pharmaceutical research teams

Abstract: Molecular discovery requires navigating vast combinatorial search spaces while balancing competing biological objectives. AI agents can automate expert-defined molecular design protocols, but automation alone does not address how to optimize workflows for new tasks or improve their development through experience. Here we introduce MoLRSI, an AI agent that combines systematic optimization of workflows and model architectures with persistent cross-task memory to recursively improve its search policy for molecular discovery. Workflow performance, refinement outcomes, and execution feedback guide subsequent searches, allowing the agent to improve both its workflows and its strategy for developing them. We evaluate MoLRSI in two challenging molecular discovery settings that require balancing competing properties. In antibiotic discovery, MoLRSI developed a screening workflow balancing antibacterial activity, cytotoxicity and structural novelty, achieving an experimental hit rate of 15.9%, compared with 8.7% for a previous expert-led workflow using the same training data and screening library. In de novo peptide-MHC binder design, MoLRSI developed workflows that jointly consider target binding and specificity, producing eight experimentally validated hits against MART-1 and SARS-CoV-1 pMHCs with preferential binding over tested off-targets while Claude Science completely failed. These findings demonstrate how experience-guided workflow optimization can address competing discovery objectives while improving the search strategies used in subsequent campaigns.

Abstract: AI co-scientists have expanded the use of large language models for generating scientific hypotheses and guiding experimental investigation. Here we investigate whether temporal patterns in the semantic representations of complete biomedical conclusions can guide hypothesis generation. We introduce ForeSCITE, a framework that identifies thematic clusters of published conclusions, estimates a direction separating earlier from more recent findings within each cluster, and projects existing conclusion embeddings along these directions. An embedding language model trained to reconstruct conclusions decodes the projected coordinates into natural-language hypotheses. Across 407 clusters derived from approximately three million pre-cutoff conclusions, we identify temporal structure and illustrate its retention after decoding. In retrospective, time-sliced evaluations, ForeSCITE increases semantic coverage beyond the historical corpus, biomedical entity-pair novelty and post-cutoff pair re-observation relative to five prompt-based and retrieval-augmented baselines. Expert review of prioritized CAR-T hypotheses identified 37 candidates as both novel and biologically plausible, and expert justifications for five selected hypotheses illustrate their biological rationale and subsequent literature support where available. These findings support temporal guidance in semantic space as a scalable mechanism for proposing biomedical hypotheses for subsequent scientific evaluation.

Abstract: Despite recent advances, current AI systems remain highly susceptible to domain shifts, particularly in biomedical imaging, where images are usually acquired under substantially different experimental conditions. Although recent domain adaptation methods have made substantial progress, significant performance gaps under domain shift persist. To measure progress in this regard, we introduce BatchBench, a leaderboard that evaluates and compares the robustness of AI systems on biomedical images from unseen experimental batches and data sources. BatchBench is built on JUMP-CP, one of the largest publicly available biomedical imaging datasets. Generated using the Cell Painting assay, JUMP-CP exhibits pronounced batch effects and domain shifts, making it a challenging testbed for evaluating robustness to distributional changes.

Abstract: Machine learning models are increasingly used for automated feature extraction from weakly annotated bioimaging data, such as microscopy and cytomorphology images. Due to the sole dependency of automated feature extraction, existing methods yield inconsistent classification performance across weakly annotated datasets. Here, we propose a model-agnostic knowledge augmentation method that enables ML models to exploit domain knowledge beyond what automated feature extraction can capture. The proposed approach improves classification performance across seven ML architectures. When integrated with masked autoencoder-based self-supervised learning, our method achieves the strongest overall performance, improving precision by 2.9% over the next-best method on three in-house microscopy datasets and by an average of 6.8% across three public cytomorphology benchmarks. We perform nucleus-level classification based on mislocalization of TAR DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm, a phenotype linked to Amyotrophic Lateral Sclerosis (ALS), using three independent microscopy datasets of motor neurons derived from human induced pluripotent stem cells. Accurate quantification of this phenotype at scale remains challenging and may contribute to inconsistencies across studies. Application of the best-performing model to these microscopy datasets reveals biological interpretations related to ALS, including dose-dependent effects of the proteasomal stressor, MG132, and the oxidative stressor, sodium arsenite (SA), on TDP-43 mislocalization, variable pathology in motor neurons from sporadic and familial ALS donors, and a lack of protection of the pharmacological compounds, edaravone and niclosamide, against SA-induced TDP-43 mislocalization. Together, our pipeline enables in-vitro cellular image analysis to advance understanding of ALS-associated pathology and potential treatments.

