Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.
Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.
New therapeutic target for rare type of childhood epilepsy
Researchers at the Francis Crick Institute, UCL and MSD have identified a potential treatment target for a genetic type of epilepsy called CDKL5 deficiency disorder (CDD). They examined mice which lacked the Cdkl5 gene, and used a technique called phosphoproteomics to scan for proteins which are a target for the CDKL5 enzyme. They identified a calcium channel, Cav2.3, as a target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to pass on electrical signals. This is needed for the nervous system to function properly, but too much calcium coming into cells can result in overexcitability and seizures. Mutations in Cav2.3 that enhance channel activity are already known to cause severe early onset epilepsy in a related condition called DEE69, which shares a lot of the same symptoms of CDD. These results suggest that Cav2.3 overactivity is a common feature of both disorders, and that inhibiting Cav2.3 could help with symptoms like seizures.
The Nurse lab has investigated how cell division is controlled by cell size. They developed a high-throughput single-cell system to assay CDK activity, which drives cell division. They were then able to identify how cell size influences CDK activity to ultimately ensure that cells divide at the correct size.
A study led by Ed Tate and Tony Holder has looked at how the NMT inhibitor blocks the human malaria parasite, Plasmodium falciparum. The team found at least three mechanisms where inhibition of NMT can disrupt parasite development, and therefore demonstrate the importance of P. falciparum NMT as a drug target.
Protein signature identifies those at highest risk from severe infection
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.
Fish, flies and fibroblasts under the spotlight: tracking Erk signalling dynamics live
Tissue development and homeostasis require coordinated communication, proliferation, and movement of cells on a grand scale. Erk is a key protein connecting these processes downstream of many signals. Depending on the signal, different Erk dynamics can be achieved that drive different cell behaviours. Researchers at the Crick wanted to investigate the role of Fgf/Erk signalling during early development using a live biosensor, called the Erk Kinase Translocation Reporter (Erk-KTR), but found that the readout was masked by off-target activity of another protein called Cdk1, a particular problem during rapid embryonic cell cycles. They therefore generated an improved Erk-specific KTR (modErk-KTR) and demonstrated its Erk-specificity in vitro and in multiple zebrafish and Drosophila tissues.
Using this tool, the researchers tracked the growth of the Fgf/Erk signalling gradient in zebrafish early embryos. In a type of cell called a mesendodermal cell, they saw that Erk activity is rapidly stopped before mitosis (cell replication). The two daughter cells reactivate Erk signalling once mitosis is complete. They conclude that mitosis creates variable pulses of Erk inactivity – called ‘mitotic erasure’ – during a key window of embryo development.
Selection for size control drives the evolution of molecular motors
How new traits can emerge in evolution has puzzled biologists since Darwin, partly because selection can act only on already existing features. In particular, our understanding of how several new attributes necessary for complex biological mechanisms jointly emerge during evolution is limited. Furthermore, the role of physics in determining fitness and the trajectory of evolution has been largely missed in theoretical models of evolution.
In this work, we tackle these challenges by investigating how natural selection can lead to the evolution of ‘molecular motors’: groups of molecules that can generate motion in one direction. Our simulations show that the selection for an average size in a collection of molecular assembly, a string of molecules, leads to treadmilling, where growth at one end is exactly compensated by shrinkage at the opposite end. Our findings show that physical constraints imposed on molecular self-assembly determines evolutionary dynamics and can lead to the emergence of complex functions.
International research team identify humans over 45,000 years old in Europe
Stone tools discovered in a cave under a castle in Germany in the 1930s are part of a group of artefacts known as the ‘Lincombian-Ranisian-Jerzmanowician’ (LRJ) which have been found in archaeological sites from the UK to Poland for over 100 years. Until now, no human remains have been found with these tools so it was unclear if they were made by Homo sapiens or Neanderthals. Researchers from the Crick are part of a large international team who re-assessed the 1930s collection with new scientific methods and did a new excavation at the site. They identified 13 bone fragments as Homo sapiens based on their morphology, proteins and DNA which they could link with LRJ artefacts from the site. Radiocarbon dating showed these people lived between 47,500 – 43,300 years ago, making them some of the oldest discovered in Europe, changing our understanding of the arrival of Homo sapiens in Europe.
Research from the Hill lab has identified the underlying molecular mechanism for two diseases that share a common causal mutation and currently have no effective treatments. The team used optogenetics and live-imaging approaches to show the link between genetic mutation and disrupted signalling that causes these diseases.
Specialised gut immune cells pinpointed that can limit progression of inflammatory bowel disease
Researchers at the Francis Crick Institute, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust have characterised a specialised type of immune cell, which plays a key role in protecting and repairing the cells in the healthy human gut. The researchers investigated tissue from over 150 patients at Guy’s and St Thomas’ NHS Foundation Trust, dissecting a major population of T cells called gamma delta (γδ) T cells in the colons of people with healthy guts and people with IBD. In healthy guts, there was a unique specialised subset of gamma delta cells, termed V-gamma-4 (V4) cells, that intriguingly were significantly altered and often conspicuously depleted in inflamed IBD samples.
