Canopy: A Heterograph Foundation Model for Metabolic Engineering

Abstract

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.