Publication highlights

Researchers at the Crick have discovered that Mtb, the bacterium causing tuberculosis (TB), alters its outermost layer, its lipid cell envelope, when it encounters low phosphate conditions. This allows it to survive inside human immune cells, where phosphate is restricted. It can scavenge phosphate from human lipids (fats), which are present in the lungs, allowing the bacteria to grow when no other source of phosphate is present. These findings demonstrate a method that Mtb employs to overcome the human host’s attempts to restrict its growth. The replacement lipids produced
when phosphate is restricted therefore represent new drug targets for the treatment of TB. Additionally, vaccines that target TB via its lipids should take into account the particular lipids present when the cell is phosphate starved, as demonstrated here.

If a tightly packed layer of epithelial cells gets overcrowded, excess cells are extruded, causing them to die. To find out how the body decides which cells are extruded, researchers at the Crick and King's College London set up live imaging of overcrowded epithelial cells under a microscope. They found that overcrowding triggers sodium channels on epithelial to open, bringing in salts and depolarising the cells. The strong ones can pump the sodium back out, repolarising themselves, but weak ones without energy can't, using a 'last gasp' of energy to activate a current that results in water rushing out of the cells, causing them to shrink and extrude.

Researchers have shown that the transfer of genes from bacteria into more complex organisms can give them an advantage but requires remodelling of the host’s biology. The lab explored the integration of a horizontally transferred gene coding for an enzyme called squalene-hopene cyclase (Shc1) from bacteria into S. japonicus yeast. They found that S. japonicus switches between using an enzyme that generates sterols in the presence of oxygen, Erg1, and the horizontally acquired Shc1 enzyme to produce hopanoids in conditions without oxygen. They showed that hopanoids are best accommodated in the membrane if it is made of asymmetrical lipids, so S. japonicus has adapted to produce two different lengths of fatty acids. The researchers concluded that the bacterial gene provided S. japonicus with an advantage against other yeast species, especially in high temperature and low oxygen environments.

Researchers have found that the small intestine grows in response to pregnancy in mice. This partially irreversible change may help mice support a pregnancy and prepare for a second. They found that pregnant mice had a longer small intestine from just seven days into the pregnancy. By the end of the pregnancy, around day 18, the small intestine was 18% longer, and it remained longer up to 35 days after lactation. The villi and crypts inside the small intestine also became longer and deeper at the same time, but returned to pre-pregnancy values just seven days after weaning. The researchers identified an increase in a membrane protein called SGLT3a early in pregnancy. This sodium and proton sensor was responsible for about 45% of the villi growth triggered by reproduction but wasn't necessary for entire small intestine lengthening. The team believe hormones may play a role in switching on the gene for SGLT3a.

Researchers at the Crick and NPL, as part of the CRUK Grand Challenges team Rosetta, have developed a multimodal imaging pipeline that extends upon the principles of correlative light, electron, and ion microscopy (CLEIM), which combines confocal microscopy reporter or probe-based fluorescence, electron microscopy (EM), stable isotope labelling and Nanoscale secondary ion mass spectrometry (NanoSIMS). Their protocol allows an unprecedented extraction of biological information from specimens, whilst being based on a series of well-established and widely available technologies, thus allowing quick adaptation of the protocol for individual research needs. This integration provides a multifaceted view of the tissue microenvironment, capturing both the internal cellular architecture and the intricate metabolic dynamics occurring within. The researchers tested their pipeline by imaging the incorporation of carbon from glucose into B and T cells in mouse liver tumours.

The germinal centres (GCs) of the body act as factories where antibody-secreting B cells are fine-tuned to reach their highest antigen affinity. GC-B cells cycle between two GC zones, undergoing antigen-driven selection and initiating cell division in the light zone (LZ), before migrating to the dark zone (DZ), where they vigorously proliferate. Initiation of cell division in the LZ was a puzzle, as the low-oxygen conditions in the LZ normally induce cell cycle arrest. Researchers at the Crick showed that a microRNA called miR-155 metabolically reprogrammes LZ GC-B cells by regulating genes that enhance energy production and prevent cell death. This process is essential for effective immune function in the face of infection.

Researchers from the University of Cape Town and the Crick worked together to investigate vitamin D supplementation and growth in children. Results from a clinical trial, conducted in a large number of African schoolchildren in Cape Town, South Africa, showed that a 3-year course of weekly vitamin D supplementation was effective in elevating vitamin D levels, however this was not associated with any effect on growth, body composition, pubertal development or lung volumes. There has been a lot of interest in the links between vitamin D deficiency in childhood and slower linear growth, reduced lean mass, obesity and precocious puberty, but this study suggests that vitamin D supplementation wouldn't be a useful intervention.

Individuals with inheritable mutations in the BRCA1 or BRCA2 tumour suppressor genes are unable to carry out a DNA repair process known as homologous recombination, and are predisposed to breast, ovarian and prostate cancers. In the clinic, these cancers are treated with inhibitors of poly [ADP-ribose] polymerase (PARPi) which knocks out a second repair process, and makes the tumour cells die. While effective at initial cancer maintenance, after a period of time the tumours unfortunately develop resistance to PARP inhibition leading to further growth. However, researchers recently discovered that loss or inhibition of a nucleotide pool sanitiser called DNPH1 sensitises BRCA-deficient cells to PARPi, offering a promising strategy for improved therapy for these individuals. The DNPH1 normally removes faulty nucleotides from the cell to stop their incorporation into DNA, so DNPH1 loss leads to an overload in the second repair pathway that is sensitive to PARPi, causing tumour cell death. There is now significant pharmaceutical interest in the development of small molecules that will target and inhibit DNPH1. Towards this goal researchers at the Crick have determined the X-ray crystal structure of DNPH1 bound to the molecule that it acts upon, which will now allow rational drug design.