultimately advance the field toward integrated models that drive new discoveries, therapeutic insights, and a deeper understanding of cellular systems.

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arXiv2025

MicroVQA: A Multimodal Reasoning Benchmark for Microscopy-Based Scientific Research

Scientific research demands sophisticated reasoning over multimodal data, a challenge especially prevalent in biology. Despite recent advances in multimodal large language models (MLLMs) for AI-assisted research, existing multimodal reasoning benchmarks only target up to college-level difficulty, while research-level benchmarks emphasize lower-level perception, falling short of the complex multimodal reasoning needed for scientific discovery. To bridge this gap, we introduce MicroVQA, a visual-question answering (VQA) benchmark designed to assess three reasoning capabilities vital in research workflows: expert image understanding, hypothesis generation, and experiment proposal. MicroVQA consists of 1,042 multiple-choice questions (MCQs) curated by biology experts across diverse microscopy modalities, ensuring VQA samples represent real scientific practice. In constructing the benchmark, we find that standard MCQ generation methods induce language shortcuts, motivating a new two-stage pipeline: an optimized LLM prompt structures question-answer pairs into MCQs; then, an agent-based `RefineBot' updates them to remove shortcuts. Benchmarking on state-of-the-art MLLMs reveal a peak performance of 53\%; models with smaller LLMs only slightly underperform top models, suggesting that language-based reasoning is less challenging than multimodal reasoning; and tuning with scientific articles enhances performance. Expert analysis of chain-of-thought responses shows that perception errors are the most frequent, followed by knowledge errors and then overgeneralization errors. These insights highlight the challenges in multimodal scientific reasoning, showing MicroVQA is a valuable resource advancing AI-driven biomedical research. MicroVQA is available at https://huggingface.co/datasets/jmhb/microvqa, and project page at https://jmhb0.github.io/microvqa.

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arXiv2025

CellFlux: Simulating Cellular Morphology Changes via Flow Matching

Building a virtual cell capable of accurately simulating cellular behaviors in silico has long been a dream in computational biology. We introduce CellFlux, an image-generative model that simulates cellular morphology changes induced by chemical and genetic perturbations using flow matching. Unlike prior methods, CellFlux models distribution-wise transformations from unperturbed to perturbed cell states, effectively distinguishing actual perturbation effects from experimental artifacts such as batch effects -- a major challenge in biological data. Evaluated on chemical (BBBC021), genetic (RxRx1), and combined perturbation (JUMP) datasets, CellFlux generates biologically meaningful cell images that faithfully capture perturbation-specific morphological changes, achieving a 35% improvement in FID scores and a 12% increase in mode-of-action prediction accuracy over existing methods. Additionally, CellFlux enables continuous interpolation between cellular states, providing a potential tool for studying perturbation dynamics. These capabilities mark a significant step toward realizing virtual cell modeling for biomedical research. Project page: https://yuhui-zh15.github.io/CellFlux/.

q-bio.QM↗

arXiv2024

How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities

The cell is arguably the most fundamental unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells. Here we propose a vision of leveraging advances in AI to construct virtual cells, high-fidelity simulations of cells and cellular systems under different conditions that are directly learned from biological data across measurements and scales. We discuss desired capabilities of such AI Virtual Cells, including generating universal representations of biological entities across scales, and facilitating interpretable in silico experiments to predict and understand their behavior using virtual instruments. We further address the challenges, opportunities and requirements to realize this vision including data needs, evaluation strategies, and community standards and engagement to ensure biological accuracy and broad utility. We envision a future where AI Virtual Cells help identify new drug targets, predict cellular responses to perturbations, as well as scale hypothesis exploration. With open science collaborations across the biomedical ecosystem that includes academia, philanthropy, and the biopharma and AI industries, a comprehensive predictive understanding of cell mechanisms and interactions has come into reach.

