Publication highlights

Mitochondria are the cell’s powerhouses and are essential for organismal health. When they malfunction, proteins meant to enter them can accumulate outside and act as distress signals, alerting the cell to potential damage. Researchers at the University of British Columbia, in collaboration with colleagues at the Crick, discovered that a small region of a mitochondrial protein plays a key role in activating a protective program that promotes mitochondrial recovery. Under normal conditions, this region enables the protein to enter mitochondria, but when blocked, it switches roles to signal stress. This finding reveals a natural “canary in a coal mine” for mitochondrial dysfunction and opens new possibilities for treating neurodegenerative and other mitochondria-related diseases.

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.

Researchers at the Crick have discovered that Mtb, the bacterium causing tuberculosis (TB), alters its outermost layer, its lipid cell envelope, when it encounters low phosphate conditions. This allows it to survive inside human immune cells, where phosphate is restricted. It can scavenge phosphate from human lipids (fats), which are present in the lungs, allowing the bacteria to grow when no other source of phosphate is present. These findings demonstrate a method that Mtb employs to overcome the human host’s attempts to restrict its growth. The replacement lipids produced
when phosphate is restricted therefore represent new drug targets for the treatment of TB. Additionally, vaccines that target TB via its lipids should take into account the particular lipids present when the cell is phosphate starved, as demonstrated here.

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.

Histone modifications are chemical marks that help regulate DNA functions. One of the most common, H4K16 acetylation (H4K16ac), is known for turning genes on in fruit flies, and it has been assumed to do so in mammalian cells too. Researchers at the Crick and the European Institute of Oncology found that in human cells, H4K16ac does not control gene activity but instead organises when and where DNA is copied during cell division. Without it, regions of the genome enriched for repetitive elements (LTRs) replicate prematurely, globally disrupting the temporal control of DNA replication. Their findings reveal an unexpected role for histone acetylation in safeguarding genome replication accuracy.

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.

If a tightly packed layer of epithelial cells gets overcrowded, excess cells are extruded, causing them to die. To find out how the body decides which cells are extruded, researchers at the Crick and King's College London set up live imaging of overcrowded epithelial cells under a microscope. They found that overcrowding triggers sodium channels on epithelial to open, bringing in salts and depolarising the cells. The strong ones can pump the sodium back out, repolarising themselves, but weak ones without energy can't, using a 'last gasp' of energy to activate a current that results in water rushing out of the cells, causing them to shrink and extrude.

Researchers at the Crick have developed a CRISPR-based screening method to rapidly assess how the loss of individual Cryptosporidium genes influence parasite survival in vivo. Using this method, they examined the parasite’s pyrimidine salvage pathway and a set of leading Cryptosporidium vaccine candidates. This targeted screening method is highly versatile and will enable researchers to more rapidly expand the knowledge base for Cryptosporidium infection biology.