Emmanuel Noutahi

Charles Jones, Emmanuel Noutahi, Jason Hartford et al.

Flow-matching generative models are increasingly used to simulate cell responses to biological perturbations. However, the design space for building such models is large and underexplored. We systematically analyse the design space of flow matching models for cell-microscopy images, finding that many popular techniques are unnecessary and can even hurt performance. We develop a simple, stable, and scalable recipe which we use to train our foundation model. We scale our model to two orders of magnitude larger than prior methods, achieving a two-fold FID and ten-fold KID improvement over prior methods. We then fine-tune our model with pre-trained molecular embeddings to achieve state-of-the-art performance simulating responses to unseen molecules. Code is available at https://github.com/valence-labs/microscopy-flow-matching

Emmanuel Noutahi, Cristian Gabellini, Michael Craig et al.

Traditional molecular string representations, such as SMILES, often pose challenges for AI-driven molecular design due to their non-sequential depiction of molecular substructures. To address this issue, we introduce Sequential Attachment-based Fragment Embedding (SAFE), a novel line notation for chemical structures. SAFE reimagines SMILES strings as an unordered sequence of interconnected fragment blocks while maintaining compatibility with existing SMILES parsers. It streamlines complex generative tasks, including scaffold decoration, fragment linking, polymer generation, and scaffold hopping, while facilitating autoregressive generation for fragment-constrained design, thereby eliminating the need for intricate decoding or graph-based models. We demonstrate the effectiveness of SAFE by training an 87-million-parameter GPT2-like model on a dataset containing 1.1 billion SAFE representations. Through targeted experimentation, we show that our SAFE-GPT model exhibits versatile and robust optimization performance. SAFE opens up new avenues for the rapid exploration of chemical space under various constraints, promising breakthroughs in AI-driven molecular design.

Hamed Shirzad, Frederik Wenkel, Dominique Beaini et al.

Knowledge graphs (KGs) offer a rich representation for relational knowledge, but their irregular structure makes retrieval challenging: ego-graph expansion grows rapidly, and dense embedding methods struggle with multi-hop compositional queries. Existing agent-based graph exploration approaches, while expressive, are often too expensive for large-scale retrieval. We introduce SeedER (Seed-and-Expand Retrieval), a retrieval framework that explicitly leverages KG structure through iterative, low-cost expansion. SeedER first seeds a compact set of core nodes using lightweight dense and entity-based retrieval, then selectively expands this set via a learned graph-aware policy trained with reinforcement learning. This design decomposes global reasoning into reusable local decisions, enabling efficient discovery of query-relevant nodes while tightly controlling expansion cost. We show theoretical limitations of dense retrieval on compositional graph queries, and establish advantages of SeedER from both compositional generalization and graph-constrained submodular optimization perspectives. Empirically, SeedER substantially improves recall with compact candidate sets over strong dense and graph-augmented baselines, making it an effective first-stage retriever for knowledge-intensive reasoning systems.

Nikhil Shenoy, Prudencio Tossou, Emmanuel Noutahi et al.

In the field of Machine Learning Interatomic Potentials (MLIPs), understanding the intricate relationship between data biases, specifically conformational and structural diversity, and model generalization is critical in improving the quality of Quantum Mechanics (QM) data generation efforts. We investigate these dynamics through two distinct experiments: a fixed budget one, where the dataset size remains constant, and a fixed molecular set one, which focuses on fixed structural diversity while varying conformational diversity. Our results reveal nuanced patterns in generalization metrics. Notably, for optimal structural and conformational generalization, a careful balance between structural and conformational diversity is required, but existing QM datasets do not meet that trade-off. Additionally, our results highlight the limitation of the MLIP models at generalizing beyond their training distribution, emphasizing the importance of defining applicability domain during model deployment. These findings provide valuable insights and guidelines for QM data generation efforts.

Yunhui Jang, Lu Zhu, Jake Fawkes et al.

Large language models (LLMs) have recently gained significant attention as a promising approach to accelerate scientific discovery. However, their application in open-ended scientific domains such as biology remains limited, primarily due to the lack of factually grounded and actionable explanations. To address this, we introduce a structured explanation formalism for virtual cells that represents biological reasoning as mechanistic action graphs, enabling systematic verification and falsification. Building upon this, we propose VCR-Agent, a multi-agent framework that integrates biologically grounded knowledge retrieval with a verifier-based filtering approach to generate and validate mechanistic reasoning autonomously. Using this framework, we release VC-TRACES dataset, which consists of verified mechanistic explanations derived from the Tahoe-100M atlas. Empirically, we demonstrate that training with these explanations improves factual precision and provides a more effective supervision signal for downstream gene expression prediction. These results underscore the importance of reliable mechanistic reasoning for virtual cells, achieved through the synergy of multi-agent and rigorous verification.

