Back

{Sigma}0-EvoCell: An AI-Native Ontology that Unifies Evolutionary and Cell Biology in Latent Space

Pan, L.

2026-07-16 bioinformatics
10.64898/2026.07.15.738795 bioRxiv
Show abstract

Foundation models for biology achieve impressive pattern recognition on molecular sequences and single-cell transcriptomics, yet they fail to outperform simple linear baselines for predicting genetic perturbation effects, exposing a gap between statistical correlation and mechanistic understanding. This gap is compounded by an interface problem: biological knowledge lives in human-readable formats (FASTA, SBML, ontology triples) that must be lossily re-encoded before a neural network can reason about them. Here we introduce the Evolutionary Cell Ontology (ECO), an AI-native formal language built on the {Sigma}0 substrate that represents biological knowledge directly as vector-encoded relational graphs. ECO uses 16 structural operators that serve simultaneously as knowledge glyphs, tensor operations, and--critically--carry a dual semantics spanning both evolutionary and cellular timescales, so the same operator that denotes speciation at the phylogenetic scale denotes irreversible APC/C commitment at the cell-cycle scale. We define a Latent Space Communication Protocol (LSCP) that maps ECO graphs into the residual stream of large language models, enabling systematic auditing of the biological knowledge a model actually contains. We illustrate ECO across three domains using controlled simulations: (i) globin protein-family evolution across roughly 1.5 billion years, where ECO epistatic attention recovers long-range coevolutionary couplings and ancestral-state reconstruction reaches 82-91% accuracy graded by conservation class; (ii) mammalian cell-cycle dynamics, where a CDK-cyclin attention graph with GATE checkpoints and FUSE commitment nodes reproduces two full oscillatory cycles with a four-attractor phase portrait emerging without explicit programming; and (iii) latent-space alignment, where ECO embedding distance tracks divergence across 60 protein families (Pearson r = 0.50) and an illustrative LSCP audit projects that relational, multi-scale concepts are encoded far more weakly than sequence-level facts. ECO replaces the human-readability constraint with an AI-processing constraint and, in doing so, turns the opacity of foundation models into a measurable, navigable coverage map.

Matching journals

The top 5 journals account for 50% of the predicted probability mass.

50% of probability mass above

"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.