Publication highlights

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. 

Researchers have mapped the human metabolic pathways that Cryptosporidium, an intestinal parasite, requires to survive. They conducted a genome-scale screening experiment that involves systematically disabling nearly every protein-coding gene, individually, from human intestinal cells, before infecting the cells with Cryptosporidium. The team found that genes involved in making cholesterol appeared to have opposing effects - some boosting infection and others blocking it. This balance hinged on a molecule midway through the cholesterol production line, squalene. This molecule protects against oxidative stress by stimulating the production of glutathione, which Cryptosporidium needs but cannot make. This leaves the parasite dependent on glutathione from the host cell, a dependency which can be targeted with a high cholesterol drug called lapaquistat. This drug reduced infection in a mouse model of disease and completely blocked intestinal damage, suggesting it could be repurposed to fight Cryptosporidium.

Researchers at the Francis Crick Institute, working with UCL and Imperial College London, have discovered a new biological pathway that is a principal driver of inflammatory bowel disease (IBD) and related conditions, and which can be targeted using existing drugs. They found an enhancer in a 'gene desert', which was active in macrophages and boosted a gene called ETS2. This gene was essential for almost all inflammatory functions in macrophages, including several that directly contribute to tissue damage in IBD. The team then found that MEK inhibitors, drugs already prescribed from other non-inflammatory conditions, could reduce inflammation in macrophages and also gut samples from patients with IBD.

Enzymes called ZDHHCs are responsible for directing a type of regulatory modification, palmitoylation, that adds a lipid to specific proteins, but humans have 23 different ZDHHCs, and understanding which proteins each one modifies has been very challenging. A team led by satellite group leader Ed Tate have developed a new method that identifies the set of proteins just one ZDHHC acts on, which has ramifications not just for our understanding of lipid biology, but also for therapeutic strategies targeting proteins whose activity depends on palmitoylation. To progress the research into drug discovery, the researchers have also screened a very large library of compounds to find effective ZDHHC inhibitors.

A group of researchers led by the Francis Crick Institute, working with the National Physical Laboratory (NPL) and Imperial College London, have discovered that breast cancer cells expressing a cancer-driving gene heavily rely on vitamin B5 to grow and survive. The researchers are part of Cancer Grand Challenges team Rosetta, funded by Cancer Research UK.

The researchers developed tumours inside mice with two different types of cells, either with high or low levels of Myc. They also transplanted human breast cancer tumour tissue into mice, which also had a mixture of Myc-high and Myc-low areas. They saw that vitamin B5 was associated with Myc-high areas of both mice and human transplanted tumours. This association was also observed in biopsies taken from patients with breast cancer. They then fed mice a vitamin B5-deficient diet, and saw that their Myc-low and Myc-high mixed tumours grew more slowly than tumours in mice who were fed a standard diet. The researchers believe that this association with tumour growth is due to the key role vitamin B5 plays in metabolism.

Unlike most insects, which lay eggs, pregnant tsetse flies (Glossina sp.) give birth to a single larva that rapidly burrows into the soil to pupate. In nature, pupae are often found clustered together, and laboratory-based studies suggest that pregnant tsetse females are attracted to suitable larviposition sites - places to give birth - by pupae-released pheromones. However, this effect could not be reproduced when tested in the flies' natural environment. So how do tsetse mothers recognise appropriate larviposition sites?

To resolve the discrepancy in the data, the researchers designed laboratory experiments that mimicked the natural situation as closely as possible. Our results show that under these conditions, females strongly prefer leaf litter-covered sand over bare sand, whereas the presence of pupae or pupal pheromones does not affect female choice. This indicates that larviposition site selection is not guided by pupal pheromones; rather, the type of ground cover (e.g. leaf litter) is the predominant cue used by pregnant females to select birthing sites. The study highlights the importance of taking the animal's ecology and natural environment into account when designing laboratory experiments.

An international collaboration led by Crick Group Leader Marcus Ralser has shown that mixed communities of young and old yeast cells can co-operate and exchange resources, increasing the lifespan of all the cells. They focused on the processes used by cells to exchange metabolites, which are produced when cells create energy, and include amino acids. When young yeast cells released amino acids into the environment, these could be taken up by older cells, and the whole community of cells lived longer. One of the amino acids, methionine, was of particular importance as it is needed to kickstart the process of building proteins and is also important in many cellular processes. Uptake of methionine changed the metabolism of the older cells, affecting key anti-ageing pathways and also led to the release of metabolites with protective properties into the environment, which could then be taken up by other cells. If applicable to higher organisms, the concept underlying these results could add a new dimension to studying cells in health and disease.