Publication highlights

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

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Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor

A study led by the Blackman lab has shed new light on a key pathway that allows the malaria parasite to escape from the host’s red blood cells. Their findings identify a target that could be used to develop a new class of antimalarial drug designed to prevent disease progression.

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Published in The EMBO Journal

Published

TRF2-independent chromosome end protection during pluripotency

This work revealed that telomere protection is solved by distinct mechanisms in pluripotent and somatic tissues. In somatic cells, TRF2 sequesters the telomere within a t-loop, preventing telomere end-to-end fusions and inviability. In contrast, TRF2 is dispensable for telomere protection in pluripotent cells; ESCs lacking TRF2 grow normally, do not fuse their telomeres and form functional t-loops. Upon differentiation this unique attribute of stem cells is lost and TRF2 assumes its full role in end protection. The retention of end protection in the presence of t-loops, but absence of TRF2, confirmed that t-loops are a key mediator of telomere end protection irrespectively of how they form.

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Published in Nature

Published

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Memory B cells (MBCs) and plasma cells (PCs) are formed during the so-called germinal center (GC) B cell reaction. In the GC reaction B cells mutate their B cell receptor (BCR) genes and those that acquire a higher-affinity BCR for a pathogen antigen are presumably selected to survive and differentiate, whereas B cells carrying a lower-affinity BCR die. However, this cannot explain retention of GC B cells with varied BCR affinities and the formation of MBCs that normally carry lower-affinity BCRs. This work re-defines selection of GC B cells as permissive to ensure clonal diversity and broad protection.

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Published in Proceedings of the National Academy of Sciences of USA

Published

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

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

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

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

SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27-null mice

Tumour development depends on cell intrinsic dysfunction, but extrinsic factors can also be important drivers. Deletion of p27, which is downregulated in many tumours, predominantly gives pituitary tumours in mice. Sox2, which is transcriptionally derepressed in the absence of P27, is also important for tumorigenesis in this and other systems. Using various approaches, we establish the regulatory interaction in vivo of SOX2 and p27 and show that SOX2 is required independently, both cell-autonomously in the endocrine cells that form the tumours and non-cell-autonomously, in adjacent pituitary stem cells, to orchestrate tumorigenesis in the absence of P27.

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Published in Proceedings of the National Academy of Sciences of USA

Published

A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

New research from the McDonald lab combined crystallography and cryo-electron microscopy to reveal how the RET receptor, tyrosine kinase, recognises different GDNF family ligand/co-receptor pairs.

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Published in Structure

Published

Frequent loss-of-heterozygosity in CRISPR-Cas9–edited
early human embryos

Crick researchers, including Kathy Niakan and James Turner, have revealed that CRISPR-Cas9 genome editing can lead to unintended mutations at the targeted section of DNA in early human embryos. The work highlights the need for greater awareness of and further research into the effects of CRISPR-Cas9 genome editing, especially when used to edit human DNA in laboratory research.

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Published in Proceedings of the National Academy of Sciences of USA

Published

Astrocytes

Reactive astrocytes in ALS display diminished intron retention

A study led by Rickie Patani has identified the trigger of a key cellular change in amyotrophic lateral sclerosis (ALS), a type of motor neurone disease. The findings could help develop new treatments for many neurological diseases with the same change, including Parkinson’s and Alzheimer’s.

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Published in Nucleic Acids Research

Published

The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens

Immune cells such as type 1 conventional dendritic cells (cDC1) can “eat” (phagocytose) dead tumour or virally-infected cells and present associated antigens to CD8+ T cells to elicit a tumour- or virus-specific cytotoxic T cell response. How antigens from the debris get presented on MHC class I (MHC-I) molecules on cDC1 has long been puzzling as MHC-I normally presents antigens found in the cytosol. This paper shows that cDC1 use the DNGR-1 receptor to induce phagosomal rupture, releasing the debris-associated antigens into the cytosol. These findings have implications for our understanding and manipulation of immunity to infection and cancer.

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Published in Nature Immunology

Published

Disruption of the MSL complex inhibits tumour maintenance by exacerbating chromosomal instability

Research from the Scaffidi lab has developed a new strategy to identify cancer-specific vulnerabilities. They identified a group of proteins, called the male-specific lethal (MSL) acetyltransferase complex, which could be used to increase chromosomal instability in cancer cells without inducing severe adverse effects in normal tissues.

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Published in Nature Cell Biology

Published

The migratory pathways of the cells that form the endocardium, dorsal aortae, and head vasculature in the mouse embryo

Using recently developed live imaging techniques, the Smith lab has investigated the migration of cells that initially form the circulatory system in the mouse embryo. Their findings show that, contrary to previous understanding, the yolk sac and embryonic circulatory systems share common origins.

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Published in BMC developmental biology

Published

Lung cancer cell.

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

A new study from the Swanton lab identified genetic changes in tumours which could be used to predict if immunotherapy drugs would be effective in individual patients.

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Published in Cell

Published

Cancer cells.

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Research led by Peter Van Loo, as part of the Pan-Cancer Analysis of Whole Genomes Consortium, has analysed the whole genomes of tumour samples from over 2,600 patients with different types of cancer. They identified a high prevalence of genetic diversity within individual tumours, which they further characterised.

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Published in Cell

Published

Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition

In this paper, we uncover the cell biological basis of a human ribosomopathy. Somewhat unusually, this project was spurred by a member of the public who asked us to create a Drosophila model of his son’s condition caused by a ribosomal mutation (RPS23[R67K]. Flies carrying this mutation are viable but display many markers of cellular stress. Surprisingly, this is not caused by insufficient protein synthesis capacity but instead by a reduced ability to eliminate misfolded proteins, perhaps because of an unusual burden from orphaned ribosomal proteins. We found that pharmacological or genetic inhibition of TOR significantly rescued cellular stress in these animals, suggesting a therapeutic strategy to alleviate the symptoms of this and other ribosomopathies.

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Published in Nature Cell Biology

Published

Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

Targeting the nutritional requirements of cancers through selective dietary intervention is an emerging therapeutic approach. Dietary limitation of the non-essential amino acids serine and glycine can limit the growth of some, but not all, cancers. This study extends this approach by showing combined treatment with an inhibitor of the intrinsic serine synthesis pathway with a serine/glycine free diet improves the therapeutic response and inhibits the growth of cancers that are not responsive to the diet alone. Extension of this work to human studies may offer an important new avenue for the treatment of a broad range of cancers.

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Published in Nature Communications

Published

Accumulation of DNA breaks (red dots) in human cancer cells treated with the PARP inhibitor Olaparib and hmdU and where the DNPH1 protein has been blocked.

Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors

A study led by the West lab has found that blocking a specific protein could increase tumour sensitivity to treatment with PARP inhibitors. Their work suggests that combining treatments could lead to improved therapy for cancer patients.

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Published in Science

Published

Mesoscale cortical dynamics reflect the interaction of sensory evidence and temporal expectation during perceptual decision-making

A study from the Znamenskiy lab has looked at how sensory information is transformed across multiple brain regions and influences behaviour. By training mice in a visual detection task, based on changing sensory information, the team found different timescales between deliberation and action across different regions of the brain.

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Published in Neuron

Published