Publication highlights

Go inside our research

Explore a selection of research cases studies from the past five years.

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Intro

Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Highlights

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Preexisting and de novo humoral immunity to SARS-CoV-2 in humans

An example of our work on COVID-19 and of the flexible and collaborative nature of the Crick, involving several labs within the Crick and our collaborating universities and university hospitals. In this work, we described the discovery of pre-existing binding and neutralising antibodies against SARS-CoV-2 in uninfected and unexposed individuals. These antibodies, likely induced by exposure to seasonal coronaviruses, are present in a small percent of adults but in the majority of children, consistent with the relative sparing of the latter from the severe form of COVID-19

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Published in Science

Published

Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure

Children with intestinal failure cannot absorb the nutrients that are essential to be healthy. In the most severe cases, patients may require transplantation. However, there is a shortage of donor organs and complications can arise after surgery. We have shown how intestinal stem cells and intestinal tissues taken from patients can be used to grow functioning intestinal grafts in the laboratory, which could offer a safe and longer-lasting alternative to traditional donor transplants.

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Published in Nature Medicine

Published

Histology of gonads from patient showing bilateral dysgenetic testis.

Testis formation in XX individuals resulting from novel pathogenic variants in Wilms’ tumor 1 (WT1) gene

Through analysis of a large collection of clinical cases of Disorders of Sex Differentiation (DSDs), and a mouse model, we showed that unlike previous association of WT1 variants with XY female development, variants of the fourth zinc finger (ZF4) WT1 are a relatively common cause of XX male development, where the gonads are testes or ovotestes. This article is typical of our interaction with clinical geneticists, where our studies on the mouse, including generating models of human disorders, provide valuable insight into conditions affecting patients, as well as revealing novel insights into the underling mechanisms.

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Published in Proceedings of the National Academy of Sciences

Published

Neutrophils support lung colonization of metastasis-initiating breast cancer cells

In this study we found that via the release of leukotrienes, neutrophils selectively support the more metastatic subset of cancer cells infiltrating the distant tissue and that this activity can be blocked by an inhibitor of leukotriene production. This is one of the most important publications from my laboratory, as it has contributed to the understanding of the crucial responses of neutrophils during metastatic progression.

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Published in Nature

Published

IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche

In this work we mined this database to refine hESC culture conditions. These data will be a powerful resource for the community and will lead to changes in how hESCs are cultured in the future. Building on these data, we demonstrated that IGF1-receptor/PI3K/AKT, but not FGF receptor, signalling is required for hESC self-renewal. We built a searchable website that includes a compendium of human embryo gene expression analysis and compiled a list of all possible ligand and receptor interactions.

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Published in Nature Communications

Published

Initiation of a conserved trophectoderm program in human, cow and mouse embryos

We discovered that the mechanism underlying the first lineage decision in human embryos is mediated via cell-cell contact, triggering a cascade of broadly evolutionarily conserved molecular events that initiates a switch to a placental progenitor programme. We believe that our study will have clinical impact given that the timing of this decision coincides with the stage when most human embryos arrest.

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Published in Nature

Published

The hydrophobic patch directs cyclin B to centrosomes to promote global CDK phosphorylation at mitosis

Disruption of a hydrophobic patch in the Cdc13 B-cyclin prevents localisation of CDK at the centrosomal spindle pole body, blocks mitosis, and compromises phosphorylation of the weakest CDK substrates. We propose this mechanism contributes to CDK substrate regulation.

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Published in Current Biology

Published

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

An important factor in determining the outcome of M. tuberculosis infection was identified in new research from the O’Garra lab. The team found that the cytokine type I interferon-induced neutrophil extracellular trap (NET) formation promotes bacterial growth and disease severity.

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Published in Nature Communications

Published

ESCRT-III/Vps4 controls heterochromatin-nuclear envelope attachments

Here we show that the inner nuclear membrane Lem2-Nur1 complex serves a substrate for the nuclear ESCRT-III/Vps4 machinery and explain how the dynamic tethering of chromosomes to this complex during interphase is linked to the establishment of nuclear compartmentalization following mitosis.

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Published in Developmental Cell

Published

Credit: Yuuki Obata and Álvaro Castaño, The Francis Crick Institute. Neuronal fibres labelled with rainbow fluorescence proteins.

Neuronal programming by microbiota regulates intestinal physiology

In this paper we explore the molecular mechanisms used by enteric neurons to monitor the luminal environment of the gut. In particular, we demonstrate that the transcription factor AhR functions as a biosensor of intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen.

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Published in Nature

Published

The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

The paper unravels the cell cycle dependent input to PKCe engagement and its proximal action through AuroraB. The non-apoptotic M-Phase role of caspase7 in cleaving a chromatin-associated pool of PKCe, alongside the site switching mechanism that plays out in the control of Topo2A by AuroraB are unusual and distinctive features of this cell cycle programme. The mechanistic insights into this transformation-associated pathway provide a specific steer to intervention oppportunities in cancer.

