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

Filter by year of publication

COVID-19 spike with biliverdin binding site.

SARS-CoV-2 can recruit a haem metabolite to evade antibody immunity

A team led by the Cherepanov lab has found a molecule that can block the binding of a subset of human antibodies to SARS-CoV-2. This could explain patients who, despite having high levels of antibodies, become ill.

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Published in Science advances

Published

Scalable and robust SARS-CoV-2 testing in an academic center

This paper decribes how we were able to successfully repurpose the Crick to increase the capacity for Sars-CoV-2 testing in unpredented times.

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Published in Nature Biotechnology

Published

COVID testing

Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers

This important paper showed very high levels of infection amongst healthcare workers in a local hospital. It has influenced government policy – asymptomatic healthcare workers are to be screened as per our recommendation (announced October 12th).

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Published in The Lancet

Published

The mechanism of eukaryotic CMG helicase activation

This paper provided the first view of how the inactive MCM double hexamer is converted to two active CMG helicases. We showed MCM remains bound to ADP after loading; firing factors trigger ADP-ATP exchange; ATP rebinding causes double hexamer splitting, initial DNA melting and CMG formation. Active helicases then translocate N-terminus first.

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Published in Nature

Published

Modular microfluidics enables kinetic insight from time-resolved cryo-EM

Cryo-EM has the potential to study any native conformation of a macromolecule. However, the sample preparation time is high, compared to the timescale of most protein interactions and conformational changes. In this paper, we established a robust method of time-resolved cryo-EM sample preparation. We produced high-quality samples for microscopy while speeding up the process of making them by several orders of magnitude. This allowed samples to be collected within 30ms of the initiation of a biochemical reaction, within the timeframe of many critically important and interesting processes. This enables a whole new class of experiments in structural biology research.

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Published in Nature Communications

Published

Spike protein of SARS-CoV-2.

SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects

We have been able to apply the knowledge we have gained from our work on the infectivity of the influenza virus to the challenge presented by the recent SARS-CoV-2 virus outbreak. In this paper we present high resolution cryo EM structures of the SARS-CoV-2 and bat RaTG13 spike glycoproteins. We describe from a structural perspective the significant differences between the strains. We draw particular attention to the addition of a furin cleavage site into the human virus spike protein. We discuss its potential role in infectivity and on the evolution of this virulent strain.

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Published in Nature Structural & Molecular Biology

Published

Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

Here we describe the conformational changes that the SARS-Cov2 spike protein undergoes in binding to the human ACE2 receptor. This represents the initial stages of the mechanism of cell invasion by the virus particle during infection. We show a series of ten cryoEM reconstructions of the spike protein binding to ACE2 through its receptor binding domain (RBD), ranging from a closed unbound spike ectodomain trimer to the fully open conformation with each RBD in the trimer bound to an ACE2 receptor. Binding to ACE2 releases the so-called fusion peptide segment and promotes membrane fusion leading to cell invasion.

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Published in Nature

Published

D614G SARS-CoV-2 variant spike protein

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Research from the Gamblin lab has compared the original SARS-CoV-2 spike protein with a mutated version which arose last spring. They have found structural differences that could help to explain why the mutated version remains the dominant form circulating in all recent variants of concern.

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Published in Proceedings of the National Academy of Sciences of USA

Published

α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease

Protein aggregation drives neuronal death in Parkinson’s disease, although how transition of monomeric protein structures to aggregated forms causes toxicity is unknown. We demonstrate that aggregation of the protein α-synuclein generates beta sheet-rich oligomers, which localise to the mitochondrial inner membrane, where they impair complex I-dependent respiration, induce oxidation of ATP synthase and cause mitochondrial lipid peroxidation. These oxidation events result in opening of the permeability transition pore, triggering mitochondrial swelling, and ultimately cell death. This work highlights how structural conversion of a protein changes its physiological interaction with proteins and lipids, and induces pathology in human cell models of disease.

