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Our annual survey highlights startups taking on gene therapy, adoptive immune cell therapy, gene editing, and drugs targeting RNA modifications and the unfolded protein response. Ken Garber, Esther Landhuis, Melanie Senior, Cormac Sheridan and Laura DeFrancesco report.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Dendritic cells (DCs) are required to establish thymic central tolerance. Here Srinivasan et al. use single-cell transcriptomics to define thymic conventional dendritic cell (cDC) subsets and find that CD8⁺ single-positive thymocytes modulate the thymus environment to regulate plasmacytoid DC and cDC2 homeostasis and interferon signatures in DCs, while CD4⁺ single-positive thymocytes regulate cDC1 activation via cognate and CD40L–CD40 interactions.

B cell subsets expanding during tumor progression have been associated with impaired anti-tumor responses and resistance to immunotherapy. Here the authors report that STING agonism or anti-PD-1 induce intratumoral B cell infiltration, and that depleting B-cells improves response to immunotherapies in preclinical models of hepatocellular carcinoma.

Chaperone-mediated autophagy (CMA) is often dysregulated in cancer, but its mechanisms remain unclear. This study reveals that MST4- mediated LAMP2A phosphorylation regulates CMA by stabilizing lysosomal LAMP2A, thereby promoting GBM tumorigenicity and immune evasion.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Nature Biotechnology’s annual survey highlights academic startups that are, among other things, designing circular RNA therapeutics, tackling cancer with arenaviruses, creating psychedelics without the trip, editing genes and cells in vivo, harnessing the power of autoantibodies and editing the epigenome.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

A single-cell multiomic immune cell atlas from 235 Japanese, including patients with COVID-19 and healthy individuals, linked with host genetics including germline and somatic mutation, plasma proteomics and metagenomics data reveals that immune cells are dynamically regulated in a cell state-dependent manner.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analyses of whole-genome sequencing data from UK Biobank and All of Us identify rare variant burden signals associated with metabolic health, including effects of protein-truncating variants in IRS2 on type 2 diabetes and chronic kidney disease risk.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

An artificial intelligence hardware approach that uses the adaptive reservoir computation of biological neural networks in a brain organoid can perform tasks such as speech recognition and nonlinear equation prediction.

The development of exciplex-type hosts for thermally activated delayed fluorescence organic light-emitting diodes is hindered by a lack of structural information for these donor:acceptor blends. Here, the authors report the pump-probe Step-Scan Fourier transform IR spectra for a D:A exciplex host.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Synthetic routes to aminoglycosides are often long and rely upon the coupling of semisynthetically produced fragments. Now, an enantioselective, copper-catalysed hydroamination of benzene has been developed to enable access to the aminoglycoside antibiotic ribostamycin. This bottom-up strategy provides modular and expedient entry into the aminocyclitol class.

A genome-wide association study highlights a variant in DOCK2, which is common in East Asian populations but rare in Europeans, as a host genetic risk factor for severe COVID-19.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

The design of host-guest systems for switchable recognition of guests upon the change of external stimuli is challenging due to the invariable host-guest affinity. Here, the authors encode a dynamic motion into a porous crystal to regulate the diffusion of CO2 and C2H2 allowing the crystal to switch the gas recognition selectivity by temperature.

The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeric antigen receptors.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

TDP-43 dysfunction in ALS/FTD causes faulty splicing of the KCNQ2 ion channel, leading to toxic protein buildup, neuron hyperactivity and a potential new biomarker and treatment target using RNA-based therapies.

Smoking-associated DNA methylation changes in whole blood have been reported by many EWAS. Here, the authors use a cell-type deconvolution algorithm to identify cell-type specific DNA methylation signals in seven EWAS, identifying lineage-specific smoking-associated DNA methylation changes.

Analysis of samples from the asteroid Ryugu provide evidence of late fluid flow in a carbonaceous asteroid, indicating that such bodies may have retained two to three times more water than previously thought.

Exciton–polariton condensates have garnered interest as a means to access macroscopic displays of quantum phenomena such as Bose–Einstein condensation and superfluidity. In this work, a direct measure of the polariton–polariton interaction is obtained.