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.

Researchers at the Crick have produced a new embryo model that self-organises around ten somites alongside a single neural tube, mirroring aspects of human embryos at 28 to 35 days after fertilisation. As the models don't contain a notochord, the team introduced signals that would have originally come from a notochord, and observed a shift in cell fates. They also saw spontaneous patterning in the neurla tube, showing it was developing into different identieis depending on the cell's location. This suggested that the somites and the neural tube were in close communication. The team confirmed that increased retinoic acid signalling in specific somite regions was likely due to signalling to the neural tube, allowing spontaneous patterning. This crosstalk helps prompt regional identities and may be important for later maturation to neuronal or skeletal tissues.

Researchers at the Crick and King's College London have used phototherapy to inhibit a protein in E. Coli bacteria that makes them resistant to antibiotics. They designed a new chemical tool, Ru1, composed of a light-activated ruthenium metal complex attached to an organic ligand that binds to NDM-1, an enzyme in drug-resistant bacteria that breaks down common beta-lactam antibiotics like penicillin. When exposed to blue light, the metal complex produces reactive oxygen species that cause damage to NDM-1, preventing it from binding and destroying an antibiotic. They showed that Ru1 can boost the activity of meropenem antibiotic against E. Coli by 53 times, without showing toxicity to human cells.

Researchers at the Crick and the Paul Scherrer Institute have developed a new imaging protocol to capture mouse brain cell connections in precise detail. Building on standard volume EM sample preparation protocols, they tested a new step - embedding the stained tissue using a resin developed in the nuclear and aerospace industries to protect against radiation. The samples were then imaged using X-rays in a synchrotron. The resulting images, produced using a specific type of X-ray imaging called X-ray ptychography, reached a resolution of 38nm. This was enough to show multiple elements of the mouse brain circuitry, including synapses, dendrites and axons.

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. 

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.

The RAS oncogene is mutated in around one in five cancers, and was once referred to as 'undruggable'. Scientists are now focusing on a particular enzyme RAS targets, called PI3K, hoping to stop uncontrolled cancer growth while maintaining the function of RAS in healthy cells. Researchers at the Crick and Vividion Therapeutics used chemical screening to find a series of small compounds thatmight stop the RAS-PI3K interaction without blocking PI3K's other functions. These compounds were then tested in mice with RAS-mutated lung tumours. The treatment effectively halted tumour growth, with no evidence of hyperglycaemia, which is a problem for current drugs on the market. It also slowed tumour growth in mice with HER2 mutations.

Chemical reactions are initiated by an energy source that can be provided by heat, electric current or light, and are generally governed by the rules of thermodynamics. Mechanical forces are an alternative means of activating chemical reactions, often steering reaction pathways that result in products different from those obtained under thermodynamic control. In this work, researchers from the Crick demonstrated that mechanical forces activate chemical reactions that are chemically forbidden, such as the reduction of an individual protein disulfide bond by an inorganic sulfur-oxyanion. Occurring within the core of a protein with a physiological mechanical role, the force-unlocked reactivity has a direct impact on protein elasticity.