Publication highlights

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

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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.

Cytokines

A balancing act: preventing an overactive immune system

Researchers at the Crick, University of Cambridge, Sanquin and the NOVA University investigated how T cells switch off immune functions as quickly as they are switched on, looking at two mRNA shutdown signals: AU-rich elements (long stretches of nucleotides that signal to other proteins to degrade the mRNA) and m6a methylation (adding chemical red flags to mRNAs to mark them for removal). They mapped all m6a methylation sites in human T cells before and after activation, observing that m6a methylation doesn't happen randomly, but often takes place near AU-rich elements. When these two signals occurred close together, the mRNA rapidly degraded, referred to as 'meta-unstable'. This system allows the immune system to keep the balance between under and overactivation.

Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation

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Published in Nature Communications

Published

Synthetic sugars

Sweet signals: tracking crucial cell messengers for the first time

Researchers at the Crick and Imperial College report a method to characterise and track sugar-coated cell sensors called proteoglycans using click chemistry. Through a 'bump and hole' engineering technique, they modified a hole in an enzyme and a bump in a sugar, to alter an enzyme that glues the two together so it accepts a bumped version of the sugar. This modified sugar contains a chemical tag which means it can be traced using click chemistry, such as attaching a fluorescent molecule to 'see' the molecule by imaging, or a molecule acting like an anchor to isolate and further study it. In the future, these molecules could be tagged and tracked in different contexts, or proteoglycan function could be altered by replacing the sugar chain with a different biological or synthetic molecule.

Xylosyltransferase engineering to manipulate proteoglycans in mammalian cells

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Published in Nature Chemical Biology

Published

Cell death programmes

Unravelling a cell death programme evaded by half of all cancers

When normal cells become cancer cells, they undergo a series of genetic changes that allow them to divide indefinitely. One such change involves the loss of a protein called Schlafen 11 (SLFN11), which occurs in half of all cancers. SLFN11 activity results in programmed cell death in response to damaged DNA, which naturally occurs during cancer cell transformation. Thus, loss of SLFN11 renders cancer cells immune to DNA damage and resistant to wide range of chemotherapies currently used in the clinic. However, how damaged DNA activates SLFN11 to cause programmed cell death is not known. Here, researchers at the Crick have uncovered what cellular processes lead to a specific type of DNA damage that activates SLFN11 and programmed cell death. This work provides insight as to why half of all cancers lose SLFN11 in response to naturally occurring DNA damage.

RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress

Published in Nature Cell Biology

Published

HeLa cells with and without f-actin antigen

Lifting cancer’s invisibility cloak

Researchers at the Crick investigated whether dendritic cells detect dead cancer cells via a receptor called DNGR-1, which detects F-actin. Looking at mice with and without the DNGR-1 receptor that had been exposed to carcinogens, they found that mice without DNGR-1 developed tumours significantly earlier and to a greater extent. Next, the team examined whether certain cancer mutations were more likely to be found in the tumours of mice without DNGR-1. They reported an increase in mutations in proteins that bind to the F-actin scaffold. This may be because, in mice with DNGR-1, mutations in these proteins are highlighted as a red flag for the immune system. Without DNGR-1, there's less evolutionary pressure for cancer cells to get rid of them.

Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity

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Published in Nature Immunology

Published

Lung-on-chip

Built to breathe: mini ‘lungs’ recreate individual response to infection

Researchers at the Crick and AlveoliX have developed the first human 'lung-on-chip' model using stem cells taken from only one person. The team produced type I and II alveolar epithelial cells and vascular endothelial cells from human-induced pluripotent stem cells. These epithelial and endothelial cells are separatley grown on the top and bottom of a very thin membrane in a device to recreate an air sac barrier, which experience rhythmic three-dimensional stretching forces on the recreated air sac barrier, mimicking the motion of breathing. The scientists then added macrophages into the chip, before adding TB bacteria. In the chips infected with TB, the team reported large macrophage clusters containing a group of dead macrophages in a necrotic core.

Autologous human iPSC-derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection

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Published in Science advances

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.