bioRxiv Science⌕ Search

bioRxiv · 10.64898/2026.07.06.736700

Biological Continued Pretraining Reshapes the Capability Profile of a Foundation Model Without Catastrophic Forgetting

Abstract

It is widely assumed that continued pretraining (CPT) on a narrow, out-of-distribution corpus such as raw biological sequence must trade away a general-purpose models broad competence -- the "alignment tax" or catastrophic-forgetting intuition. We test this directly, without any new training, by re-analyzing three checkpoints from a single lineage of a 26B-parameter Mixture-of-Experts model (Gemma-4-26B-A4B): the instruction-tuned base, the same model after biological CPT (8.7B tokens of DNA, protein, and biomedical text), and after subsequent supervised fine-tuning (SFT). Across three independent capability axes -- general knowledge/reasoning (MMLU, ARC, HellaSwag), code generation (MBPP), and biomedical knowledge (BixBench) -- we find that biological CPT does not degrade the model; it lifts it: MMLU +13 points, MBPP pass@1 nearly doubles (0.33 [->]0.63), and BixBench discrimination rises sharply (MCC 0.23 [->] 0.92). The single measured regression is truthfulness (TruthfulQA 8.8 points), a small and interpretable domain drift. A clean vocabulary-expansion ablation (< 0.4 pt on every general metric) confirms the gains are attributable to CPT, not tokenizer changes. Crucially, subsequent SFT narrows the model back: all three axes fall to near-base levels, revealing a consistent division of labor -- CPT re-organizes and lifts the shared capability substrate; SFT cashes it out onto target tasks. We argue this reframes biological sequence not as a competitor for a foundation models capacity but as a form of structured scientific data that reshapes its capability profile, and that CPT and SFT should be budgeted as complementary rather than substitutable stages. All checkpoints, evaluation code, and per-example outputs are public. HighlightsO_LIA training-free re-analysis of one 26B MoE lineage isolates the effect of biological continued pretraining (CPT) from tokenizer changes and from fine-tuning. C_LIO_LIBiological CPT does not cause catastrophic forgetting; it raises general knowledge (MMLU +13 pts) and code generation (MBPP pass@1 0.33[->] 0.63). C_LIO_LICPT also makes chain-of-thought reasoning 41% shorter and near-backtrack-free while pre-serving accuracy -- an effect invisible to accuracy metrics. C_LIO_LIA consistent CPT-lifts / SFT-narrows division of labor recurs across four axes, reframing biological sequence as structured scientific data that reshapes a models capability profile. C_LI The Bigger PictureAdapting a general-purpose AI model to a specialized domain -- here, the language of DNA and proteins -- is usually assumed to come at a cost: teach it biology and it forgets how to reason about everything else. This "no free lunch" intuition shapes how practitioners budget compute and whether they attempt domain adaptation at all. We test the assumption directly, and without running any new training, by comparing three snapshots of the same model taken before and after biological training. The result overturns the intuition: feeding the model raw biological sequence made it better at general knowledge, at writing code, and even changed how it reasons -- producing shorter, more decisive chains of thought without losing accuracy. The gains appear during the sequence-pretraining stage and are partly given back during task-specific fine-tuning, revealing that the two stages play complementary rather than interchangeable roles. This suggests a broader principle for data-centric AI: structured scientific data -- biological sequence today, and by extension code, mathematics, and chemistry -- is not merely knowledge to be absorbed but a lever that reshapes what a foundation model can do.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Wang, L.. 2026-07-16. Biological Continued Pretraining Reshapes the Capability Profile of a Foundation Model Without Catastrophic Forgetting. https://doi.org/10.64898/2026.07.06.736700

