Publication highlights

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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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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

NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control

In this paper we showed that cDC1 recruitment and infiltration in several mouse tumour models depends on the chemokines CCL5 and XCL1 produced by NK cells. In human cancers, CCL5/XCL chemokine transcripts correlate with gene signatures for NK cells and cDC1 and predict overall survival in melanoma, head and neck cancer, breast cancer and lung adenocarcinoma. Therefore, our data uncovered a mechanism for cDC1 recruitment into tumours that is translatable to humans and cancer patient survival.

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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

Cancer cells colliding with fibroblasts

STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy

This work shows why stromal fibroblasts are an important source of inflammatory modulators in tumours. We show fibroblasts can respond to cGAMP produced by cancer cells, but only when the two cell types are in direct contact. This in turn promotes the STING and IRF3 dependent expression of interferon beta and various chemokines. The subsequent up-regulation of interferon-stimulated gene expression undermines the efficacy of oncolytic viruses. We propose the requirement for direct contact represents a ‘tissue level’ mechanism for triggering this response specifically in the context of tissue damage, as in healthy tissue, the basement membrane precludes such interactions.

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Published in Nature Cell Biology

Published

Image showing colonies of cells, showing differentiation in the first germ layers.

GATA3 mediates a fast, irreversible commitment to BMP4-driven differentiation in human embryonic stem cells

This manuscript was the first demonstration that irreversible commitment to cellular differentiation during early development happens unexpectedly early. The paper reflects our interdisciplinary work, combining single cell imaging, mathematical modelling and -omics approaches. We discovered a new class of genes which we termed early commitment genes (ECG) that are responsible for the pluripotency-to-differentiation transition. It was also our first manuscript in developmental biology, a new field outside of our lab’s expertise.

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Published in Cell Stem Cell

Published

Active sampling state dynamically enhances olfactory bulb odor representation

Animals engage actively with their environment, yet how active sampling strategies impact neural activity was unknown. We showed that mice adapt sniffing during learning in a way that enhances neuronal representation. Furthermore, this work resolves a long-standing conundrum that seemingly non-olfactory information is prominently represented in the OB: context influences sniffing, which in turn changes neural activity.

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Published in Neuron

Published

Figurative illustration of a brain-computer interface

Massively parallel microwire arrays integrated with CMOS chips for neural recording

Neuroprosthetics and neuroscience research alike are limited by the bandwidth of neural recording. At the same time, ever-more powerful silicon-based technology is ubiquitous in our phones, tablets and computers. Here we showed that progress in neural recording can be coupled to this by fusing bundles of microwires to pixel array chips, lifting silicon technology to the third dimension for deep brain recording.

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Published in Science advances

Published

Metabolic precision labeling enables selective probing of O-linked N-acetylgalactosamine glycosylation

The first publication from our group at the Crick comprises the development of a precision tool to understand O-GalNAc glycosylation, one of the most abundant and disease-relevant types of glycans. We apply the technique to run state-of-the-art methods of biology, including chemical glycoproteomics with the Proteomics STP and a genome-wise CRISPR screen with collaborators from Stanford. We also collaborate in-house with Vivian Li to apply the probe to imaging intestinal organoids.

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Published in Proceedings of the National Academy of Sciences of USA

Published

Handprints made by hunter-gatherer ancestors in Cueva de las Manos, Patagonia, around 9,000 years ago.

Insights into human genetic variation and population history from 929 diverse genomes

In this paper, led by the Sanger Institute, we characterised global human genetic diversity in whole-genomes at a greater scale and with broader diversity than before. We documented complex divergence between modern humans and archaic groups such as Neanderthals. Lead author Anders Bergström started work on the project during PhD studies at the Sanger, and continued it with my input as a Crick postdoc from April 2018 until publication in 2020.

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Published in Science

Published

Skull of an ancient dog next to a skull of a modern wolf

Origins and genetic legacy of prehistoric dogs

This first research paper led by our lab presents the first large-scale study of ancient genomes from early domestic dogs. We show that dogs were domesticated prior to the agricultural transition, with a dynamic history that includes collapse of early genetic diversity of dogs in Europe, and a complex evolution of genetic adaptation to starch rich diets.

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Published in Science

Published

Microscopic image of a mouse colon.

The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity

This paper demonstrates a cell intrinsic role for AHR in intestinal stem cells. AHR deficiency in intestinal epithelium causes dysregulation of the Wnt pathway, overproliferation of crypt stem cells and impaired epithelial differentiation following injury, culminating in tumorigenesis.

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Published in Immunity

Published

Image showing a red blood cell infected with the malaria causing parasite.

An exported kinase family mediates species-specific erythrocyte remodelling and virulence in human malaria

We demonstrate species-specific remodelling of red blood cells by the most virulent malaria-causing parasite, mediated by a species-specific expansion of an exported kinase family. Systematic deletion of all 20 members and quantitative phosphoproteomics identifies the kinase targets and supports their role in pathogenesis.

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Published in Nature Microbiology

Published

Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

The MRTF-SRF and the YAP-TEAD transcriptional regulatory networks both respond to extracellular signals and mechanical stimuli: the MRTFs are controlled directly by G-actin, while YAP activity is somehow potentiated by F-actin. Cancer-associated fibroblasts play an important pro-invasive role in stimulating cancer progression, and previous studies have shown that this involves YAP-TEAD signalling. This paper shows that CAFs also exhibit mechanically-dependent MRTF activation, which is also required for their contractile and pro-invasive activity. The two pathways are mutually dependent, requiring recruitment of MRTF and YAP to DNA via their respective DNA-binding partners, and reflecting their ability to control cytoskeletal gene expression.

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Published in Genes & Development

Published

Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme

Unlike kinases, PPP-family phosphatases such as PP1 have little intrinsic specificity. PP1 acts in partnership with over 200 different PP1-interacting proteins, but it has remained unclear how they might confer sequence-specificity on PP1. We used proteomics to identify dozens of candidate Phactr1/PP1 substrates, and used structural and biochemical approaches to show that the Phactr1/PP1 holoenzyme is sequence-specific. Phactr1 binding reshapes the PP1 hydrophobic groove, thereby creating a novel composite hydrophobic surface for substrate recognition. This study explains how cofactors can enhance the reactivity of PP1 toward specific substrates, and suggests a way forward for the development of PP1 holoenzyme-specific inhibitors.

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Published in eLife

Published

Escape from nonsense-mediated decay associates with anti-tumor immunogenicity

Fs-indels that escape the nonsense-mediated decay (NMD) pathway, can elicit anti-tumor immune responses, especially those the highly elongated neo open reading frames. NMD-escape fs-indels represent an attractive target for biomarker optimisation and immunotherapy design.

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Published in Nature Communications

Published