Ihab Bendidi, Shawn Whitfield, Kian Kenyon-Dean et al.

Understanding the relationships among genes, compounds, and their interactions in living organisms remains limited due to technological constraints and the complexity of biological data. Deep learning has shown promise in exploring these relationships using various data types. However, transcriptomics, which provides detailed insights into cellular states, is still underused due to its high noise levels and limited data availability. Recent advancements in transcriptomics sequencing provide new opportunities to uncover valuable insights, especially with the rise of many new foundation models for transcriptomics, yet no benchmark has been made to robustly evaluate the effectiveness of these rising models for perturbation analysis. This article presents a novel biologically motivated evaluation framework and a hierarchy of perturbation analysis tasks for comparing the performance of pretrained foundation models to each other and to more classical techniques of learning from transcriptomics data. We compile diverse public datasets from different sequencing techniques and cell lines to assess models performance. Our approach identifies scVI and PCA to be far better suited models for understanding biological perturbations in comparison to existing foundation models, especially in their application in real-world scenarios.

Frederik Wenkel, Wilson Tu, Cassandra Masschelein et al.

Accurately predicting cellular responses to genetic perturbations is essential for understanding disease mechanisms and designing effective therapies. Yet exhaustively exploring the space of possible perturbations (e.g., multi-gene perturbations or across tissues and cell types) is prohibitively expensive, motivating methods that can generalize to unseen conditions. In this work, we explore how knowledge graphs of gene-gene relationships can improve out-of-distribution (OOD) prediction across three challenging settings: unseen single perturbations; unseen double perturbations; and unseen cell lines. In particular, we present: (i) TxPert, a new state-of-the-art method that leverages multiple biological knowledge networks to predict transcriptional responses under OOD scenarios; (ii) an in-depth analysis demonstrating the impact of graphs, model architecture, and data on performance; and (iii) an expanded benchmarking framework that strengthens evaluation standards for perturbation modeling.

Mathieu Alain, So Takao, Xiaowen Dong et al.

The problem of classifying graphs is ubiquitous in machine learning. While it is standard to apply graph neural networks or graph kernel methods, Gaussian processes can be employed by transforming spatial features from the graph domain into spectral features in the Euclidean domain, and using them as the input points of classical kernels. However, this approach currently only takes into account features on vertices, whereas some graph datasets also support features on edges. In this work, we present a Gaussian process-based classification algorithm that can leverage one or both vertex and edges features. Furthermore, we take advantage of the Hodge decomposition to better capture the intricate richness of vertex and edge features, which can be beneficial on diverse tasks.

Yassir El Mesbahi, Emmanuel Noutahi

SMILES-based molecular generative models have been pivotal in drug design but face challenges in fragment-constrained tasks. To address this, the Sequential Attachment-based Fragment Embedding (SAFE) representation was recently introduced as an alternative that streamlines those tasks. In this study, we investigate the optimal setups for training SAFE generative models, focusing on dataset size, data augmentation through randomization, model architecture, and bond disconnection algorithms. We found that larger, more diverse datasets improve performance, with the LLaMA architecture using Rotary Positional Embedding proving most robust. SAFE-based models also consistently outperform SMILES-based approaches in scaffold decoration and linker design, particularly with BRICS decomposition yielding the best results. These insights highlight key factors that significantly impact the efficacy of SAFE-based generative models.

Emmanuel Noutahi, Jason Hartford, Prudencio Tossou et al.

Drug discovery is fundamentally a process of inferring the effects of treatments on patients, and would therefore benefit immensely from computational models that can reliably simulate patient responses, enabling researchers to generate and test large numbers of therapeutic hypotheses safely and economically before initiating costly clinical trials. Even a more specific model that predicts the functional response of cells to a wide range of perturbations would be tremendously valuable for discovering safe and effective treatments that successfully translate to the clinic. Creating such virtual cells has long been a goal of the computational research community that unfortunately remains unachieved given the daunting complexity and scale of cellular biology. Nevertheless, recent advances in AI, computing power, lab automation, and high-throughput cellular profiling provide new opportunities for reaching this goal. In this perspective, we present a vision for developing and evaluating virtual cells that builds on our experience at Recursion. We argue that in order to be a useful tool to discover novel biology, virtual cells must accurately predict the functional response of a cell to perturbations and explain how the predicted response is a consequence of modifications to key biomolecular interactions. We then introduce key principles for designing therapeutically-relevant virtual cells, describe a lab-in-the-loop approach for generating novel insights with them, and advocate for biologically-grounded benchmarks to guide virtual cell development. Finally, we make the case that our approach to virtual cells provides a useful framework for building other models at higher levels of organization, including virtual patients. We hope that these directions prove useful to the research community in developing virtual models optimized for positive impact on drug discovery outcomes.

