Research Briefing

The mechanical sensor PIEZO1 regulates the traction force that is critical for cytotoxic T cells to target tumour cells. This finding creates avenues for enhancing the efficacy of T cell-targeted immune therapies.

By coating manganese dioxide on the surface of fixed bacteria, we obtained mineralized bacteria with the ability to potently activate multiple immune signalling pathways. Immunotherapy with mineralized bacteria suppressed various types of cancer in multiple animal models, eliciting both immune memory and abscopal antitumour effects.

CRISPR–Cas12a was used to directly replace mouse antibody variable chain genes with human versions in primary B cells. The edited cells underwent affinity maturation in vivo, improving the potency of HIV-1 and SARS-CoV-2 neutralizing antibodies without loss of bioavailability. Affinity maturation of edited cells also enables new vaccine models and adaptive B cell therapies.

Cellular encapsulation holds promise for immunosuppression-free pancreatic islet transplantation. However, long-term graft survival remains a challenge, especially at the subcutaneous site. We harnessed temporary, controlled, inflammation-induced neovascularization to create a modified subcutaneous cavity that supports long-term survival and function of a customized islet encapsulation device without immunosuppression.

Many genetic therapies are limited by a lack of methods for delivering them to target cells in the body. We have developed technologies to engineer biological nanovesicles to load therapeutic proteins, target recipient immune cells and deliver Cas9 to knock out CXCR4 in primary human T cells.

We compared a range of linear and nonlinear models based on how accurately they could describe resting-state functional magnetic resonance imaging and intracranial electroencephalography dynamics in humans. Linear autoregressive models were the most accurate in all cases. Using numerical simulations, we demonstrated that spatiotemporal averaging has a critical and robust role in this linearity.

We show that nonlinear latent factors and structures in neural population activity can be modelled in a manner that allows for flexible dynamical inference, causally, non-causally and in the presence of missing neural observations. Further, the developed neural network model improves the prediction of neural activity, behaviour and latent neural structures.

We revealed that the RNA-targeting activity of the Cas13 family of nucleases allows them to directly target endogenous RNA in mammalian cells. Such activity limits the usage of lentiviral Cas13 systems, and suggests a need for caution when applying Cas13-based systems.

We functionally assessed clinically observed mutations of the BRCA2 gene and analysed structure–function relationships of variants of the gene by using high-throughput CRISPR-mediated mutagenesis and pooled screening in locally haploid human pluripotent stem cells and in fibroblasts differentiated from them.

We developed OxoScan-MS, a mass spectrometric acquisition technology for high-throughput quantification of glycopeptides. When applied to plasma of patients with COVID-19, OxoScan-MS revealed differential glycosylation in disease-relevant proteins. This approach offers potential for large-scale applications, moving beyond traditional protein abundance measurements to explore glycosylated protein biomarkers.

Demultiplexing PET–MRI data of solid tumours using machine learning allows the spatial characterization of intratumour tissue heterogeneity in mice and humans. Predicted maps of tissue subtypes within the tumour could aid in conducting image-guided biopsies and provide valuable insights linking the outcome of cancer therapies with phenotypic heterogeneity.

We engineered integrase-deficient lentiviruses to act as vectors for the delivery of large gene knock-ins via homology-directed repair. This technology enables the non-cytotoxic, targeted insertion of difficult-to-express transgenes into genomic loci that are essential to cell survival, thereby overcoming the gene silencing that otherwise limits primary immune cell engineering.

We developed exponentially amplified rolling circle amplification with CRISPR–Cas12a as a one-pot, isothermal assay for microRNA detection. This method has single-digit femtomolar sensitivity and single-nucleotide specificity, and can be deployed for point-of-care testing. The assay has been adapted for the microRNA profiling of extracellular vesicles, which is used in the diagnosis of pancreatic cancer.

INSPECTR is a technique for detecting nucleic acids that couples the sensitivity and specificity of nucleic acid splinted ligation with the versatile readouts of cell-free gene expression. The result is an ambient-temperature workflow that enables the detection of pathogenic viruses at low copy numbers.

In this study, spherical nucleic acids (SNAs) were designed using defined placements of two classes of antigen that each activate different types of T cell. Use of SNA modularity illustrated the role of antigen placement within a vaccine architecture on subsequent processing and immune responses. The study defines design rules for multi-antigen vaccines.

We developed an at-home microsampling approach that measures thousands of metabolites, lipids and proteins in small volumes of blood. Dense multi-omic sampling generates a ‘molecular movie’ that integrates with data from wearables to reveal new insights into the dynamics of human physiology.

An extracellular matrix biomaterial delivered into the bloodstream selectively binds to blood vessels in inflamed tissues, such as those caused by myocardial infarction and traumatic brain injury. The biomaterial dampened the inflammatory response and promoted tissue repair and regeneration when tested in rat and pig models of myocardial infarction.

The inability to precisely manipulate mammalian mitochondrial DNA has stalled our understanding of mitochondrial biology and the generation of cellular and animal models in which to study it. DNA base editing technologies have enabled the generation of a library of mitochondrial base editors that precisely ablate every protein-coding gene in the mouse mitochondrial genome.

Graph deep learning applied to multiplexed immunofluorescence data from tumour microenvironments reveals spatial cellular structures that are indicative of cancer prognosis.

Developing gene therapy for use in the central nervous system has been hampered by the lack of an efficient vector for gene delivery. We report an adeno-associated virus vector with an enhanced ability to cross the blood–brain barrier in both rodents and non-human primates, and use it to develop systemic anti-tumour gene therapies for glioblastoma.