Publication highlights

Scientists from Imperial College London and the Francis Crick Institute have uncovered genetic variants which help to explain why some children with mild COVID-19 go on to develop a severe inflammatory condition weeks after their infection. Throughout the COVID-19 pandemic, severe SARS-CoV-2 infections in children and infants were rare. But an estimated 1 in 10,000 children went on to develop multisystem inflammatory syndrome in children (MIS-C), presenting with a range of symptoms including rash, swelling and nausea and vomiting. In an analysis including more than 150 cases of MIS-C from Europe and the United States, the researchers in this study found that rare variations of a gene which helps regulate the lining of the gut made children four-times more likely to develop systemic inflammation and an array of symptoms. Understanding the genetic basis of MIS-C provides new insights into how the condition develops, who is at risk, and how patients and those with related conditions might be better treated.

Researchers from the Francis Crick Institute and UCL, part of the eDyNAmic Cancer Grand Challenges team, have shown that rogue genetic material called extrachromosomal DNA (ecDNA) can drive the survival of some of the most aggressive cancers. The team analysed Genomics England data from nearly 15,000 people with one of 39 different types of cancer, finding that over 17% of the samples contained ecDNA, with the highest rates seen in sarcomas, glioblastoma and a type of breast cancer. They then found that ecDNA was associated with shorter survival across all cancer types. The researchers hope that identifying and targeting vulnerabilities in ecDNA could stop tumours from evolving and becoming resistant to treatment.

In this work, Jones and colleagues shed light on the role of a highly conserved yet poorly understood gene, FAM83F. This gene has been linked with human cancer, yet very little is known about its function. Using zebrafish embryonic development as a model, they show that loss of FAM83F leads to impairment of the mechanism by which cells clear away and degrade cellular materials. Mutant zebrafish embryos are more sensitive to stress caused by DNA damage and hatch prematurely. These findings have implications for our understanding of the role of FAM83F in both development and disease.

Chronic hepatitis B (CHB) affects 254 million people globally, contributing significantly to cirrhosis and liver cancer. Work led by Philippa Matthews through the UK NIHR 'Health Informatics Collaborative' for viral hepatitis looked at the dynamics of hepatitis B virus (HBV) viral load and its relationship with liver disease in patients with CHB who were on long-term nucleos/tide analogue (NA) treatment. Virologic responses to NA therapy showed significant variability, and in 20% of individuals on treatment, HBV was not suppressed, or declined slowly on treatment over more than a year. In some cases, this was associated with a twofold increased risk of liver disease progression. These insights are relevant to supporting the management of CHB patients, helping the development of personalised treatment approaches.

Once upon a time, you were one cell, and of course when you were one cell, you were only one kind of cell. You are now made up of perhaps 400 kinds of cells. How did each cell decide what to be?

These questions have been studied for a long time. Waddington’s famous work of the 1950s suggested cells roll downhill to a Y-junction, where they choose between two potential fates. A research team at the Crick's contribution is to observe that often there is no Y-junction. They observe cases where one cell type, the majority, continues its development along a straight path while the other potential fate branches off from this. This new insight has been enabled by single-cell RNA-seq technology, which enables them to study gene expression at high resolution, a new mathematical insight, and software (TrajectoryGeometry) that they have created to exploit this insight.

Tuberculosis is most commonly thought of an encountered as a lung disease. However it may also enter the brain to cause meningitis (TBM) which causes death or disability in approximately 50% of those affected and kills approximately 78200 adults every year. Antibiotic treatment is based on that used for lung disease which overlooks important differences in the ability of drugs to reach the brain. TBM has a profound inflammatory component which also requires treatment, yet only steroid have shown benefit. There is now an active pipeline of new anti-TB drugs, and the increasing availability of better and more specific anti-inflammatory therapies could bring a a new era of improved TBM treatment and outcomes. Yet, to date, TBM studies have been relatively few, progress is slow, and a new approach is required. In this article the views of a global consortium of TBM researchers are articulated towards a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes from this life-threatening infection.

The Stem Cell Biology and Developmental Genetics Laboratory at the Crick has shown that in a mouse model of human hypopituitarism, low doses of aspirin and the balance of bacteria in the gut can influence symptoms. The brains of these mice, which lack the Sox3 gene, had a reduced number of a hypothalamic cell type, NG2 glial cells. Treating Sox3-deficient animals with a low dose of aspirin for 21 days increased NG2 glia numbers and reversed the hypopituitarism, but highly surprisingly, the makeup of the gut microbiome also had a significant effect; the change in microbiome resulting from the mice migrating into the Crick animal facility from elsewhere was enough to rescue the hormonal deficiencies. In addition to providing a clear case where extrinsic factors can influence a robust phenotype caused by a mutation, the work has implications for experimental consistency between research facilities, and has garnered wide interest in the field.

An effective response to infection is critically dependent on the maturation and proliferation of infection-fighting killer CD8+ T cells. This requires the cytokine IL-2, but how IL-2 is delivered to maturing CD8+ cells has been poorly understood. The Signalling and Transcription Laboratory Laboratory at the Crick has now shown that the transcription factor SRF plays a crucial role in the process. SRF was first discovered as a regulator of genes associated with cell proliferation, but somewhat unexpectedly, its role in CD8+ T cell proliferation is to help in the assembly of cell clusters. This activity requires SRF's MRTF cofactors, which control multiple cytoskeletal structural and regulatory genes. Cell clustering allows IL-2 to be efficiently trafficked between cells, and without it sustained proliferation of CD8+ T cells cannot occur. This work demonstrates a novel way by which SRF can promote cell proliferation.