Lu Zhu, Emmanuel Noutahi

Generative chemical language models (CLMs) have demonstrated strong capabilities in molecular design, yet their impact in drug discovery remains limited by the absence of reliable reward signals and the lack of interpretability in their outputs. We present SAFE-T, a generalist chemical modeling framework that conditions on biological context -- such as protein targets or mechanisms of action -- to prioritize and design molecules without relying on structural information or engineered scoring functions. SAFE-T models the conditional likelihood of fragment-based molecular sequences given a biological prompt, enabling principled scoring of molecules across tasks such as virtual screening, drug-target interaction prediction, and activity cliff detection. Moreover, it supports goal-directed generation by sampling from this learned distribution, aligning molecular design with biological objectives. In comprehensive zero-shot evaluations across predictive (LIT-PCBA, DAVIS, KIBA, ACNet) and generative (DRUG, PMO) benchmarks, SAFE-T consistently achieves performance comparable to or better than existing approaches while being significantly faster. Fragment-level attribution further reveals that SAFE-T captures known structure-activity relationships, supporting interpretable and biologically grounded design. Together with its computational efficiency, these results demonstrate that conditional generative CLMs can unify scoring and generation to accelerate early-stage drug discovery.

Ihab Bendidi, Yassir El Mesbahi, Alisandra K. Denton et al.

Understanding cellular responses to stimuli is crucial for biological discovery and drug development. Transcriptomics provides interpretable, gene-level insights, while microscopy imaging offers rich predictive features but is harder to interpret. Weakly paired datasets, where samples share biological states, enable multimodal learning but are scarce, limiting their utility for training and multimodal inference. We propose a framework to enhance transcriptomics by distilling knowledge from microscopy images. Using weakly paired data, our method aligns and binds modalities, enriching gene expression representations with morphological information. To address data scarcity, we introduce (1) Semi-Clipped, an adaptation of CLIP for cross-modal distillation using pretrained foundation models, achieving state-of-the-art results, and (2) PEA (Perturbation Embedding Augmentation), a novel augmentation technique that enhances transcriptomics data while preserving inherent biological information. These strategies improve the predictive power and retain the interpretability of transcriptomics, enabling rich unimodal representations for complex biological tasks.

Julien Horwood, Emmanuel Noutahi

The fundamental goal of generative drug design is to propose optimized molecules that meet predefined activity, selectivity, and pharmacokinetic criteria. Despite recent progress, we argue that existing generative methods are limited in their ability to favourably shift the distributions of molecular properties during optimization. We instead propose a novel Reinforcement Learning framework for molecular design in which an agent learns to directly optimize through a space of synthetically-accessible drug-like molecules. This becomes possible by defining transitions in our Markov Decision Process as chemical reactions, and allows us to leverage synthetic routes as an inductive bias. We validate our method by demonstrating that it outperforms existing state-of the art approaches in the optimization of pharmacologically-relevant objectives, while results on multi-objective optimization tasks suggest increased scalability to realistic pharmaceutical design problems.

Emmanuel Noutahi, Dominique Beaini, Julien Horwood et al.

Recent work in graph neural networks (GNNs) has led to improvements in molecular activity and property prediction tasks. Unfortunately, GNNs often fail to capture the relative importance of interactions between molecular substructures, in part due to the absence of efficient intermediate pooling steps. To address these issues, we propose LaPool (Laplacian Pooling), a novel, data-driven, and interpretable hierarchical graph pooling method that takes into account both node features and graph structure to improve molecular representation. We benchmark LaPool on molecular graph prediction and understanding tasks and show that it outperforms recent GNNs. Interestingly, LaPool also remains competitive on non-molecular tasks. Both quantitative and qualitative assessments are done to demonstrate LaPool's improved interpretability and highlight its potential benefits in drug design. Finally, we demonstrate LaPool's utility for the generation of valid and novel molecules by incorporating it into an adversarial autoencoder.