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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Bone marrow backup needed to tackle respiratory infections

Researchers in the Reis e Sousa lab have found how the immune system triggers an ‘emergency’ dendritic cell response during infection. Dendritic cells have an important role in the immune system, detecting infectious bacteria, fungi or viruses that have entered the body and alerting T cells which recognise and attack the invader. However, there are few dendritic cells in healthy tissue like the lungs which means that, on infection, their numbers need to be boosted. In their study, the team monitored dendritic cells in mice infected with flu virus and found that, after infection, new dendritic cells are released from the bone marrow in response to a chemokine ‘distress’ signal which directs them to the site of infection.

Recruitment of dendritic cell progenitors to foci of influenza A virus infection sustains immunity

Published in Science Immunology

Published

New tool to control of fruit fly gene expression using light

Researchers in the Vincent Lab, , in collaboration with the group of Yohanns Bellaiche at Institut Curie in Paris, have developed a new tool for robust control of gene expression in Drosophila using light. They successfully used the new method to activate key genes in different tissues and at various developmental stages and demonstrated gain and loss-of-function phenotypes at animal, organ, and cellular levels. Their work provides developmental biologists with the ability to control gene expression with high temporal and spatial resolution, a valuable addition to the Drosophila genetic toolkit.

Rapid and robust optogenetic control of gene expression in Drosophila

Published in Developmental Cell

Published

Cell division in high resolution

Researchers in the Costa and Diffley labs have used high resolution cryo-electron microscopy techniques to observe replicative helicase activation following loading onto DNA. As a prelude to cell division, the genome must be duplicated, and replicative helicases play a fundamental part in this, unwinding DNA and exposing the single-stranded template for the replicative polymerases. The team characterised the role of the key enzymes involved in selectively activating the replicative helicases at the right time and in the right places on DNA, an important step forward in understanding exactly how DNA replication works in both health and disease.

Structural mechanism for the selective phosphorylation of DNA-loaded MCM double hexamers by the Dbf4-dependent kinase

Published in Nature Structural and Molecular Biology

Published

Scientists find that the way tumours grow impacts their genetics

Researchers from the Bates, Turajlic and Sahai labs have collaborated to develop a computer model to analyse how the way in which tumours grow affects their genetic makeup. Using this new model, they have identified links between tumour growth and shape, and how quickly a patient’s cancer might progress.

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

Published in Nature Ecology and Evolution

Published

Researchers identify new PKCε target as key to successful cell division

Researchers in the Parker lab have unpicked the action of protein kinase C (PKC) in modulating cell growth and division. The team developed a novel trap for proteins regulated by PKC by engineering UV-photocrosslinkable amino acids into PKCε to produce a sort of molecular flypaper. They captured a previously unknown PKCε target, the RNA-binding protein SERBP1, and showed that SERBP1 was required for successful chromosome segregation and cell division. Their work provides a new insight into how cells protect their genome during division and also which regulatory processes could play a key role when cells become cancerous.

A genetically-encoded crosslinker screen identifies SERBP1 as a PKCε substrate influencing translation and cell division

Published in Nature Communications

Published

HELQ enzyme facilitates DNA repair

Researchers from the Boulton Lab, in collaboration with the MRC London Institute of Medical Sciences and the Memorial Sloan Kettering Cancer Center, have uncovered the mechanism by which an enzyme called HELQ assists in repairing DNA. Through the use of biochemical analysis and single-molecule imaging, the team have shown HELQ can mend DNA double-stranded breaks by virtue of two distinct activities that are enhanced through its interaction with two other proteins, RAD51 and RPA. Loss of HELQ causes defects in DNA repair, which can lead to cancer and cause infertility, and these results explain the reason for its importance.

HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51

Published in Nature

Published

Gene-editing used to create single sex mice litters

Researchers in the Turner lab, in collaboration with the University of Kent, used gene editing technology to create female-only and male-only mice litters with 100% efficiency. Targeting the Top1 gene, which is essential to DNA replication and repair, their method uses CRISPR-Cas9 to induce sex-linked lethality before embryo implantation, allowing only the desired sex to develop. This proof of principle study demonstrates how the technology could be used to improve animal welfare in scientific research and perhaps also agriculture.

CRISPR-Cas9 effectors facilitate generation of single-sex litters and sex-specific phenotypes

Published in Nature Communications

Published

Researchers identify role of key gene in embryonic development

A zebrafish study by researchers in the Hill lab has provided new insights into the role of the SMAD4 protein in vertebrate embryo development. Very early in development, SMAD4 was thought to be required to transmit signals from two closely related members of the TGF-β protein family, BMP and Nodal, which are responsible for organising different parts of the body plan of an embryo. Surprisingly, when the Smad4 gene was deleted in zebrafish, the parts of the embryo patterned by BMP signalling were severely disrupted, but those for which Nodal was responsible were far less affected. SMAD4 is thus differentially required for signalling by different TGF-β family members, which has implications for diseases such as cancer where it is mutated or deleted.

Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways

Published in Nature Communications

Published

Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation

This work reveals that amino acids, rather than fructose 1,6-bisphosphate, are the relevant cellular regulators of pyruvate kinase M2 (PKM2), a critical node in cancer metabolism. It further elucidates the molecular mechanism of PKM2 regulation by amino acids with a new algorithm that predicts allosteric pathways in proteins, a major and difficult problem in structural biology.