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arXiv2024

Harmonizing the Generation and Pre-publication Stewardship of FAIR Image Data

Alongside molecular insights into genes and proteins, biological imaging holds great promise for deepening scientific understanding of complex cellular systems and advancing predictive, personalized therapies for human health. To realize this potential, quality-assured image data must be shared globally across laboratories to enable comparison, pooling, and reanalysis-unlocking value far beyond the original purpose of data collection. Two broad sets of requirements are essential to enable image data sharing in the life sciences. The companion article Enabling Global Image Data Sharing in the Life Sciences outlines the need to develop cyberinfrastructure for sharing bioimage data. In this manuscript, we detail a broad set of requirements, which involves collecting, managing, presenting, and propagating contextual information essential to assess the quality, understand the content, interpret the scientific implications, and reuse bioimage data in the context of the experimental details. We start by providing an overview of the main lessons learned to date through international community activities, which have recently made considerable progress toward generating community standard practices for imaging Quality Control (QC) and metadata. We then provide a clear set of recommendations for amplifying this work. The driving goal is to address remaining challenges and democratize access to everyday practices and tools for a spectrum of biomedical researchers, regardless of their expertise, access to resources, and geographical location.

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arXiv2024

Enabling Global Image Data Sharing in the Life Sciences

Coordinated collaboration is essential to realize the added value of and infrastructure requirements for global image data sharing in the life sciences. In this White Paper, we take a first step at presenting some of the most common use cases as well as critical/emerging use cases of (including the use of artificial intelligence for) biological and medical image data, which would benefit tremendously from better frameworks for sharing (including technical, resourcing, legal, and ethical aspects). In the second half of this paper, we paint an ideal world scenario for how global image data sharing could work and benefit all life sciences and beyond. As this is still a long way off, we conclude by suggesting several concrete measures directed toward our institutions, existing imaging communities and data initiatives, and national funders, as well as publishers. Our vision is that within the next ten years, most researchers in the world will be able to make their datasets openly available and use quality image data of interest to them for their research and benefit. This paper is published in parallel with a companion White Paper entitled Harmonizing the Generation and Pre-publication Stewardship of FAIR Image Data, which addresses challenges and opportunities related to producing well-documented and high-quality image data that is ready to be shared. The driving goal is to address remaining challenges and democratize access to everyday practices and tools for a spectrum of biomedical researchers, regardless of their expertise, access to resources, and geographical location.

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arXiv2021

New views of old proteins: clarifying the enigmatic proteome

All human diseases involve proteins, yet our current tools to characterize and quantify them are limited. To better elucidate proteins across space, time, and molecular composition, we provide provocative projections for technologies to meet the challenges that protein biology presents. With a broad perspective, we discuss grand opportunities to transition the science of proteomics into a more propulsive enterprise. Extrapolating recent trends, we offer potential futures for a next generation of disruptive approaches to define, quantify and visualize the multiple dimensions of the proteome, thereby transforming our understanding and interactions with human disease in the coming decade.

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arXiv2021

Spatial mapping of protein composition and tissue organization: a primer for multiplexed antibody-based imaging

Tissues and organs are composed of distinct cell types that must operate in concert to perform physiological functions. Efforts to create high-dimensional biomarker catalogs of these cells are largely based on transcriptomic single-cell approaches that lack the spatial context required to understand critical cellular communication and correlated structural organization. To probe in situ biology with sufficient coverage depth, several multiplexed protein imaging methods have recently been developed. Though these antibody-based technologies differ in strategy and mode of immunolabeling and detection tags, they commonly utilize antibodies directed against protein biomarkers to provide detailed spatial and functional maps of complex tissues. As these promising antibody-based multiplexing approaches become more widely adopted, new frameworks and considerations are critical for training future users, generating molecular tools, validating antibody panels, and harmonizing datasets. In this perspective, we provide essential resources and key considerations for obtaining robust and reproducible multiplexed antibody-based imaging data compiling specialized knowledge from domain experts and technology developers.

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arXiv2019

ImJoy: an open-source computational platform for the deep learning era

Deep learning methods have shown extraordinary potential for analyzing very diverse biomedical data, but their dissemination beyond developers is hindered by important computational hurdles. We introduce ImJoy (https://imjoy.io/), a flexible and open-source browser-based platform designed to facilitate widespread reuse of deep learning solutions in biomedical research. We highlight ImJoy's main features and illustrate its functionalities with deep learning plugins for mobile and interactive image analysis and genomics.

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