Publication highlights

Researchers at the Crick and UCL have shown that reported that astrocytes show signs of hypoxic stress long before neurons begin to die in ALS. Using stem cells from patients to generate astrocytes carrying ALS-linked mutations in a gene called VCP, which is linked to inherited forms of ALS, the team showed that astrocytes exhibited clear signs of 'pseudo-hypoxia'. This meant they had switched on a low-oxygen response despite being in normal oxygen conditions. This was driven by HIF-1a, a master regulator of how cells respond to oxygen. Instead of being degraded under normal conditions, it had accumulated in the nucleus and activated genes involved in metabolism, energy production and stress responses. As a result ALS astrocytes showed mitochondrial dysfunction and a reduced ability to support motor neurons. This is particularly exhibited as an inability to correct the mislocalisation of RNA-binding proteins, a well-known molecular hallmark of ALS, compromising neuron survival.

Human induced pluripotent stem cells (iPSCs) mimic early embryos and can become any cell type, making them a powerful tool to study development and disease. However, most existing cell lines aren't suited to study sex differences. In collaboration with AstraZeneca, Turner lab researchers Ruta Meleckyte and Wazeer Varsally addressed this by creating new iPSCs with either XX (female) or XY (male) sex chromosomes. All other chromosomes were identical, so any differences observed can be linked to sex. These openly available iPSCs will enable more accurate modelling of sex-specific biology and may help in developing better, more personalised treatments in the future.

A team of scientists from the University of Cambridge, the Crick and the Polytechnique Montreal have, for the first time, directly visualised and quantified the protein clusters believed to trigger Parkinson's disease. Their new technique uses ultra-sensitive fluorescence microscopy to detect and analyse millions of oligomers in post-mortem brain tissue. They found that oligomers exist in both healthy brains and brains from people with Parkinson's disease, but the main difference was the size of the oligomers, which were larger, brighter and more numerous in disease samples, suggesting a direct link to the progression of the disease. They also observed a sub-class of oligomers that appeared only in people with Parkinson's disease, which could be the earliest viable markers of the condition, appearing potentially years before symptoms appear.

In this study, researchers at the Crick and UCL investigated how an epigenetic change called DNA methylation cooperates with genetic changes in non-small cell lung cancer (NSCLC) using 217 tumour and normal regions from 59 TRACERx patients. This is the first multiregional lung cancer cohort integrating genomic, transcriptomic, and epigenomic data to map tumour evolution in such detail. They uncovered a novel mechanism, where DNA methylation fine-tunes how oncogenes are switched on together by compacting the DNA. We also identified hypermethylated driver genes emerging early in tumour evolution and developed a new metric, Mr/Mn, to distinguish functional from passenger methylation changes. Our work highlights epigenetic drivers with therapeutic potential.

Several models of cell fate lineages have been presented, some proposing a traditional straight path and others a more dynamic model, where cell fate remains more flexible. Researchers at the Crick combined a range of experimental techniques - single cell transcriptomics, quantitative live cell imaging and mathematical modelling - to track cell fate and determine which path is the right one. They found that there was no singular path, and these theories were not competing explanations but complementary snapshots of human development. The team also observed the influence of two important signalling molecules, Activin and BMP4, in determining which route cells would take between mesoderm or endoderm layers.

Cells need to be made in the right place at the right time in developing tissue, but how these two cues are coordinated to control cell identify is not well understood. Using mouse stem cell models of the neural tube, researchers at the Crick found a surprising "master clock" mechanism that modifies the chromatin of neural cells, making different DNA regions accessible at specific times during development. Working with the High Throughput Screening team, they identified key molecular regulators, including a transcription factor called Nr6a1, that control the temporal programme by altering chromatin accessibility. Disrupting these factors altered the identity of cells before and after becoming specialised. The ability of temporal factors in the mice to control chromatin accessibility over time explains how the same spatial progenitor domains can produce different cell types as development progresses. Taking into account the cell’s temporal clock could help engineer the generation of specific neurons and glial cells from stem cells for regenerative medicine purposes.

Researchers at the Crick and UCL have shown that genetic messages, called mRNAs, are misplaced in nerve cells in a model of Alzheimer's disease and frontotemporal dementia. They looked at corticial neurons specialised from skin cells from people with inherited forms of Alzheimer's disease or FTD who had mutations in APP or PSEN1 genes (Alzheimer's disease) and VCP (FTD). Between 82 and 140 mRNAs were found in a different place in the neurons with the mutations compared to control neurons. These included ten that were common to both diseases, all found to carry messages from genes related to mitochondrial function. The team also found that mitochondrial DNA was leaking out of the mitochondria, and that diseased neurons had fewer and smaller mitochondria. Treating these cells with a drug called ML240 returned the misplaced mRNAs to their typical locations, reduced the amount of mitochondrial DNA leakage and raised mitochondrial activity back to normal levels.

Researchers at the Francis Crick Institute have developed a new stem cell model of the mature human amniotic sac, which replicates development of the tissues supporting the embryo from two to four weeks after fertilisation. The new 3D model – called a post-gastrulation amnioid (PGA) – closely resembles the human amnion and other supportive tissues after gastrulation. The team developed PGAs by culturing human embryonic stem cells in a series of steps with just two chemical signals over 48 hours, after which the cells organised themselves into the inner and outer layers of the amnion. A sac-like structure formed by day 10 in over 90% of the PGAs, which expanded in size over 90 days. The researchers showed that a transcription factor called GATA3 is necessary to kick-start amnion development and that signals from the amnion can communicate with embryonic cells to stimulate growth. Finally, they believe PGAs could also provide an alternative source of amniotic membranes for medical procedures like cornea reconstruction.

The initiation of DNA replication occurs at tens of thousands of sites on the human genome during every S phase, but in the absence of any consensus DNA sequence, it is unclear how these sites are specified. Researchers at the University of Cambridge and the Crick identified sites with increased density during quiescence and G1 phase that overlap with DNA replication origins. The increased density derives from changes made by enzymes at these sites, and inhibition of these enzymes reversibly prevented DNA replication and cell proliferation. These findings provide a mechanism for the epigenetic specification and semiconservative inheritance of DNA replication origin sites, and for the once-per-cell cycle control of origin activation.

Researchers at the Crick and UCL Queen Square Institute of Neurology have shown that alpha-synuclein, the protein that aggregates in Parkinson’s disease, can trigger widespread RNA editing in astrocytes as part of an anti-viral innate immune response. They used human stem cells to generate astrocytes, the most abundant cell type in the brain. Using molecular biology, genomic and computational approaches, they showed that forms of alpha-synuclein trigger the same innate immune pathways in astrocytes that viruses do. One consequence of this response was a marked increase in RNA editing, with extensive changes throughout the genetic code as it is converted into proteins.

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.

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.