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Published in Nature Communications

Published

DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput

This paper demonstrates the power of neural networks in deconvoluting complex biological data. We developed an easy-to-use integrated software suite, DIA-NN, that exploits deep neural networks and new quantification and signal correction strategies for the processing of data-independent acquisition (DIA) proteomics experiments. DIA-NN improves the identification and quantification performance in conventional DIA proteomic applications, and is particularly beneficial for high-throughput applications, as it is fast and enables deep and confident proteome coverage when used in combination with fast chromatographic methods.

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Published in Nature Methods

Published

A COVID-19 virus particle

Ultra-high-throughput clinical proteomics reveals classifiers of COVID-19 infection

Point-of-care diagnostic classifiers for COVID-19 are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that can be implemented in regulated clinical laboratories. We use our platform to identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. This work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.

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Published in Cell systems

Published

Apical length governs computational diversity of layer 5 pyramidal neurons

This is the first paper from my lab. We showed that layer 5 pyramidal neurons, the main cell type in the cortex, are functionally more diverse than previously thought. This has wide-ranging implications for the modular organisation and cortex and for computational capabilities. Furthermore, using numerical modelling, we discovered how the shape of neurons governs their computational ability, a simple, yet very powerful finding.

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Published in eLife

Published

Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control

The paper establishes isoform specificity of the action of Hypoxia Inducible Factors in specific physiological control mechanisms; specifically the non-redundant role of HIF2 in ventilatory acclimatisation to sustained hypoxia. It also establishes that pharmaceutical antagonism of HIF2 using agents which are undergoing trials in clinical renal cancer have the ability to disrupt normal human ventilatory control.

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Published in Journal of Clinical Investigation

Published

Cyclooxygenase-dependent tumor growth through evasion of immunity

In this paper, we uncovered a potent mechanism of cancer immune evasion, namely cyclooxygenase (COX)-dependent secretion of prostaglandin E2 (PGE2) by tumour cells. We further showed that the growth of PGE2-secreting tumours in mice can be reversed by a combination of checkpoint blockade immunotherapy and COX inhibitors, suggesting that COX inhibition might be a useful addition to both conventional and immune-based therapy of cancer. This paper led to seven clinical trials worldwide to test combinations of prostaglandin E2 inhibition with checkpoint blockade cancer therapies.

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Published in Cell

Published

Single-domain antibodies as crystallization chaperones to enable structure-based inhibitor development for RBR E3 ubiquitin ligases

In collaboration with GSK and the Crick-GSK LInkLabs we selected single-domain antibodies (dAbs) based on a human scaffold that recognise the catalytic domain of HOIP, a subunit of the multi-component E3 ligase LUBAC. We used these dAbs to interrogate the ubiquitin transfer mechanism of HOIP, and as crystallisation chaperones to crystallise a HOIP RBR/dAb complex. This complex now serves as a robust platform for soaking of ligands that target the active site cysteine of HOIP, thereby providing easy access to structure-based ligand design for this important class of E3 ligases.

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Published in Cell Chemical Biology

Published

Structural transitions in influenza haemagglutinin at membrane fusion pH

The influenza HA is one of two glycoproteins on the surface of influenza virus and mediates receptor binding and membrane fusion during viral entry.In order to understand the function of HA in influenza infectivity it is necessary to understand the mechanism of endocytosis. It has previously been established that endocytosis involves a large conformational rearrangement of the HA protein that can be triggered by a change in pH, revealed by structures of initial and final states. Here, we directly image structural transformations in the HA at the pH of membrane fusion and solve the structure of three structural intermediates including a 150 Å-long triple-helical coiled coil of the HA2 transmembrane subunit. This was a long sought-after result and showed new, surprising concerted conformational rearrangements important to the membrane fusion mechanism.

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Published in Nature

Published

Imaging showing the different types of tissue structure organised by fibroblasts.

Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions

In this study, we used our bank of patient-dervied stromal fibroblasts to ask why some fibroblasts generate highly aligned extra-cellular matrices and other do not. We were able to show how cell migration and cell-cell collisions can dictate the patterns formed by fibroblasts, and that furthermore, the higher order organisation of fibroblasts and matrix is associated with millimetre scale contraction of reconstituted tissues and cancer invasion. The quantitative tool developed during the course of this work and a related study is now being tested for its prognostic value in simple histological stains of breast and prostate cancers.

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Published in Nature Materials

Published

Image showing mouse breast cancer cells (orange) within lung tissue (light pink) connected with protein fibres (purple).

Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination

We set up a complex model for lung alveoli by co-culturing lung fibroblasts and alveolar epithelial type I and type II cells on a gas permeable support, with the expectation that the fibroblasts would strongly influence the behaviour of cancer cells introduced into the system. However, we discovered that the largest effect came from the alveolar epithelial cells, and we then used a range of approaches to delineate the signalling mechanisms involved. This work, together with a concomitant study from the Malanchi group, established the role of epithelial cells in the tumour microenvironment of indolent and micro-metastases.

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Published in Nature Cell Biology

Published