Publication highlights

Cell movement is essential, and to move, a cell must first decide where its “front” and “back” are, a process known as polarisation. Most explanations for this behaviour focus on complex chemical signalling inside the cell. Researchers in the Polarity and Patterning Networks Laboratory asked a simpler question: could mechanical forces within a cell be sufficient to make it polarize and move without an external cue? They built a computational model of a simplified cell made of elastic connections, contractile forces, and attachment points to its surroundings. This minimal setup could spontaneously develop a front and a back and begin moving persistently. The team then showed that when the attachment points break under mechanical load at an intermediate rate, forces build up unevenly, leading to detachment and forward motion, as in living cells. This suggests that cell polarisation and movement can emerge spontaneously from mechanical properties alone, highlighting an important and overlooked role for mechanics in cell behaviour.

LMNA-related congenital muscular dystrophy (L-CMD) is a severe and incurable muscle disease caused by changes in the LMNA gene. Researchers in the Stem Cells and Neuromuscular Regeneration Laboratory developed stem cell-based artificial muscle models to understand the disease and develop therapeutic approaches. Muscle cells with the disease showed abnormal nuclei and inflammatory gene expression. They used a gene editing strategy called CRISPR to test different approaches to correcting the LMNA gene. Removal of the affected piece of DNA did not correct these abnormalities, whereas precise correction restored normal nuclear shape and reduced inflammatory gene expression. These models provide a valuable platform for understanding disease processes and developing therapies.

HIV-1 co-opts the cellular chromatin-binding protein LEDGF to facilitate integration into human chromosomes while preferentially targeting highly active transcription units. Integrase, the viral enzyme responsible for this process, binds both ends of the viral DNA molecule to form the intasome. How the intasome engages host-cell chromatin for integration remains poorly understood. Researchers in the Chromatin Structure & Mobile DNA Laboratory showed that HIV-1 intasomes use LEDGF to interact with multiple nucleosomes carrying histone H3 trimethylated at Lys36. Using cryo-EM, the team visualised the intasome from a related ovine lentivirus and showed that LEDGF molecules decorate its chromatin-facing surface, imposing structural constraints on how chromatin can approach the active site. Together with biochemical studies, the structures help explain how LEDGF directs lentiviral integration within chromatin while integration preferentially occurs in linker DNA rather than nucleosome cores.

Wnt proteins are cell signalling molecules that control growth patterning and stem cell maintenance. Wnt proteins are unusual in that they carry a lipid modification that renders them insoluble, raising questions about how they are secreted and spread within tissue. In the secretory pathway, the Wnt lipid is shielded by a dedicated chaperone, Wntless. However, Wnts must subsequently disengage from Wntless to be released from secreting cells. Researchers in the Epithelial Cell Interactions Laboratory show that, in a developing epithelium, this is triggered by a change in lipid composition at the apical membrane although rapid endocytosis prevents release there. Wingless then traffics to specialised endosome before being targeted to the basal side of the epithelium where it forms a gradient and engages with receptors to control growth and patterning.

Poxviruses, including the viruses responsible for smallpox and mpox, can only replicate by smuggling their genetic material into human cells. The Structural Biology of Cells and Viruses and Cellular Signalling and Cytoskeletal Function labs have now uncovered the detailed structure of the “portal complex”, the molecular gateway that the viruses build for this purpose. Using cutting-edge imaging techniques, they identified the proteins that form the channel and showed how it helps the virus establish infection. By exposing a critical vulnerability in the viral life cycle, the work points towards new antiviral approaches that could target a range of poxviruses.

Parkinson's disease is usually thought of as a brain condition, but the most common genetic cause — a mutation in a gene called LRRK2 — also affects immune cells. Researchers in the Host-Pathogen Interactions in Tuberculosis Laboratory studied this genetic change in macrophages, which contain small compartments called lysosomes that break down waste materials inside the cell. When these compartments are damaged, cells need to respond quickly to survive. The scientists found that macrophages carrying a mutation in LRRK2 don't handle this damage well — they change how they communicate internally, and they're more likely to die. This increase in cell death wasn’t caused by the part of LRRK2 targeted by drugs, suggesting that targeting other parts of the protein might hold promise for Parkinson’s disease treatment.

