Paper
Sparse autoencoders reveal organized biological knowledge but minimal regulatory logic in single-cell foundation models: a comparative atlas of Geneformer and scGPT
Authors
Ihor Kendiukhov
Abstract
Background: Single-cell foundation models such as Geneformer and scGPT encode rich biological information, but whether this includes causal regulatory logic rather than statistical co-expression remains unclear. Sparse autoencoders (SAEs) can resolve superposition in neural networks by decomposing dense activations into interpretable features, yet they have not been systematically applied to biological foundation models. Results: We trained TopK SAEs on residual stream activations from all layers of Geneformer V2-316M (18 layers, d=1152) and scGPT whole-human (12 layers, d=512), producing atlases of 82525 and 24527 features, respectively. Both atlases confirm massive superposition, with 99.8 percent of features invisible to SVD. Systematic characterization reveals rich biological organization: 29 to 59 percent of features annotate to Gene Ontology, KEGG, Reactome, STRING, or TRRUST, with U-shaped layer profiles reflecting hierarchical abstraction. Features organize into co-activation modules (141 in Geneformer, 76 in scGPT), exhibit causal specificity (median 2.36x), and form cross-layer information highways (63 to 99.8 percent). When tested against genome-scale CRISPRi perturbation data, only 3 of 48 transcription factors (6.2 percent) show regulatory-target-specific feature responses. A multi-tissue control yields marginal improvement (10.4 percent, 5 of 48 TFs), establishing model representations as the bottleneck. Conclusions: These models have internalized organized biological knowledge, including pathway membership, protein interactions, functional modules, and hierarchical abstraction, yet they encode minimal causal regulatory logic. We release both feature atlases as interactive web platforms enabling exploration of more than 107000 features across 30 layers of two leading single-cell foundation models.
Metadata
Related papers
Fractal universe and quantum gravity made simple
Fabio Briscese, Gianluca Calcagni • 2026-03-25
POLY-SIM: Polyglot Speaker Identification with Missing Modality Grand Challenge 2026 Evaluation Plan
Marta Moscati, Muhammad Saad Saeed, Marina Zanoni, Mubashir Noman, Rohan Kuma... • 2026-03-25
LensWalk: Agentic Video Understanding by Planning How You See in Videos
Keliang Li, Yansong Li, Hongze Shen, Mengdi Liu, Hong Chang, Shiguang Shan • 2026-03-25
Orientation Reconstruction of Proteins using Coulomb Explosions
Tomas André, Alfredo Bellisario, Nicusor Timneanu, Carl Caleman • 2026-03-25
The role of spatial context and multitask learning in the detection of organic and conventional farming systems based on Sentinel-2 time series
Jan Hemmerling, Marcel Schwieder, Philippe Rufin, Leon-Friedrich Thomas, Mire... • 2026-03-25
Raw Data (Debug)
{
"raw_xml": "<entry>\n <id>http://arxiv.org/abs/2603.02952v1</id>\n <title>Sparse autoencoders reveal organized biological knowledge but minimal regulatory logic in single-cell foundation models: a comparative atlas of Geneformer and scGPT</title>\n <updated>2026-03-03T13:05:11Z</updated>\n <link href='https://arxiv.org/abs/2603.02952v1' rel='alternate' type='text/html'/>\n <link href='https://arxiv.org/pdf/2603.02952v1' rel='related' title='pdf' type='application/pdf'/>\n <summary>Background: Single-cell foundation models such as Geneformer and scGPT encode rich biological information, but whether this includes causal regulatory logic rather than statistical co-expression remains unclear. Sparse autoencoders (SAEs) can resolve superposition in neural networks by decomposing dense activations into interpretable features, yet they have not been systematically applied to biological foundation models.\n Results: We trained TopK SAEs on residual stream activations from all layers of Geneformer V2-316M (18 layers, d=1152) and scGPT whole-human (12 layers, d=512), producing atlases of 82525 and 24527 features, respectively. Both atlases confirm massive superposition, with 99.8 percent of features invisible to SVD. Systematic characterization reveals rich biological organization: 29 to 59 percent of features annotate to Gene Ontology, KEGG, Reactome, STRING, or TRRUST, with U-shaped layer profiles reflecting hierarchical abstraction. Features organize into co-activation modules (141 in Geneformer, 76 in scGPT), exhibit causal specificity (median 2.36x), and form cross-layer information highways (63 to 99.8 percent). When tested against genome-scale CRISPRi perturbation data, only 3 of 48 transcription factors (6.2 percent) show regulatory-target-specific feature responses. A multi-tissue control yields marginal improvement (10.4 percent, 5 of 48 TFs), establishing model representations as the bottleneck.\n Conclusions: These models have internalized organized biological knowledge, including pathway membership, protein interactions, functional modules, and hierarchical abstraction, yet they encode minimal causal regulatory logic. We release both feature atlases as interactive web platforms enabling exploration of more than 107000 features across 30 layers of two leading single-cell foundation models.</summary>\n <category scheme='http://arxiv.org/schemas/atom' term='q-bio.GN'/>\n <category scheme='http://arxiv.org/schemas/atom' term='cs.LG'/>\n <category scheme='http://arxiv.org/schemas/atom' term='q-bio.CB'/>\n <published>2026-03-03T13:05:11Z</published>\n <arxiv:primary_category term='q-bio.GN'/>\n <author>\n <name>Ihor Kendiukhov</name>\n </author>\n </entry>"
}