Abstract: Drug discovery for neurological disease has traditionally centered on the molecules altered by disease. But the molecules that cause pathology are not necessarily the best points from which to reverse it. Here, we ask which otherwise unaltered molecular control points can be engaged to restore pathological neural circuits toward functional states. We present CircuitATLAS, a provenance-grounded systems-neuroscience knowledge graph and agentic framework for target discovery in circuitopathies. It structures literature-derived relationships across diseases, phenotypes, electrophysiology, circuits, brain regions, cell types and molecular effectors, while deliberately excluding direct disease-gene and disease-protein edges to reduce shortcut reasoning. The graph contains 3.83 million nodes and 7.66 million edges, including 5.31 million LLM-extracted relations, and incorporates structured datasets such as the Human Cell Atlas and new multimodal in vivo measurements. We then introduce an agentic workflow that reasons from measurable disease phenotypes through their circuit and cellular substrates to molecular interventions, therapeutic feasibility and clinical constraints. Finally, we introduce a human-governed in vivo lab-in-the-loop linking hypothesis generation to experimental iteration. Within this framework an agent nominated ATP1A3, the neuronal alpha3 Na+/K+-ATPase, as a control point on cortical excitability; interneuron-restricted expression of ATP1A3 abolished the beta- and gamma-band response to a focal 4-aminopyridine challenge in vivo, and the validated target was then carried into a structure-guided small-molecule campaign terminating in a defined assay to resolve the direction of modulation. CircuitATLAS thus provides a framework for discovering therapeutics based not only on what is molecularly disrupted in disease, but on what can be controlled to restore circuit function.

Abstract: Molecular optimization must improve target activity and satisfy developability constraints within limited evaluation budgets. Classical methods require tailored rules or training to incorporate chemical instructions and property feedback. Frozen language models can condition edits on this information, but need explicit constraint control and relevant experience. We therefore present PharmAgent, a constraint-aware molecular search method driven by adaptive external state. Its Lagrangian controller translates violations in accepted states into accumulated constraint pressure, keeping this history separate from current property measurements. Structure-indexed replay complements this feedback with relevant evaluated transitions that guide subsequent proposals. As a curriculum progressively activates constraints, candidates and the incumbent are compared under the same current objective, and the accepted state determines the next multiplier update. We derive an exact identity that characterizes how accepted-state violations accumulate in the controller's multipliers. Across five tasks with five independent runs, PharmAgent achieves a summed area under the target-score curves (AUC) of 3.9208 in target-only search, improving over MOLLEO by 37.3%. With online constraints, it achieves a property-adjusted AUC of 0.7076, improving over the strongest online baseline, ExLLM, by 53.8%. These results rank first among all evaluated methods in both target-only and constraint-aware search. The online comparison covers all five baseline frameworks. The full system leads every ablation variant in target quality, property-adjusted performance, and Pareto hypervolume. All five molecular cases reach feasible final states, documenting target gains and trade-offs.

Abstract: Animal models are widely used to study human biology and health interventions, yet translating findings from animal studies to humans remains challenging. Evidence across preclinical and clinical research informs experimental and translational decisions. Artificial Intelligence (AI) tools are increasingly reshaping how this evidence is searched, synthesized, and used, but it remains unclear how they should support the diverse stakeholders involved in assessing animal-to-human evidence. We conducted semi-structured interviews with 13 stakeholders to examine their evidence practices, challenges, and expectations for AI support. We found that stakeholders approach the same incomplete evidence base with different goals, expertise, and heuristics. Participants valued AI particularly for locating, screening, and extracting evidence, but were more cautious about automated interpretation and quality judgments. They emphasized transparency, source traceability, uncertainty communication, and human oversight. Based on these findings, we derive design implications for role-sensitive AI tools that support more systematic and transparent reasoning about animal-to-human translation.

Abstract: Scientific information-extraction systems often return a claim with an evidence string, which users must locate in the original PDF. This is challenging because the extracted evidence and PDF text layer are different representations: line wrapping, Unicode variants, superscripts, citation markers, and fragmented items alter text sequences and geometry. We present a source-preserving alignment framework: normalize text for robust matching while preserving provenance for accurate localization. It aligns evidence with normalized page text, maps matches back to source-character spans, and renders only their geometry. When exact alignment fails, line-break-aware token alignment recovers supported spans while excluding unmatched noise. Experiments on 1,020 chemistry papers show that the framework achieves a 92.6\% quote-level automatic localization rate, compared with 43.6\% for text search and 19.1\% for a precomputed bounding-box baseline. Component ablation confirms distinct contributions from normalization and approximate token alignment, while human verification assesses the visual correctness of returned highlights. Overall, these results demonstrate that reliable evidence verification requires robust matching and precise localization within a shared source-preserving alignment representation.

