Publication highlights

When we think about cell signalling, be it developmental transitions, or be it the sequential events that make up the cell growth and division cycle, we think of regulators. Typically, a kinase is thought to exert control over downstream events, such as the cyclin-dependent kinase (CDK), which has master control over cell cycle progression. Researchers at the Crick revisit how CDK phosphorylates each of its many cell cycle targets at the right time. Not merely a decision by the kinase, they realise that the substrates themselves contribute to deciding when their phosphorylation time has come. ‘Substrate control’ likely more widely forms part of cell signalling decisions.

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.

Organisms grow through the division of the cells that make up our bodies. As well as growth, cell division is also essential for different types of cells to decide what cell type they will become (from different neurons in our brains to the cells that line our guts). How cells divide therefore needs to be tightly controlled both in space (so that the daughter cells after division end up in the right place) and in time (so that daughter cells make the correct choice of what to become). To make this process even more complicated, each cell type is very different in terms of shape, behaviour etc…, so cell division must adapt to the needs of each tissue, an aspect of biology we know very little about. Researchers at the Crick have found a protein called Meru (called after the Bengali word for “polar”) that can tell a cell in which direction and when to divide. Meru is located at one of the poles of a cell type called the sensory organ precursor and allows this cell to orient itself in the tissue and to time its division just right to allow both daughter cells to create the right structure.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, infects lung macrophages and subverts immune responses. In this work, researchers at the Crick developed genetically encoded probes to visualise calcium fluxes in human macrophages. By visualising calcium, they discovered that calcium is an important signal during infection that leaks from Mtb phagosomes. This calcium flux triggers a complex membrane remodelling and the association of autophagic proteins ATG8/LC3 to these membranes. They show that this membrane remodelling is important to limit the damage that Mtb inflicts in macrophage membranes and restrict Mtb infection as part the innate immune response.

Researchers at the Francis Crick Institute, King’s College London and the University of Fribourg have developed polymer water channels, similar to commonly used plastics, that can draw salt out of water, inspired by the body’s own water filtering system. If their innovation could be scaled up and produced industrially, this could help to filter seawater to create drinking water. The new channels mimicked aquaporins, proteins that rapidly transport water across cell membranes while excluding salt, and were organised into a helix structure called polymers or into cyclic structures called macrocycles. The pores inside the two types of channels were filled with a chemical mixture of fluorine and molecules called hydrocarbons, which together create a greasy layer. Through a series of experiments, the team confirmed that the channels actively transported water across a membrane and excluded salt.

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 have identified genetic changes in blood stem cells from frequent blood donors that support the production of new, non-cancerous cells. The team at the Crick, in collaboration with scientists from the DKFZ in Heidelberg and the German Red Cross Blood Donation Centre, analysed blood samples taken from over 200 frequent donors - people who had donated blood three times a year over 40 years, more than 120 times in total - and sporadic control donors who had donated blood less than five times in total. Samples from both groups showed a similar level of clonal diversity (of blood cells), but the makeup of the blood cell populations was different. For example, both sample groups contained clones with changes to a gene called DNMT3A, which is known to be mutated in people who develop leukaemia. Interestingly, the changes to this gene observed in frequent donors were not in the areas known to be preleukemic.

Hepatitis B core related antigen (HBcrAg) is a biomarker of replication in hepatitis B virus (HBV) infection. There are very few data representing the use of HBcrAg in African populations, and measuring it using a Point of Care Test has only been done in one other African setting. This study helps determine a use case and explores the extent to which a positive HBcrAg correlates with existing biomarkers for people living with HBV in Kenya.

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.

Researchers at the Crick have uncovered which genes on the Y chromosome regulate the development of sperm and impact fertility in male mice. They generated thirteen different mouse models, each with different Y genes removed, and investigated their fertility. The team found that several Y genes were critical for reproduction, and that if these genes were removed, the mice couldn’t produce young. Some other genes had no impact when removed individually, but did lead to the production of abnormal sperm when removed together. The results suggest that many Y genes play a role in fertility and can compensate for each other if one gene is lost. This also means that some cases of infertility likely result from multiple genes being deleted at the same time.

DNA in our cells must be copied only once in the life cycle of a cell to maintain gene copy number and prevent genome instability. To make sure that this happens, loading of the enzyme (MCM), which separates two strands of the double helix, is separated in time from its activation. Once activated, MCM uses the energy derived from ATP hydrolysis to move along one DNA strand and physically separate the other strand, achieving DNA unwinding. Before activation, MCM is recruited by a loader onto the double helix. Researchers knew that, to complete loading, ATP hydrolysis by MCM is required but did not know why. Here researchers at the Crick show that MCM uses ATP hydrolysis to move along duplex DNA away from its loader. Their study also provides new mechanistic information about how polymer translocases (like DNA motors or the proteasome) use ATP hydrolysis to drive movement.