Publication highlights

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.

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.

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.