Publication highlights

Children born with mutations in the ARPC5 protein, which is part of the internal cytoskeleton, experience immunodeficiency and a high risk of sepsis. Researchers at the Crick investigated immune system function in mice with and without ARPC5 mutations, observing inflammation in adult mice with ARPC5 deficiency that mirrored that in humans. They showed that this was due to a big change in bacterial composition in the gut after weaning, triggering intestinal inflammation, as giving antibiotics to ARPC5-deficient mice at a critical four-week time point fully prevented the disease from developing. Finally, the team showed that macrophages with ARPC5 mutations had lost their usual shape and could no longer kill bacteria effectively, leading to an overwhelming response to the microbiome.

Researchers at the Crick have found that hunger can make virgin female mice aggressive towards pups, but only in certain hormonal states. These mice would usually ignore other females' pups or show parent-like caring behaviour. The team found that AgRP neurons mediated the effect of food deprivation on behaviour towards pups, by targeting the medial preoptic area. Mice at certain stages of the reproductive estrous cycle were more likely to become aggressive towards pups, dictated by the ratio of oestradiol and progesterone setting the responsiveness of MPOA neurons. They showed that hunger information carried by the AgRP neurons dampens neuronal activity in the MPOA, stimulating the switch from caring behaviour to pup-directed aggression. 

About half of glioblastomas have rogue rings of DNA floating outside of chromosomes called extrachromosomal DNA (ecDNA). The Cancer Grand Challenges eDyNAmiC team, including researchers from Stanford University, Queen Mary University of London and the Crick, integrated genomic and imaging data from people with glioblastomas with advanced computational modelling of the evolution of ecDNAs in space and time. Their analysis revealed that most ecDNA rings contained EGFR, a potent cancer-driving gene. EGFR DNA appeared early in the cancer's evolution and also frequently gained extra changes that made the cancer more aggressive. The time between the first appearance of EGFR ecDNA and the emergence of more aggressive variants may represent a window of opportunity to detect and treat the disease.

As ALS involves disruption to RNA-binding proteins, which coordinate the movement and metabolism of genetic messages called RNAs, researchers at the Crick and UCL investigated how changes to an RNA-binding protein called SFPQ could underpin some of the disease pathology. They identified an alternative version of the SFPQ protein, which is found in a different cellular location compared to the regular SFPQ protein. The team then found that ALS-affected cells are more likely to produce and use the alternative SFPQ protein rather than the regular one, which mirrors findings in ALS patient tissues that SFPQ is often found in abnormal places in the cell. Finally, they showed that the alternative SFPQ has different behaviour and function, which may underlie hallmarks of the disease in ALS-affected cells. This work suggests that correcting levels of alternative SFPQ might alleviate some of the negative downstream consequences for RNA molecules and ultimately damage to nerve cells in ALS.

Researchers have mapped the human metabolic pathways that Cryptosporidium, an intestinal parasite, requires to survive. They conducted a genome-scale screening experiment that involves systematically disabling nearly every protein-coding gene, individually, from human intestinal cells, before infecting the cells with Cryptosporidium. The team found that genes involved in making cholesterol appeared to have opposing effects - some boosting infection and others blocking it. This balance hinged on a molecule midway through the cholesterol production line, squalene. This molecule protects against oxidative stress by stimulating the production of glutathione, which Cryptosporidium needs but cannot make. This leaves the parasite dependent on glutathione from the host cell, a dependency which can be targeted with a high cholesterol drug called lapaquistat. This drug reduced infection in a mouse model of disease and completely blocked intestinal damage, suggesting it could be repurposed to fight Cryptosporidium.

Researchers from the Francis Crick Institute, UCL, Gustave Roussy and Memorial Sloan Kettering Cancer Center (MSK), have discovered that expansion of mutant blood cells, a phenomenon linked to ageing, can be found in cancerous tumours, and this is associated with worse outcomes for patients. Clonal haematopoiesis of indeterminate potential (CHIP) is a condition where blood stem cells accumulate mutations over time. The researchers found that tumour-infiltrating clonal haematopoiesis, not CHIP alone, was associated with greater risk of relapse and cancer death. Patients with TI-CH had an expansion of myeloid cells which can support tumour progression and support. They also discovered that blood cells with TET2 mutations were more likely to be tumour-infiltrating, and that TET2 mutant myeloid cells remodelled the tumour microenvironment. Finally, they validated their findings in over 49,000 patients, finding that mutations were more common in harder-to-treat cancer types.

Scientists from the Crick, UCL, UCLH and Personalis have found that a test to detect circulating tumour DNA can predict lung cancer outcome in a Cancer Research UK-funded study. The researchers tested a platform called NeXT Personal, which can detect very small amounts – 1 part per million – of ctDNA (fragments of DNA released into the blood by tumours). They applied the platform to blood plasma samples from 171 people with early-stage lung cancer in the TRACERx cohort, finding that people with a low level of ctDNA before surgery were less likely to relapse and had improved overall survival rates than people with a high level of ctDNA. The high sensitivity of the test meant that smaller amounts of ctDNA could be detected, which prevented people with a lower amount of ctDNA from being incorrectly labelled ctDNA negative.