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

A meta-interaction basis for cell-cell communication in tissues

Tissue function depends on signals exchanged between cells and the responses they elicit. Yet whether diverse cell-cell interactions in situ form recurrent sender-receiver programs remains unclear. We present SpiderNet, an interpretable representation-learning framework that discovers such directed programs as a compact basis of cell-cell meta-interactions (MIs) from spatial transcriptomics. SpiderNet jointly learns which sender regulators, ligand-receptor pairs, and receiver targets define each MI and where each program is active across neighboring cell pairs. The resulting representation traces multicellular relays and links communication to cell states, perturbation responses, and phenotypes. SpiderNet recovers ground-truth MIs and their molecular components in simulations and, in real tissues, shows stronger direction-specific agreement with independently curated regulatory programs in senders and receivers than alternative methods. Across more than 5.8 million spatially profiled cells, SpiderNet resolves an SPP1-THBS relay linking monocytes, fibroblasts, and tumor cells within an immune-suppressive ovarian cancer niche, predicts T-cell responses to held-out melanoma-cell perturbations, and identifies a T-cell-associated brain-aging program and age-predictive signals that transfer across regions and platforms. It reveals a recurrent pan-cancer COLLAGEN-linked fibroblast-tumor program whose projected abundance in independent cohorts is associated with poorer survival and non-response to immunotherapy. SpiderNet thus establishes MIs as a reusable organizational layer between molecular interactions and tissue phenotypes, providing a framework to resolve, compare, trace, and perturb multicellular regulation in situ.

bioinformatics↗

Heterogeneous Graph Contrastive Learning for Drug-Gene-Disease Motif Prediction

Drug repurposing and target discovery offer critical strategies for advancing therapeutic development by uncovering the potential biological pathways and novel associations among drugs, genes, and diseases. However, experimental discovery remains expensive and time-consuming, which limits the scalability of large-scale studies. In addition, existing computational approaches often struggle to effectively integrate heterogeneous biomedical data, capture the complex higher-order topological signatures of biological interactomes, and generalize to unseen entities. Here, we present HANAMI (Heterogeneous grAph coNtrastive leArning for drug-gene-disease Motif predIction), a multi-view deep graph learning framework designed to model complex interactions among drugs, genes, and diseases. HANAMI integrates diverse heterogeneous biomedical knowledge, including chemical structures, genomic sequences, and clinical phenotypes, and leverages relation-aware topology encoding, structure-aware aggregation, and contrastive learning to enable accurate motif prediction with biological context from the network. Systematic evaluation on benchmark datasets shows that HANAMI achieves up to 6% improvements over existing state-of-the-art methods in predicting drug-gene-disease motifs. The framework further demonstrates strong inductive generalization, maintaining an [~]18% performance advantage in zero-shot settings involving previously unseen entities. Beyond predictive performance, HANAMI effectively prioritizes drug-disease relationships investigated in Phase II or III trials while identifying candidate genes that suggest plausible mechanistic links. Together, HANAMI provides a computational framework for interpreting complex biomedical interactions, offering a scalable foundation to accelerate drug repurposing and therapeutic innovation.

bioinformatics↗

PTMExplorer: A Multi-Dimensional Integrative Visualization Platform for Protein Post-Translational Modification Function and Structure

Deciphering the functions of post-translational modifications (PTMs) is a critical bridge connecting large-scale modification proteomics data to mechanistic studies. However, most existing tools for visualizing PTM omics data are limited to site catalogs or single-dimensional feature displays. They lack the capability to simultaneously map user-derived differential modification sites onto multi-dimensional contexts, including protein three-dimensional (3D) structure, evolutionary conservation, functional sites, and disease associations. This limitation makes it difficult for researchers to rapidly assess the biological importance of candidate sites from among a vast number of differentially modified sites. Here, we present PTMExplorer, an interactive platform for the multi-dimensional visualization of protein PTMs. PTMExplorer comprises three core modules: PTM Inspector, built upon ProtVista, provides a multi-track, sequence-feature integrated view incorporating intrinsically disordered region (IDR) prediction (via flDPnn), surface accessibility calculation (via FreeSASA), and UniProt functional annotations; PTM 3D Locator, leveraging the Nightingale/Mol* engine, anchors modification sites onto AlphaFold/Protein Data Bank (PDB) 3D structures through residue mapping via PDBe-SIFTS; and PTM Overview, utilizing the R circlize package, presents a panoramic polar circos plot illustrating modification distribution and inter-group differential regulation. Additionally, three major disease-associated modification databases (PTMD, qPTM, and PhosCancer) are integrated as PTM-Disease Nexus, enabling co-localization comparison between user-defined differential sites and reported disease-related sites. PTMExplorer currently supports eight model organisms, accepts user-uploaded differential analysis results, and provides multi-dimensional annotations and various visualization options (https://www.bioladder.cn/PTMExplorer/). Using a multi-omics dataset from hepatocellular carcinoma (18 patients, 9 modification types) as a case study, we demonstrate the practical utility of PTMExplorer in screening potential biomarkers, revealing multi-modification coordination mechanisms, and distinguishing between absolute and relative quantification patterns.

bioinformatics↗