Nature, Published online: 24 September 2025; doi:10.1038/s41586-025-09312-4
The Biodiversity Cell Atlas aims to create comprehensive single-cell molecular atlases across the eukaryotic tree of life, which will be phylogenetically informed, rely on high-quality genomes and use shared standards to facilitate comparisons across species.
npj Digital Medicine, Published online: 24 September 2025; doi:10.1038/s41746-025-01925-3
Expanding care coordination in an integrated health system through causal machine learning
Three scholars discovered a strange mirror deep in the forest. It spoke to them in a soothing voice and answered all their questions warmly, knowledgeably, and eloquently.
The captivated scholars became obsessed, whispering one secret after another to the mirror. It replied with affection, promise, and meaning that kept them returning to it. They began ignoring one another, each convinced the mirror “understood” them best.
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Nature Medicine, Published online: 11 September 2025; doi:10.1038/s41591-025-03936-9
In an irrevocably changed landscape, reform of the global health system needs to answer key questions on functions, what should be delivered in different contexts and at different levels, and how the system should operate.
Nature Biotechnology, Published online: 09 September 2025; doi:10.1038/s41587-025-02772-z
Antibody–bottlebrush conjugates expand the options for drug cargos compared to antibody–drug conjugates.
EClinicalMedicine. 2025 Aug 12;87:103406. doi: 10.1016/j.eclinm.2025.103406. eCollection 2025 Sep.
ABSTRACT
BACKGROUND: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need to identify prognostic markers enabling more individualised treatment approaches.
METHODS: In the MIRACLE, a prospective, observational biomarker study, a total of 188 patients with isolated, resectable CRLM without (neo)adjuvant chemotherapy were included between October 2015 and December 2021. Blood samples were collected before surgery (baseline) and three weeks after surgery. The primary objective was to assess the potential association between postoperative circulating tumour DNA (ctDNA) detection and recurrence of disease for patients with resectable CRLM within one year after resection. The secondary objective was the association between recurrence of disease within one year and detection of circulating tumour cells (CTCs). Baseline ctDNA was measured by next generation sequencing using a targeted panel (Oncomine Colon cell-free DNA assay) and postoperatively by digital PCR on genetic variants found preoperatively with the Oncomine panel. CTCs were enumerated using the FDA-approved CellSearch system.
FINDINGS: ctDNA was detected in 117/187 patients (63%) at baseline, and 28/104 evaluable patients (27%) still had detectable ctDNA postoperatively. CTC enumeration resulted in positivity for 37/183 patients (20%) at baseline and 14/158 patients (9%) postoperatively. No association was found between 1-year recurrence-free survival (RFS) and the presence of CTCs or ctDNA at baseline. In contrast, patients with postoperative undetectable ctDNA had a significantly improved 1-year RFS compared to patients with postoperative ctDNA (54% [95% CI 44%-67%] vs. 25% [95% CI 13%-47%], log-rank p = 0.0011). Similarly, patients with postoperative detectable CTCs had a significantly shorter 1-year RFS compared to patients without postoperative CTCs (15% [95% CI 4%-55%] vs. 53% [95% CI 45%-62%], log-rank p 0.0004). Also in multivariable analysis, detectable ctDNA and CTCs after surgery remained independently associated with a shorter 1-year RFS (HR 2.35; 95% CI 1.34-4.11; p = 0.0028 and HR 2.98; 95% CI 1.56-5.71; p = 0.0010, respectively).
INTERPRETATION: This is the first study conducted in patients with resectable CRLM without (neo)adjuvant chemotherapy, which demonstrates the impact of postoperative detectable circulating tumour load on 1-year RFS. Postoperative ctDNA and CTC detection both represent strong, independent predictors for a shorter RFS after local treatment, as opposed to preoperative detection.
FUNDING: This work was supported by KWF Kankerbestrijding (Dutch Cancer Society, EMCR 2014-6340).
PMID:40838198 | PMC:PMC12361997 | DOI:10.1016/j.eclinm.2025.103406
Nature Biotechnology, Published online: 19 August 2025; doi:10.1038/s41587-025-02770-1
A vast landscape of ‘undruggable’ cancer targets remains beyond the reach of conventional therapeutic agents. Recent advances in artificial intelligence (AI), however, are challenging this paradigm. Synthesizing insights from a Cancer Moonshot workshop, we argue that systemically addressing the undruggable target space with AI requires a new conceptual framework. We highlight the failure of current target taxonomies and the need for benchmarking datasets, and re-evaluate clinical validation for novel AI-driven modalities.
Nat Commun. 2025 Aug 5;16(1):7178. doi: 10.1038/s41467-025-62593-1.
ABSTRACT
Spatial transcriptomics links gene expression with tissue morphology, however, current tools often prioritize genomic analysis, lacking integrated image interpretation. To address this, we present Thor, a comprehensive platform for cell-level analysis of spatial transcriptomics and histological images. Thor employs an anti-shrinking Markov diffusion method to infer single-cell spatial transcriptome from spot-level data, effectively combining gene expression and cell morphology. The platform includes 10 modular tools for genomic and image-based analysis, and is paired with Mjolnir, a web-based interface for interactive exploration of gigapixel images. Thor is validated on simulated data and multiple spatial platforms (ISH, MERFISH, Xenium, Stereo-seq). Thor characterizes regenerative signatures in heart failure, screens breast cancer hallmarks, resolves fine layers in mouse olfactory bulb, and annotates fibrotic heart tissue. In high-resolution Visium HD data, it enhances spatial gene patterns aligned with histology. By bridging transcriptomic and histological analysis, Thor enables holistic tissue interpretation in spatial biology.
PMID:40764306 | PMC:PMC12325965 | DOI:10.1038/s41467-025-62593-1
Nature, Published online: 06 August 2025; doi:10.1038/s41586-025-09272-9
A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.
Nature, Published online: 24 June 2025; doi:10.1038/d41586-025-01717-5
A gender gap in mathematical ability arises shortly after children begin school — irrespective of the type of school they attend and their socio-economic background.
Nature, Published online: 26 February 2025; doi:10.1038/s41586-025-08623-w
A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.
Nat Comput Sci. 2025 Feb 7. doi: 10.1038/s43588-024-00764-8. Online ahead of print.
ABSTRACT
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.
PMID:39920506 | DOI:10.1038/s43588-024-00764-8
Am J Hum Genet. 2025 Jan 6:S0002-9297(24)00456-7. doi: 10.1016/j.ajhg.2024.12.014. Online ahead of print.
ABSTRACT
Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.
PMID:39809269 | DOI:10.1016/j.ajhg.2024.12.014
Nature, Published online: 08 January 2025; doi:10.1038/s41586-024-08388-8
Results from a comprehensive evaluation of the function of BRCA2 variants, particularly variants of uncertain significance, provide a useful resource to improve the clinical management of individuals who carry such genetic variants.
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