Publication highlights

Growth is a key feature of development, but animals, organs and tissues must know when to stop growing. Researchers at the Crick have shown that the sac-like structures that give rise to fly wings do not stop growing abruptly. Instead, growth slows down over the course of days. Measurements of global gene activity during growth deceleration suggest that, as the primordium expands, it becomes increasingly hypoxic. Decreasing oxygen availability, perhaps due to inefficient import as tissue size increases, was confirmed with new genetic sensors of cellular oxygen. This study uncovers a feedback loop whereby growth (and increasing tissue size) leads to hypoxia, which in turn dampens growth to ensure that oxygen demand does not overwhelm dwindling supplies.

Mislocalisation of the RNA binding protein TDP-43 is the pathological hallmark of the neurodegenerative conditions, motor neuron disease (MND) and frontotemporal dementia (FTD). This causes genes to be spliced differently, typically leading to loss of proteins or the formation of proteins with additional peptide sequences. This work uncovers another consequence of TDP-43 pathology: the formation of novel 3’UTRs (non-coding sequences towards the end of RNAs which regulate their functions). These were identified in stem cell-derived neurons and then found specifically in post mortem MND and FTD brains. Intriguingly, certain novel 3’UTRs can make RNAs more long-lived stop RNAs breaking down, leading to increased protein production. These findings shed light on potential novel molecular mechanisms of disease and offer new opportunities for identifying new disease biomarkers.

Correlative light and electron microscopy (CLEM) is a very powerful method for understanding structure and function within cells. Aligning volumetric images from such different modalities is extremely challenging to automate, and is usually performed manually, which is slow and prone to subjective errors. Researchers at the Crick have created this tool to automate the process, with further use cases of other multimodal combinations in mind.

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.

Researchers from the Crick and Liverpool John Moores University (LJMU) have extracted and sequenced the oldest Egyptian DNA to date from an individual who lived around 4,500 to 4,800 years ago, the age of the first pyramids. The individual was buried in Nuwayrat, a village 265km south of Cairo, and had been buried in a ceramic pot in a tomb cut into the hillside. Most of his ancestry mapped to ancient individuals who lived in North Africa and the remaining 20% of his ancestry could be traced to ancient individuals who lived in the Fertile Crescent. This is genetic evidence that people moved into Egypt and mixed with local populations at this time, which was previously only visible in archaeological artefacts. Finally, the team used evidence from his skeleton to suggest he could have worked as a potter or in a trade requiring comparable movements.

The DNA replication checkpoint is essential for maintaining genome stability. Without it, when DNA copying restarts after a stall, too many replication origins—the starting points for copying—are mistakenly activated, ultimately leading to cell death. Researchers at the Crick showed, in human cells lacking this checkpoint, that excessive DNA synthesis from surplus origins consumes the vital replication proteins PCNA and RFC, preventing normal restart of stalled copying at replication forks. Without the protection of PCNA and RFC, the ends of the forks are attacked by a protein called HLTF, causing irreversible damage. Removing HLTF helps cells survive even in the absence of the checkpoint, which has implications for how resistance to anti-checkpoint cancer therapies may arise.

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.

DNA is kept stable through a network of proteins that shape chromatin structure and modify chemical markers. While many of these proteins and pathways have been studied individually, how they interact remains unclear. Researchers at the Crick and the European Institute of Oncology disrupted 200 genes involved in the process, one by one or in combination, and found that most regulators are nonessential due to a variety of backup mechanisms. Cancer-related mutations weaken this network, making instability more likely. This work helps explain how cells maintain stability despite disruptions and how this balance shifts in disease.

Researchers have demonstrated that a genetic method called ‘pooled prime editing’ can screen hundreds of variants in a gene at once and identify which variants affect the gene’s function. The team optimised prime editing to engineer large numbers of variants at the same time in human cells, testing this on two tumour suppressor genes, SMARCB1 and MLH1. These experiments identified loss-of-function variants in areas of the genes matching reports in clinical databases, showing that pooled prime editing can efficiently screen thousands of variants at once, either for basic research to assess variants, or one day for use in the clinic as a diagnostic tool.