MetaboLLM: a metabolomics-specialized large language model for biochemical knowledge integration and predictive metabolite graph construction

Designing microbial strains that produce high-value chemicals at commercially viable titers remains a central challenge in metabolic engineering. Existing computational approaches either rely on stoichiometric constraint-based models that cannot learn from experimental data, or apply tabular machine learning to hand-crafted features that discard the relational structure of biological knowledge. We present Canopy, a heterogeneous graph foundation model that integrates ten public and proprietary data sources into a unified knowledge graph (KG) of 6.9M nodes across 13 types and 34 edge types, covering genes, proteins, metabolites, reactions, pathways, strains, and fermentation experiments. Node features are encoded through domain-specific foundation models (ESM-2 for protein sequences, MoLFormer for chemical SMILES, and PubMedBERT for biomedical text), yielding a multi-modal representation within a single graph. We pretrain a Heterogeneous Graph Transformer (HGT) augmented with SignNet positional encodings, Jumping Knowledge aggregation, and virtual nodes using four self-supervised objectives (link prediction, masked node modelling, distance prediction, and contrastive experiment clustering), balanced via learned homoscedastic uncertainty weighting. On the downstream task of fermentation titer prediction, frozen Canopy embeddings achieve $R^{2} = 0.41$ with a lightweight probe, outperforming tabular baselines (best $R^{2} = 0.24$) and homogeneous GNN variants.

Large Language Models (LLMs) are increasingly being investigated for physiological time-series prediction, yet their effectiveness may depend not only on the model itself, but also on how physiological information is represented and presented at inference time. This study investigates prompt-based general-purpose LLMs for postprandial hyperglycemia and hypoglycemia prediction in individuals with type 1 diabetes. Using the OhioT1DM dataset, we evaluate multiple open-weight LLMs under zero-shot and few-shot inference across prediction horizons of 30, 60, and 90 minutes. The analysis varies both the textual representation of the available physiological information and the amount of information exposed to the model, ranging from glucose observations alone to derived descriptors and additional contextual variables related to insulin, meals, carbohydrates, and physical activity. Performance is compared with conventional patient-specific supervised models and with Gluco-LLM, a language-model-based architecture explicitly adapted to glucose time-series forecasting. Results show a marked task-dependent behavior. Conventional supervised models achieve the strongest performance for hyperglycemia prediction, whereas the best observed prompt-based LLM configurations improve performance for hypoglycemia across all investigated horizons. The effectiveness of prompt-based inference is also strongly influenced by how physiological information is represented, while providing additional contextual information does not lead to a systematic improvement. Overall, these findings highlight physiological information representation as a central design factor in prompt-based LLM approaches to glycemic-event prediction.

Predicting the effect of an unseen gene knockout perturbation on transcriptomic gene expression remains a highly challenging problem for virtual cell models. Recent progress has been made by leveraging biological knowledge graphs to provide a notion of similar perturbation, allowing for improved extrapolation beyond the set of training perturbations. In this work, we demonstrate that the simplest model to leverage these assumptions - a K-nearest neighbour from the knowledge graph - achieves highly competitive performance on this task, and that this can be improved further using LLMs optimised via reinforcement learning (RL) for predictive performance. Specifically, we find that the K-nearest neighbour approach beats almost all methods on out-of-distribution perturbation prediction, and when a reasoning LLM is trained via RL to make changes to the neighbourhood, it obtains equivalent performance to current state of the art methods on the cell lines from Replogle et al. (2022). We also demonstrate that the RL training improves the LLM's performance on the downstream task of differential expression prediction, despite not being trained on this directly. Overall, these findings demonstrate the efficacy of knowledge graphs as model priors, and show early signs that RL can refine LLMs into generalizable tools for predicting complex biological responses.