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Published in eLife

Published

COVID-19 vaccine booster provides good antibody protection against Omicron

As part of the CAPTURE study, researchers in collaboration with the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre found that antibodies generated in people who had received only two doses of either the Oxford/AstraZeneca vaccine or the Pfizer/BioNTech vaccine were less able to neutralise the Omicron variant as compared to the Alpha and Delta variants. They also found that antibody levels dropped off in the first three months following the second dose but that a third ‘booster’ dose raised levels of antibodies that effectively neutralise the Omicron variant.

Three-dose vaccination elicits neutralising antibodies against omicron

Published in The Lancet

Published

CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis

Intestinal homeostasis requires a continuous dialogue between commensal bacteria and intestinal immune cells. Natural Killer T (NKT) cells are a population of CD1d-restricted lipid-reactive lymphocytes contributing to the regulation of mucosal immunity, but the mechanisms underlying this are poorly understood. Here we show that lipid presentation by CD1d+ intestinal dendritic cells and macrophages controls NKT cell function and activation which in turn regulates commensal bacteria and immune cell populations in the gut. These results reveal an NKT cell-dendritic cell crosstalk as a key mechanism for the regulation of intestinal homeostasis.

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Published in EMBO Journal

Published

CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth

This work identifies a cancer stem cell (CSC) population in pancreatic ductal adenocarcinoma (PDAC) marked by the tetraspanin CD9. We showed that CD9Hi CSCs are required for the epithelial and mesenchymal cellular heterogeneity seen in PDAC. We found that CD9 assembles a protein complex involved in regulating PDAC metabolism on the cell surface. CD9 depletion dramatically inhibited PDAC growth, identifying CD9 as a therapeutic PDAC target.
These findings suggest that the cellular composition of pancreatic cancer is controlled by a CSC population.

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Published in Nature Cell Biology

Published

3D image of a pancreas

Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis

This study introduces a new technique, FLASH, which enables immunostaining of whole organs for imaging and opens up the possibility of analysing a plethora of antigens and tissues that were previously impossible to study in 3D. By achieving this feat, we were able to study epithelial deformation from the moment of transformation within the intact pancreas, to show that early tumours adopt different shapes depending on tissue curvature, due to the distribution of intracellular forces. The work connects cell mechanics with the biology of tumour development in an unprecedented manner.

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Published in Nature

Published

Image of mouse eyeball taken with light-sheet fluorescent microscopy, with the blood vessels shown in green.

Mouse retinal cell behaviour in space and time using light sheet fluorescence microscopy

We successfully performed the first lightsheet 3D/4D imaging of mouse retinas (focussing on vessels and neurons) to demonstrate that current confocal methods distort vessel tissue. This brings a much improved way to observe and quantify the devastating changes to vessels and neurons in retinopathy mouse models.

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Published in eLife

Published

Phospho-dependent regulation of SAMHD1 oligomerisation couples catalysis and restriction

This study explained the mechanism of SAMHD1 regulation by phosphorylation/tetramerisation and correlated restriction activity with the capacity of SAMHD1 to form long lived, stable tetramers. These data form the basis of the prevailing model for SAMHD1 restriction of HIV-1 where dNTP-stabilised SAMHD1 tetramers deplete and maintain low levels of dNTPs in the non-permissive cells resistant to HIV-1 infection.

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Published in PLOS Pathogens

Published

A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells

This study showed that egress involves an enzyme cascade in which the serine protease SUB1 activates a second, cysteine protease called SERA6, enabling SERA6 to rapidly and precisely cleave the major red cell cytoskeletal protein β-spectrin and dismantle the cytoskeleton. It provides the first plausible model to explain how the parasite accomplishes timely rupture of its host cell membrane.

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Published in Nature Microbiology

Published

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

Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds

In this paper we define the heterogeneity and the clonogenic potential of human thymus stroma; characterise progenitor cells capable of extensive expansion in vitro, thereby achieving clinically relevant numbers with resilience to long-term storage; and report an epithelial-mesenchymal hybrid phenotype of thymus epithelial cells in vivo and in vitro that affects cell behaviour, a unique feature among any epithelia so far reported. We describe a protocol for organs that lack a main vascular access that allowed us to specify the role of natural ECM in supporting organ morphogenesis ex vivo and in vivo; and reconstitute a functional human thymus long-term in vivo.

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Published in Nature Communications

Published

Versatile humanized niche model enables study of normal and malignant human hematopoiesis

Immunodeficient mouse models have been instrumental in improving our understanding of human healthy haemopoietic stem cells and their hierarchical organisation as well as of the functional and phenotypic heterogeneity of leukaemic stem cells in acute myeloid leukaemia. However, xenotransplantation models failed at reconstituting the human bone marrow niche which remains of mouse origin. Using a bioengineered scaffold, we developed a new versatile humanised bone marrow niche which supports the engraftment of both normal and leukaemia stem cells in vivo. This 3D scaffold represents a suitable model to study and dissect the human bone marrow composition and test the effect of specific stroma cell types and niche factor functions during both normal human haemopoiesis and leukaemia.

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Published in Journal of Clinical Investigation

Published

Stabilization of reversed replication forks by telomerase drives telomere catastrophe

This study defined the mechanism leading to critically short telomeres in the absence of RTEL1 and showed that telomerase, which extends telomeres in normal cells, is pathological when forks encounter an obstacle within the telomere. We showed that replication forks stall and reverse at persistent t-loops, which creates a pseudo-telomere substrate that is inappropriately stabilised by telomerase. Removing telomerase or blocking replication fork reversal rescued telomere dysfunction in Rtel1 deficient cells. We proposed that when persistent t-loops stall the replisome, telomerase inhibits fork restart, triggering the excision of the t-loop by SLX1/4 and loss of a substantial part of the telomere.

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Published in Cell

Published