The researchers also observed that, in people whose inflammation had improved, those with restored V4 T cell function were less likely to relapse than those who did not. This suggests that assessing the status of V4 T cells could be a useful biomarker for disease progression.
Evolution of the SARS-CoV-2 spike protein in the human host
Researchers in the Gamblin lab identified structural changes in the spike proteins of recently emerged SARS-CoV-2 variants which provide clues to how the virus is evolving to have greater levels of infectivity.
Confirmation of a new drug target for the malaria parasite
Malaria is caused by the parasite Plasmodium falciparum, which lives in human red blood cells. Malaria remains a large health burden with nearly 650,000 deaths per year. Resistance to all frontline drugs has been reported, while highly effective vaccines are not available. In this collaborative study, four teams worked together to show the effectiveness of new inhibitors of the Plasmodium falciparum lactate transporter in cells and mice. Using new genetic methods, the authors show that the transporter is essential for the parasite to grow, and that the identified drugs act by blocking it.
Although parasites can develop resistance against the drugs, only a limited set of mutants can arise, some of which don’t survive. This makes development of resistance in patients less likely. Collectively the results from this study show that the P. falciparum lactate transporter is a good drug target and provide critical insights into developing better inhibitors that overcome resistance.
Published in Antimicrobial Agents and Chemotherapy
Published
A sticky role for GDNF in synaptic connectivity
A protein called GDNF is under investigation as a neuroprotective agent in Parkinson’s disease. Beyond its well-characterised therapeutic potential, GDNF also plays a further role in promoting synaptic adhesion in hippocampal neurons. Researchers in the McDonald lab at the Crick uncovered the molecular mechanism through which GDNF drives adhesion between two synaptic membranes. This occurs through the formation of a unique assembly of ten subunits with another receptor called GFRa1. They reconstituted this adhesion complex between membranes and imaged this process by X-ray crystallography and cryo-electron tomography. Its role as a synaptic organising complex was validated by counting dendritic spines in rat hippocampal neurons. Finally, they found that the assembly was disrupted by interaction with either the RET receptor or proteoglycans, impacting on neuronal synapse formation. These findings suggest GDNF has a more complex relationship to neuronal function than previously thought, with its signalling outputs dependent on the cellular context.
Glial cells crucial to maintaining healthy gut immunity
Researchers from the Pachnis lab have uncovered a fundamental role of glial cells in the gut nervous system in maintaining a healthy intestine. These cells have been found to coordinate the immune responses of the gut following pathogen invasion and could be key targets when exploring new treatments for inflammatory bowel conditions.
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.
Promising progress towards a pan-coronavirus vaccine
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.
Optimising energy production without respiration in yeast
Establishing the rules of carbon metabolism, which produces biomass and energy, is critical for our understanding of life, from evolution to development to disease. Glycolysis is an ancient metabolic pathway which doesn't need oxygen - one molecule of glucose is used to produce two molecules of ATP, the “energy currency” of the cell, and two molecules of pyruvate, an intermediate molecule which can be metabolised further in respiration. Respiration is the most efficient way of generating ATP (overall producing up to 36 ATPs/glucose in mammals) and regenerating the electron carrier NAD+, which is required for growth. Most eukaryotes - like animals, fungi or plants - live in environments with lots of oxygen, and respire. Yet, rapidly growing human cancer cells and single cell organisms, such as yeasts, often choose glycolysis over respiration, even when oxygen is available. We know little about the metabolic rewiring required to cope with the lack of respiration.
Here the researchers use an evolutionary cell biology approach in two related fission yeasts, one which acquires energy by respiration and one which doesn't, to find the critical points at which respiration feeds into central carbon metabolism. They show how both ATP production and NAD+ regeneration can be optimized to ensure rapid growth and discuss possible trade-offs of choosing between respiration and glycolysis.
Research from the Schaefer lab has found that mice can sense extremely fast and subtle changes in the structure of odours and use this to guide their behaviour. The findings alter the current view on how odours are processed in the mammalian brain.
Stem cells can use same method as plants and insects to protect against viruses
Research from the Reis e Sousa lab has found a mechanism, previously thought to have disappeared as mammals evolved, that helps protect mammalian stem cells from RNA viruses such as SARS-CoV-2 and Zika virus. The lab suggest this could one day be exploited in the development of new antiviral treatments.
Research from Ian Taylor’s lab has investigated the molecular basis of Ty1 transposition, which is regulated by copy number control. Their work presents the structural, biophysical and genetic analyses of p18m, a key protein that directs copy number control through disruption of Ty1 virus-like particle assembly.
A study from the Bishop lab has looked into HIV-1 uncoating, the process by which the viral core breaks down during infection. Their work suggests that uncoating or remodelling of the HIV-1 capsid lattice occurs at the nuclear pore, and that this step is essential for a productive infection.