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Published in Nature Communications

Published

Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

Aberrant protein-lipid interactions occur in neurodegeneration, although their role is unclear. We show how the protein α-synuclein interacts with lipids to drive a form of cell death, ferroptosis. As α-synuclein aggregates, oligomeric species with hydrophobic domains incorporate into the plasmalemmal membrane, leading to altered membrane conductance and abnormal calcium influx following glutamatergic and dopaminergic stimuli. Aggregates induce iron dependent generation of free radicals, and peroxidation of polyunsaturated fatty acids, which underlies the incorporation of aggregates into the membranes. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling in human neurons, highlighting a new causative role for lipid homeostasis in Parkinson’s disease.

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Published in Cell Death and Differentiation

Published

Antioxidant role for lipid droplets in a stem cell niche of Drosophila

This paper is a continuation of our major research theme on how dividing stem cells in the CNS are able to resist environmental stresses that shut down proliferation in most other developing tissues. It reports the first identification, in any species, of lipid droplets as protectors of stem cells. We discovered that hypoxia induces lipid droplets in the neural stem cell niche and that these protect the neural stem cells themselves from damaging polyunsaturated fatty acid (PUFA) peroxidation reactions. This study laid the foundation for our current mechanistic studies into the antioxidant functions of lipid droplets during development and tumorigenesis.

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Published in Cell

Published

Early-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila

This reports the first identification, in any species, of the microbiome as a key mediator of developmental stress-induced longevity. We found that mild oxidative stress during development robustly increases lifespan via the selective elimination of Acetobacter from the microbiome. This study also highlights that targeted remodelling of the early-life microbiome can provide an efficient strategy for extending healthspan and lifespan.

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Published in Nature Communications

Published

Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population

Stem cell numbers in the hippocampus of young adults stabilise due to coordinated changes in stem cell behaviour which ensures lifelong hippocampal neurogenesis, according to new research from the Guillemot lab.

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Published in Cell Stem Cell

Published

High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

The immune system is increasingly acknowledged to be integrated with general physiology, but the genetic pathways underpinning those are largely unknown. This study demonstrated that high-content immunophenotyping could be accomplished at scale, compatible with a genetic screen and in so doing identified 80 novel immunoregulators (“hits”) and established striking correlations of immunological traits with blood biochemistry markers such as cholesterol and sodium. The paper formed a basis for the successful and rapid application of high-content high-throughput profiling to COVID-IP and to cancer immunomonitoring, and has spawned mechanistic follow-up studies of several of the hits.

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Published in Nature Immunology

Published

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.

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Published in Nature Medicine

Published

A temporal window for signal activation dictates the dimensions of a nodal signaling domain

This paper shows how temporal information in the zebrafish embryo is transformed into a spatial pattern. We demonstrate how the Nodal signalling gradient is formed in the early zebrafish embryo and show that its size and shape are determined by a temporal signal activation window created by a microRNA-mediated delay in the translation of Lefty, a Nodal antagonist. This paper was important as it not only challenged the long-held view in the field that the Nodal gradient was formed by a reaction–diffusion mechanism, but highlighted the importance of signalling duration in gradient formation.

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Published in Developmental Cell

Published

Long-range signaling activation and local inhibition separate the mesoderm and endoderm lineages

The induction of endoderm and mesoderm by the signalling molecule Nodal has long been a textbook example of how a morphogen patterns vertebrate tissues. This study overturned the view that tissues are patterned through a single long-range morphogen gradient. Instead we demonstrated that Nodal functions in an incoherent feedforward loop with Fgf, to determine endoderm and mesoderm specification. Nodal induces long-range Fgf signaling, which is required for mesoderm induction, while simultaneously inducing a cell-autonomous Fgf signaling inhibitor within cells destined to become endoderm. This work represents a major step forward in deciphering the organising principles underlying early embryonic patterning.

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Published in Developmental Cell

Published

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

Using a combination of structural biology, genome editing, and biochemistry, a new study from the Hill lab showed that Shprintzen–Goldberg syndrome is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, as previously predicted.

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Published in eLife

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.

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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

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Published in Science

Published