Abstract: Despite the promise of Large Language Models (LLMs) in computational chemistry, rigorous combinatorial chemistry problems remain difficult because they require quantitatively constrained molecular modification, candidate validation, and systematic revision after failed attempts. Existing tool-augmented chemical agents demonstrate useful planning and tool use, but they rarely provide a unified loop for property-driven molecular optimization and workflow-level composition. To bridge this gap, we propose Tool-Grounded Multi-Agent Reasoning for Compositional Chemical Problem Solving (TMCS), a step-by-step multi-agent framework that formalizes chemical problem solving as an interpretable, tool-augmented workflow. At the task level, specialized agents leverage external tools, few-shot trajectory memory, and structured reflection to iteratively refine solutions. At the workflow level, TMCS chains generation, understanding, editing, description, and optimization into a closed-loop pipeline. Evaluations across multiple chemical tasks demonstrate that TMCS consistently enhances chemical reasoning across both open- and closed-source base models, achieving state-of-the-art performance.

Abstract: Spatial Transcriptomics (ST) has transformed biomedical research by enabling the spatial mapping of gene expression across tissue sections. However, high operational costs, specialized equipment requirements, and sensitivity to experimental noise limit the accessibility and scalability of ST. Recent computer vision approaches aim to overcome these limitations by predicting spatial gene expression directly from histopathology images. While effective, current approaches often suffer from gene expression over-smoothing and overly uniform predictions across tissue regions, suggesting that further progress depends on learning representations that reflect the hierarchical and asymmetric structure of gene regulation and tissue morphology. To address these issues, we propose Hyperbolic Contrastive Learning with Entailment for Spatial Transcriptomics (HyCLoST), a hyperbolic contrastive learning model that captures the intrinsic hierarchical relationships within ST data. By leveraging hyperbolic geometry and a gene-to-image entailment loss, HyCLoST learns structured, biologically grounded representations that improve gene expression prediction accuracy, achieving a 6% reduction in MSE and an 8% increase in PCC across 26 ST datasets, over previous methods. Our source code is publicly available at https://github.com/BCV-Uniandes/HyCLoST

Abstract: Longitudinal single cell atlases now capture matched pre treatment and post treatment states from responders and non responders, presenting an opportunity to mechanistically explain why two patients on the same drug diverge. We introduce scDEFT (single cell Drug EFfect Transducer), which treats a drug as a conditioning operator on cell representations, enabling prediction and explanation. In scDEFT, feature wise linear modulation produces drug conditioned cell latents, learned under abundant per cell supervision and then frozen. Two independent heads aggregate those latents over shared transcriptional neighborhoods to predict drug induced state change and responder status. A backward stage ranks the latent dimensions by how strongly they separate responders from non responders and maps them to genes under a cell composition control. On a harmonized inflammatory bowel disease atlas of 1.16 million cells, three cohorts and two drug classes, scDEFT predicts state change at 45% of the baseline to reproducibility ceiling headroom and stratifies responders before treatment at AUROC 0.70, where standard predictors remain at chance. These predictions and the drivers behind them support target and co target nomination, patient stratification, and counterfactual prediction of unseen drug cohort effects.

Abstract: Scientific ideation is the capacity to formulate novel and testable hypotheses from scientific evidence, and autonomous AI scientists depend on it. Existing evaluations largely assess it by asking models to generate ideas from a static, curated set of reference papers. That passive setup departs from the retrieval-and-reasoning workflow of modern AI scientists, and it becomes less discriminative as models improve. We introduce AgentIdeaBench, a multidisciplinary benchmark that evaluates scientific ideation under two matched settings, static observation and active exploration. We report matched Static-Active evaluations for 33 LLMs across 40 densely scored subfields spanning five disciplines, using a multidimensional, literature-verified scoring framework whose critics assess originality against retrieved prior art. Active exploration reveals considerably more capability headroom, and that headroom is unevenly distributed across models. Performance scales about twice as fast as under static observation, and the exploration gain is capability-gated, favoring the strongest models over the weakest. The gain reflects better grounding, improving feasibility, clarity, and specificity while leaving measured originality unchanged under our critics. We further explore Scientific World Modeling, a generation-time loop that refines a draft hypothesis through structured thought experiments. It benefits mid-capability models, and its impact diminishes among frontier models that appear to have internalized such reasoning patterns already. AgentIdeaBench gives future work on scientific ideation a measurement basis suited to the agent era.