Metal complexes have unique properties that make them attractive starting points for new medicines, yet little is known about which proteins they interact with inside cells. Researchers in the Biological Inorganic Chemistry Laboratory have developed reactive metallo-scaffolds (r-mS), which are metal complexes designed to form a permanent chemical bond with cysteine residues on proteins. Using chemoproteomics, they showed that both the choice of metal and the surrounding molecular structure strongly influence which proteins are targeted. One scaffold, r-mS-2, selectively bound to and inhibited PRMT1, a methyltransferase linked to gene regulation and cancer. This work provides a foundation platform for designing more selective metal complexes as next-generation chemical probes and medicines.

The Mathematical and Physical Laboratory at the Crick and the University of Lausanne investigated why, during sexual reproduction, the two mating yeast cells look exactly the same but are split into two different mating types and distinct roles during mating. Through experimental and computational work, the team found that P and M mating types produce different amounts of proteins, called meitoic factors, needed for a key stage of sexual reproduction called meiosis. If fusion failed, the yeast cells with large amounts of meiotic factors struggled to then divide asexually. Splitting the factors 50-50 would mean both cells are likely to die if meiosis fails, whereas splitting them unequally between two different mating types ensures at least one cell survives if meiosis doesn’t work.

Often mutated in cancer, the ATRX gene helps cells copy their DNA without damage. Keen to understand how ATRX mutations can stop a cell repairing DNA damage, and how this might lead to cancer or ATRX syndrome, the DSB Repair Metabolism Laboratory used CRISPR gene editing to remove ATRX from cells and examine which other genes the cells needed to survive. Cells deficient in ATRX became dependent on two other protein complexes, CST and 9-1-1. CST helps to replicate the protective telomere caps at the ends of DNA strands, and 9-1-1 supports the replication fork. And removing ATRX and either CST or 9-1-1 was lethal for the cell, representing a new way to target ATRX-mutated cancers.

Organs such as the intestine, liver and pancreas are spatially specialised, but how and why this differs between sexes is poorly understood. Researchers in the Organ Development and Physiology Laboratory used the fruit fly intestine to investigate the basis of these sex-specific differences. Using whole-organ 3D mapping and metabolic profiling, they found clear sex- and region-specific patterns of gene activity and metabolism. They showed these patterns are controlled by the opposing effects of the sex-determining factor Doublesex and the growth regulator Myc. In males, Doublesex suppresses Myc, leading to higher Myc activity in females. Female Myc increases cell DNA content, changes lipid-processing genes, and promotes fat storage in specific gut regions, supporting whole-body fat reserves and reproduction.

Researchers in the Stem Cell Biology and Developmental Genetics Laboratory at the Crick and IIS BioGipuzkoa have uncovered a role for the Sox2 regulatory region 2 (Srr2), a small non-coding DNA enhancer, in governing neural stem cell fate decisions in the adult mouse. They found that Srr2 maintains the levels of the key stem cell factor SOX2 during neural stem cell proliferation. Loss of Srr2 leads to widespread chromatin compaction, impaired activation of neurogenic gene programs, and defects in neuronal and oligodendroglial differentiation. Importantly, the enhancer-dependent regulation of SOX2 is required not only for gene expression but also for establishing a chromatin landscape that keeps neural stem cells competent to respond to differentiation cues. These findings provide new mechanistic insight into how regulatory elements shape stem cell behaviour and brain plasticity.

Mutations in the neurodegenerative risk genes, ANXA11 and CHMP2B can lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using advanced live cell imaging, researchers at the Crick and the UKDRI have discovered that ANXA11 and CHMP2B were recruited sequentially to sites of plasma membrane damage and helped repair this membrane. Disease associated mutations in either ANXA11 or CHMP2B affected their ability to relocalise to sites of membrane damage and compromised the repair process. This work identifies two separate neurodegenerative risk genes operating in the same pathway to keep cells alive, suggesting that plasma membrane repair may be a key pathway protecting against neurodegeneration.

Most people infected with tuberculosis never become ill, for reasons that have remained a mystery. By studying immune cells taken directly from the airways of TB patients and their recently exposed household contacts, the Immunoregulation and Infection Laboratory and colleagues uncovered two very different immune responses. Individuals who developed disease showed excessive inflammatory activity, while those who stayed healthy generated resilient, long-lived protective immune cells. The findings provide one of the clearest views yet of the critical early decisions that determine the outcome of infection and could help guide the development of better vaccines and therapies.

