Publication highlights

Go inside our research

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

Read now
A Crick researcher reading a scientific paper on a screen.

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

Filter by year of publication

A COVID-19 virus particle

A dynamic COVID-19 immune signature includes associations with poor prognosis

SARS-CoV-2 infection and life-threatening COVID-19 caused the world’s most severe infectious disease pandemic in 100 years. An immediate priority was to decipher what was happening to patients’ immune systems. Rapidly deploying its skill-sets in high-content, high-throughput immunoprofiling, the Immunosurveillance Laboratory identified a dynamic, COVID-19 immune signature that blended textbook immunoprotection with examples of immune dysregulation that today’s textbooks do not describe. Among those, three molecules measured upon hospital admission seemingly predict a patient’s likelihood of deterioration over the next week; knowledge which can benefit health-care resource management, and offer novel therapeutic targets in COVID-19 and other inflammatory infectious diseases.

View the publication

Published in Nature Medicine

Published

Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development

This study describes the ubiquitome of several stages of the intra-erythrocytic development and extracellular stage of the malaria parasite in the blood stream. It highlights the remarkable changes in ubiquitylation that occur and a number of very interesting substrates. Using a chemical biology approach we show the importance of the first step in the pathway and the consequences of its inhibition during intra-erythrocytic development.

View the publication

Published in PLOS Pathogens

Published

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

View the publication

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.

View the publication

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.

View the publication

Published in Proceedings of the National Academy of Sciences

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.

View the publication

Published in Nature Communications

Published

Genome editing reveals a role for OCT4 in human embryogenesis

The first demonstration of the utility of CRISPR–Cas9-mediated genome editing for investigating gene function in the context of human embryonic development. We revealed a distinct role for the developmental regulator OCT4 in human versus mouse development.

View the publication

Published in Nature

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.

View the publication

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.

View the publication

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.

View the publication

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.

View the publication

Published in Developmental Cell

Published

Lineage-dependent spatial and functional organization of the mammalian enteric nervous system

In this paper we use genetic lineage tracing and clonal analysis to characterise mammalian enteric nervous system progenitors, define differentiation trajectories for enteric neurons and glia during development and propose a new model for the 3-D organisation of the enteric nervous system.

View the publication

Published in Science

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.

View the publication

Published in Nature

Published

Reactive oxygen species localization programs inflammation to clear microbes of different size

How inflammatory programmes are tuned to recruit sufficient numbers of neutrophils to clear microbes of different size remained unknown. Furthermore, neutrophils were not thought to serve as major regulators of inflammation in vivo. We showed that reactive oxygen species localisation allows neutrophils to regulate their own recruitment by setting the appropriate level of cytokine production.

View the publication

Published in Immunity

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.

View the publication

Published in Nature Communications

Published

A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models

We addressed the hypothesis that impairment of neuroprotective astrocytic mechanisms are disrupted in ALS using in vivo models, and patient-specific iPSCs. We found that EphB1, a neuronal signal, can induce a neuroprotective astrocyte phenotype through the EphrinB1 receptor / JAK-STAT pathway and that this response fails in ALS astrocytes.

View the publication

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.

View the publication

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.

View the publication

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.

View the publication

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.

View the publication

Published in Journal of Clinical Investigation

Published