Research Briefing

Most bacteria cannot be grown in the laboratory, which means that their genetic diversity is hidden to traditional culture-based studies. We combined a new DNA extraction method, long-read sequencing, bioinformatics and chemical synthesis to access the genetic diversity of uncultured soil bacteria and abiotically decode it to discover bioactive small molecules.

A new screen platform named DEFUSE (DEath FUSion Escape) enables high-throughput discovery of small molecule protein degraders. DEFUSE identified SKPer1, a molecule that works by inducing proximity between an oncogenic driver and an E3 ligase, opening new avenues for targeted protein degradation.

Antibody–drug conjugates (ADCs) are promising targeted cancer therapies but have a limited payload scope. Antibody–bottlebrush prodrug conjugates offer modular synthesis and high drug-to-antibody ratios, enabling the use of a broad range of payloads, including lower potency drugs, while performing favorably compared to traditional ADCs in preclinical models.

We developed a universal control system and multitarget optimization framework that enables dynamic and synchronized expression of multiple genes and facilitates the overproduction of specific secondary metabolites in Streptomyces species.

Precision CRISPR–Cas9-mediated genome engineering remains challenging, particularly gene integration and editing in non-dividing cells. We present Pythia, a deep learning solution that forecasts optimal repair templates and enables predictable and accurate genome editing in diverse cellular contexts, both in vivo and in vitro.

A robust, clinically tractable skin metatranscriptomics workflow provides high technical reproducibility of profiles, uniform coverage across genes, and strong enrichment of microbial messenger RNAs across different skin sites. This workflow is useful for identifying active species and microbial functions in vivo for future biomarker discovery.

PepMLM, a protein language model fine-tuned on protein–peptide data, can generate potent, target-specific linear peptides capable of binding to and degrading proteins ranging from cancer receptors to drivers of neurodegeneration and viral proteins, all without requiring protein structural information.

Cells in a tissue influence each other through physical and chemical cues as they differentiate to their final fates and migrate through space. A new technique integrates spatial transcriptomic data with the dynamics of RNA transcription and splicing across an entire tissue to model the directions of cell differentiation and migration.

We developed low-input multiple methylation sequencing (LIME-seq) to detect RNA modifications in plasma cell-free RNA (cfRNA) and identified microbiome-derived RNA modification signatures that can distinguish people with colorectal cancer from those without. We suggest that monitoring the modification levels on cfRNA or other RNA species could aid disease diagnosis and prognosis.

We developed Dual Selective Organ-Targeting Lipid Nanoparticles (Dual SORT LNPs) capable of delivering base editors to multiple organs. Base editor Dual SORT LNPs corrected disease-causing mutations in both the liver and lungs, the primary organs affected in alpha-1 antitrypsin deficiency.

Protein materials are promising drug delivery vehicles, but their use for intracellular protein and nucleic acid cargo delivery has been limited. We have developed self-assembling elastin-like polypeptide (ELP)-based protein nanoparticles that are functionalized to enable complexation and intracellular delivery of biomacromolecular cargo, including gene editors in the form of mRNA, plasmid DNA and ribonucleoproteins.

Proteomics samples of human cancer biopsies were combined to derive an atlas of protein–protein associations for human tissues. Differences between tissues are not strongly driven by gene expression but could, in part, be due to tissue-specific subcellular components and processes.

How modifications to RNA molecules and the proteins they interact with on the cell surface contribute to cancer is largely unknown. Preclinical evidence indicates that cell surface nucleophosmin (NPM1, an RNA-binding protein) is a novel druggable biomarker in acute myeloid leukemia, with potential implications for improving detection and immunotherapy strategies for several cancer types.

Crop yield improvement has plateaued in the past three decades, owing largely to genetic bottlenecks in the germplasm of staple food crops. We used a chemical intervention method that increases yield in the field, providing a sustainable means to improve yields of wheat and potentially other crops.

We introduce a method that detects viral sequences in RNA sequencing data on the basis of highly conserved proteins, enabling the detection of more than 100,000 RNA virus species. We analyzed the presence of novel viruses and host gene expression in parallel to characterize viral tropism and host immune responses in individual cells.

A lack of broadly applicable methods to precisely control therapeutic gene expression is a key challenge for gene therapies. We present a technology that offers a photoactivatable RNA base editor for tunable and reversible regulation of gene expression, with implications for improving the safety and efficacy of gene therapy.

Gene transfer enables bacteria to adapt to their environment. To sensitively detect gene transfer, we created a synthetic biology tool that introduces an identifiable barcode into RNA when microbes exchange DNA. When applied in a wastewater community, high-throughput sequencing revealed which microbes in the community participated in gene transfer.

We introduce volumetric DNA microscopy, a technique that enables three-dimensional imaging of tissue morphology and gene expression in a single measurement. This feat is achieved by forming a huge intermolecular network of DNA barcodes within an intact specimen and encoding their pairwise proximities into a DNA sequence library.

DNA delivery using lipid nanoparticles results in severe toxicity in mice. However, we find that the incorporation of endogenous anti-inflammatory lipids into the lipid nanoparticles mitigates this toxicity and enables prolonged gene expression.

The mechanism of translation initiation in linear and circular mRNAs influences translation efficiency. Covalent attachment of an N⁷-methylguanosine (m⁷G) cap increases protein production from circular mRNAs in mice. Hybridization with capped endogenous RNAs also promotes protein production in cells, suggesting that this interaction might also occur between endogenous RNAs.