Publication highlights

How complex organisms are constructed from far simpler embryos is a central problem of biology. During embryonic development, pluripotent cells are guided to a variety of cell fates by a series of decision-making processes involving gradients of chemical and mechanical signals. A concentration gradient of the Nodal protein has long been thought to specify endodermal and mesodermal cell fates, depending on how much Nodal a cell is exposed to. However, this model is too simple, as neighbouring cells in the embryo can adopt different fates despite being exposed to similar concentrations of Nodal. The Hill lab has demonstrated that rather than pushing cells down a particular path, a gradient of Nodal signalling establishes a window of competency in which cells can switch to an endodermal fate. Those that don’t switch become mesoderm. Switching is a random event, the likelihood of which is modulated by signalling from another protein, Fgf. This imprecise mechanism is honed at later stages to produce clearly defined endoderm.

Chromosomes are formed from chromatin, a complex of DNA and proteins. When cells die, chromatin is released into the surroundings and can cause inflammation and cytotoxicity. A process known as chromatin clearance is needed to remove extracellular chromatin and protect against severe disease. A collaboration led by Crick group leader Veni Papayannopoulos has found that in samples taken from people with the severest form of COVID-19 pneumonia, chromatin clearance was hindered in all cases, and when this process was affected the most, patients were less likely to survive.

Further analysis of the chromatin buildup showed that DNAses, a group of enzymes that help to break down chromatin, were being inhibited by another molecule, actin, which is released when cells die. Blood plasma samples taken from a second group of patients with microbial sepsis demonstrated a build-up of chromatin which correlated with high levels of actin in the blood. Using this information, the team developed a ‘proteomic profile’, a signature of protein levels and enzyme activity in the blood, that characterised the most severe and high-risk cases of infection. With further development, this signature could be used to help distinguish patients who might require additional treatment.

Understanding how proteins fold has been a central question in biophysics for decades. Machine learning-based approaches have recently made great progress in predicting protein structures, but the dynamics of folding required to achieve these structures are more challenging to predict, generally requiring experimental observation. Using single-molecule force spectroscopy, the Garcia-Manyes lab has developed a new method to watch a single protein fold for days rather than hours, revealing rare excursions into configurations that were previously hidden from observation. They focused on a segment of the protein talin, which is involved in sensing and responding to external forces applied to cells, and by also doing measurements in the presence of one of talin’s binding partners, vinculin, they were also able to probe the biological relevance of the folding states, including those that were misfolded, that they observed.

Given that the trapping of proteins in metastable high-energy states is one of the hurdles in the design of novel proteins, the detailed characterisation of such states made possible by this approach may help improve computational methods for protein design, as well as potentially providing insights into the range of diseases caused by protein misfolding. It also has implications for our understanding of many force-induced gene expression programmes, ultimately related to cell function.

The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, but their functional impact was unclear. The Scaffidi lab has shown that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavourable environments by promoting the emergence of stress-resistant subpopulations via a process they term transcriptional numbness. Their findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.

The processes governing host cell exit by the intracellular parasite Toxoplasma gondii are regulated by several signalling pathways, but how these pathways are connected remains largely unknown. Researchers in the Treeck lab have used a combination of phosphoproteomics, lipidomics, reverse genetics and biochemical assays to demonstrate the presence of a feedback loop linking calcium signalling with the upstream cyclic nucleotide and phospholipid signalling pathways to enhance signalling during Toxoplasma egress. The work improves understanding of how the parasite integrates various signalling inputs to a single phenotypic outcome.

Cell therapies to treat severe muscular dystrophies are inefficient. Major hurdles include the limited ability to expand mature myogenic cells in vitro, as well as the minimal migration capacity of myogenic cells upon transplantation, which inhibits dispersal into affected tissues. Researchers in the Tedesco lab have used directed iPSC differentiation, single-cell profiling, microfluidics and 3D tissue engineering to show that hiPSC-derived muscle satellite stem cells, which may be useful in cell therapies for muscular dystrophy, can have their in-vivo migration enhanced through activating the NOTCH and PDGF pathways, via treatment with DLL4 and PDGF-BB.

The HIF and mTOR signalling pathways are frequently dysregulated in cancer. In the most common kidney cancer, clear cell renal carcinoma, HIF is upregulated, and mTOR is hyperactivated, but their interplay is poorly understood, in part because of difficulties in simultaneous measurement of global and mRNA-specific translation. Yoichiro Sugimoto and Peter Ratcliffe describe a new method, high-resolution polysome profiling followed by sequencing of the 5′ ends of mRNAs (HP5), that addresses this challenge, and use it to analyse the interplay of HIF and mTOR in kidney cancer cell lines. They show that specific classes of HIF1A and HIF2A target genes have different sensitivity to mTOR, in a manner that suggests combined use of HIF2A and mTOR inhibitors is a rational therapeutic strategy for kidney cancer.

The adult dentate gyrus (DG) of rodents hosts a neural stem cell (NSC) niche capable of generating new neurons throughout life. The embryonic origin and molecular mechanisms underlying formation of DG NSCs are still being investigated. In a hunt for genes regulated by Sox9, a transcription factor known to control both gliogenesis (generation of non-neuronal glial cells) and NSC formation, researchers in the Lovell-Badge lab found Hopx. SOX9 is required for HOPX expression in the embryonic archicortex, which will give rise to the hippocampus, including the dentate gyrus, in the mature mammalian brain. Both genes are highly expressed in the cortical hem, while only weakly in the adjacent dentate neuroepithelium. Experiments to determine the developmental potential of these two areas suggested that SOX9 and HOPX work in a dose-dependent manner to drive either differentiation of astrocytes (specialised glial cells) in the cortical hem, or NSC formation in the dentate neuroepithelium.

Researchers in the Gandhi lab published work detailing how in the early stages of Parkinson’s, clumps of the protein alpha-synuclein collect heavily on the surface of the mitochondria damaging its surface, causing holes to form on the membrane and interfering with the mitochondria’s ability to create energy. Eventually, this leads to the mitochondria releasing signals that cause the neuron to die.

Researchers in the Kassiotis lab have shown that a specific area of the SARS-CoV-2 spike protein is a promising target for a pan-coronavirus vaccine that could offer some protection against new virus variants, common colds, and help prepare for future pandemics.

Researchers in the Downward lab have studied the effects of combining immune checkpoint blockade with KRAS inhibitors, in mice. In tumours where there were already high numbers of active immune cells, so called ‘immune hot’ tumours, the treatment successfully controlled the cancer. However, in cases where the immune system was not able to mount a strong response, the combination treatment was ineffective.

Researchers in the Bonnet lab have investigated the role of the protein, CKS1, in leukaemic stem cells and found it is vital to their self-renewal capabilities. Blocking the protein in mice did not harm healthy stem cells and, in fact, provided a protective effect for these healthy stem cells from some of the side-effects of chemotherapy.