Publication highlights

Researchers at the Francis Crick Institute, UCL and MSD have identified a potential treatment target for a genetic type of epilepsy called CDKL5 deficiency disorder (CDD). They examined mice which lacked the Cdkl5 gene, and used a technique called phosphoproteomics to scan for proteins which are a target for the CDKL5 enzyme. They identified a calcium channel, Cav2.3, as a target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to pass on electrical signals. This is needed for the nervous system to function properly, but too much calcium coming into cells can result in overexcitability and seizures. Mutations in Cav2.3 that enhance channel activity are already known to cause severe early onset epilepsy in a related condition called DEE69, which shares a lot of the same symptoms of CDD. These results suggest that Cav2.3 overactivity is a common feature of both disorders, and that inhibiting Cav2.3 could help with symptoms like seizures.

Does infection or vaccination induce nasal neutralising antibodies to SARS-CoV-2 variants? The Covid Surveillance Unit has developed a fast, easy method to test if antibodies in nasal mucosa stop SARS-CoV-2 replicating in cells in swabs from participants in the UCLH-Crick Legacy study. Both vaccination and infection boosted antibody levels in nasal mucus, and repeated vaccinations could enhance this. Importantly, the range of nasal antibodies differs from that in blood, which means current vaccines may not stop infections with new antigenically different variants. The methodology used in the study will make it easy to evaluate next generation vaccines, including mucosal vaccines.

Researchers at the Francis Crick Institute have discovered that a common dietary supplement could protect against chronic Cryptosporidium infections which are particularly prevalent in children under two and in areas with poorer sanitation. The researchers exposed mice to the Cryptosporidium parasite and observed that infection triggered an expansion of immune cells in the intestinal epithelium, which are part of the first line of defence against the parasite. When these CD8+ T cells were transferred to mice with weakened immune systems, the researchers saw that the mice were now able to fight off Cryptosporidium infection. Mice that lack the AHR receptor, or healthy mice fed a diet specifically deficient in indoles, had a reduced population of intestinal CD8+ T cells. This meant the mice were less able to fight off the infection, and showed that CD8+ T cells are reliant on the AHR system to protect the intestine.

Ed Tate and Wouter Kallemeijn in the Chemical Biology and Therapeutic Discovery Satellite Lab at the Francis Crick Institute and Imperial College London, in work led by Jesus Gil at the MRC-LMS (Laboratory of Medical Sciences) at Imperial College, have uncovered critical insights that can pave the way for novel therapeutic approaches to tackle cancer, fibrosis, and many age-related conditions. Ed and Wouter identified and patented NMT inhibitors to selectively kill senescent cells, which have stopped growing but can drive inflammation in cancer and fibrosis. Crick/Imperial spin-out Myricx Bio is now developing NMT inhibitors as potential senolytic drugs.

How new traits can emerge in evolution has puzzled biologists since Darwin, partly because selection can act only on already existing features. In particular, our understanding of how several new attributes necessary for complex biological mechanisms jointly emerge during evolution is limited. Furthermore, the role of physics in determining fitness and the trajectory of evolution has been largely missed in theoretical models of evolution.

In this work, we tackle these challenges by investigating how natural selection can lead to the evolution of ‘molecular motors’: groups of molecules that can generate motion in one direction. Our simulations show that the selection for an average size in a collection of molecular assembly, a string of molecules, leads to treadmilling, where growth at one end is exactly compensated by shrinkage at the opposite end. Our findings show that physical constraints imposed on molecular self-assembly determines evolutionary dynamics and can lead to the emergence of complex functions.

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.

Researchers at the Francis Crick Institute and Heidelberg University in Germany have shown that sex differences in animals vary dramatically across species, organs and developmental stages, and evolve quickly at the gene level but slowly at the cell type level. The researchers analysed the activity of genes in males and females over time in humans and four species (mice, rats, rabbits, opossums and chickens), covering the development of five organs (brain, cerebellum, heart, kidney and liver), into adulthood in the animals and up to birth in humans.

They discovered that organs which are different between the sexes vary across species, and in all animals and humans, few sex differences occurred while organs were developing, instead increasing sharply around sexual maturity. Only a very small number of sex-biased genes were shared across species, suggesting that sex differences have evolved quickly, but the same type of cells are sexually dimorphic across species.

An international team of researchers led by Arnab Pain (Professor at King Abdullah University of Science and Technology, Saudi Arabia) and Tony Holder (recently retired from the Crick) with additional scientists in Oxford, California, Saudi Arabia and India, have identified a key protein which regulates human malaria parasite development and disease. During the cycle of malaria gene expression within infected red blood cells, this DNA-binding protein (in the APiAP2 transcription factor family) controls parasite differentiation, replication, and release from the host cell. It also allows the parasite to modify the host red blood cell, which helps it to evade the immune system. By knocking out the gene producing the DNA-binding protein, it was shown to be essential at two stages within the 48-hour cell cycle. Novel therapeutic strategies to combat malaria are suggested by these findings.

Cell-surface and secreted proteins play critical roles in human development, growth factor signalling, and cell adhesion. Proteoglycans are an important subset of these proteins and are modified with long chains of sugar molecules called Glycosaminoglycans (GAGs) such as heparan sulphate (HS) or chondroitin sulphate (CS), but they all start with the same four sugars – only after the addition of the fifth sugar is the fate of the growing chain sealed.

While protein and DNA synthesis are template-driven, from DNA or RNA, synthesis of the proteoglycan GAG chains are not. In a collaboration between the Crick and Imperial, the researchers devised a synthesis system to allow precise control of eight of the enzymes in the biosynthesis pathway. They discovered that chrondroitin sulphate is the “default” modification, and that the enzyme responsible for priming chrondroitin sulphate synthesis modifies all sites equally. They also found that the enzyme responsible for priming heparan sulphate synthesis (EXTL3) has a positively charged patch that interacts with negatively charged amino acids near the attachment site and will only modify certain substrates. This will help to predict how mutations surrounding the glycosaminoglycan attachment sites could be implicated in diseases like cancer or developmental conditions.