Every time a cell divides, it performs one of biology's most extraordinary feats: copying its entire genetic blueprint with remarkable accuracy. The Macromolecular Machines Laboratory, helped by longtime collaborator John Diffley, have now described a crucial molecular step that has eluded researchers for three decades. Using advanced imaging and AI-assisted analysis, the team revealed how the machinery that unwinds DNA is assembled and activated. The discovery solves a longstanding mystery at the heart of cell division and provides important insights into processes that, when disrupted, can contribute to cancer and developmental disorders.

The human brain contains billions of mitochondria, but until now scientists could not follow the activity of single mitochondria inside living neurons. Using microscopic "nanotweezers", the Mitochondrial Neurobiology Laboratory and collaborators extracted and analysed individual mitochondria without harming the cell. This allowed them to track changes in mitochondrial gene activity over time and detect early effects linked to proteins associated with Parkinson's disease. The technology offers an unprecedented view of how these cellular power stations function and fail, opening new opportunities to understand neurodegenerative diseases at their earliest stages.

The Cancer Evolution and Genome Instability Laboratory and colleagues have identified a signature of 14 proteins in the blood that predicts lung cancer risk more than five years before diagnosis. Rather than detecting cancer itself, the signature appears to reveal a harmful IL-1 beta-driven inflammatory state that creates the conditions for cancer to emerge, and predicts reduction in lung cancer incidence in patients treated with an antibody to IL1-beta in the Cantos trial of 4500 patients. The findings could help identify people most likely to benefit from preventive treatments and move medicine closer to a future where cancer is prevented before it begins.

Immune cells called type 1 conventional dendritic cells are effective at capturing material from dead cancer cells and presenting it to T cells, but are not found in high numbers. Researchers from the Immunobiology Laboratory at the Crick explored directing other, more abundant immune cells to take on the same role. They developed biological reagents that link F-actin from the scaffolding of dead cancer cells to receptors on nearby immune cells, triggering a T cell response against the tumours. When tested in mice, the antibodies effectively redirected non-specialised immune cells to present a broader range of tumour antigens, leading to reduced tumour growth, especially when combined with chemotherapy or radiotherapy, which increase the amount of dead tumour material.

Every second, millions of proteins are moved around our cells with astonishing precision. Using state-of-the-art cryo-electron tomography, the Membrane Architecture Laboratory and collaborators visualised a core transport system inside human cells in unprecedented detail. The work settles a long-running debate about how transport vesicles are formed and organised between two key cellular compartments. By revealing the architecture of one of the cell's fundamental logistics networks, the study provides an important foundation for understanding diseases caused by failures in protein transport and delivery.

New research from the Cancer-Neuroscience Laboratory focused on the nervous system’s early warning mechanism in cancer – specialised sensory nerves that detect extreme thermal, physical or chemical threats and trigger protective responses in the body. Using mouse models of lung cancer, they activated and deactivated these nerves in the lung and then examined how nerve-derived signals influence immune cells. The team found that lung tumours increased both the length and activity of the nerves and in turn, increased neuronal activity accelerated tumour growth. This was traced to increased levels of the chemical messenger calcitonin gene-related peptide, which broke down immune organisation. Further, cigarette smoke extract increased both neuronal activity and accelerated tumour progression, revealing a mechanism by which smoking can promote cancer progression beyond its role in causing DNA damage.

The Mathematical and Physical Biology Laboratory, working with EMBL, used theoretical modelling and computer simulations to predict how morphogens are likely to be affected by tissue material properties, like rigidity. They combined this with experiments to understand how rapid changes in tissue rigidity are coordinated with biochemical processes. The investigation showed that tissue rigidity and cell patterning are both regulated by the same morphogen, Nodal, which can't diffuse as far into the tissue where it becomes rigid. This smart feedback loop means Nodal makes the tissue become more rigid, which in turn stops Nodal from diffusing too far, switching off patterning in this area. Nodal also can promptly activate its own inhibitor, Lefty, meaning that developmental cell signalling is intrinsically linked to structural changes at the tissue level, ensuring that the correct amount of a certain cells are made.