mlsanityData to 7 Oct 2026

Discovery of a Hematopoietic Manifold in scGPT Yields a Method for Extracting Performant Algorithms from Biological Foundation Model Internals

arXiv 2603.10261 ↗First posted 10 Mar 2026cs.LG q-bio.CB q-bio.GNcited by 0

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Abstract (arXiv)

We report the discovery and extraction of a compact hematopoietic algorithm from the single-cell foundation model scGPT, to our knowledge the first biologically useful, competitive algorithm extracted from a foundation model via mechanistic interpretability. We show that scGPT internally encodes a compact hematopoietic manifold with significant developmental branch structure, validated on a strict non-overlap Tabula Sapiens external panel and confirmed via frozen-head zero-shot transfer to an independent multi-donor immune panel. To isolate this geometry, we introduce a general three-stage extraction method consisting of direct operator export from frozen attention weights, a lightweight learned adaptor, and a task-specific readout, producing a standalone algorithm without target-dataset retraining. In 88-split donor-holdout benchmarks against scVI, Palantir, DPT, CellTypist, PCA, and raw-expression baselines, the extracted algorithm achieves the strongest pseudotime-depth ordering and leads on key subtype endpoints (CD4/CD8 AUROC 0.867, mono/macro AUROC 0.951). Compared to standard probing of frozen scGPT embeddings with a 3-layer MLP, the extracted head is BH-significantly better on 6/8 classification endpoints while completing a full 12-split evaluation campaign 34.5x faster with approximately 1000x fewer trainable parameters. The exported operator compresses from three pooled attention heads to a single head without statistically significant loss, and further to a rank-64 surrogate. Mechanistic interpretability of the compact operator reveals a concentrated four-factor core explaining 66.2% of ablation impact, with factors resolving into explicit T/lymphoid, B/plasma, granulocytic, and monocyte/macrophage gene programs. A supplementary second-manifold validation (intercellular communication geometry) confirms that the extraction method generalizes beyond hematopoiesis.

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References · 21

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9 more
  1. 2023The Linear Representation Hypothesis and the Geometry of Large Language Modelscited by 679
  2. 2024Sparse Feature Circuits: Discovering and Editing Interpretable Causal Graphs in Language Modelscited by 412
  3. 2021Causal Abstractions of Neural Networkscited by 401
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  6. 2020BERTology Meets Biology: Interpreting Attention in Protein Language Modelscited by 85
  7. 2026Systematic Evaluation of Single-Cell Foundation Model Interpretability Reveals Attention Captures Co-Expression Rather Than Unique Regulatory Signalcited by 7
  8. 2026Sparse autoencoders reveal organized biological knowledge but minimal regulatory logic in single-cell foundation models: a comparative atlas of Geneformer and scGPTcited by 4
  9. 2026Causal Circuit Tracing Reveals Distinct Computational Architectures in Single-Cell Foundation Models: Inhibitory Dominance, Biological Coherence, and Cross-Model Convergencecited by 1

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