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.
4,000-year-old plague DNA found – the oldest cases to date in Britain
Researchers at the Francis Crick Institute have identified three 4,000-year-old British cases of Yersinia pestis, the bacteria causing the plague – the oldest evidence of the plague in Britain to date, reported in a paper published in Nature Communications. Working with the University of Oxford, the Levens Local History Group and the Wells and Mendip Museum, the team identified two cases of Yersinia pestis in human remains found in a mass burial in Charterhouse Warren in Somerset and one in a ring cairn monument in Levens in Cumbria.
They took small skeletal samples from 34 individuals across the two sites, screening for the presence of Yersinia pestis in teeth. This technique is performed in a specialist clean room facility where they drill into the tooth and extract dental pulp, which can trap DNA remnants of infectious diseases. They then analysed the DNA and identified three cases of Yersinia pestis in two children estimated to be aged between 10-12 years old when they died, and one woman aged between 35-45. Radiocarbon dating was used to show it’s likely the three people lived at roughly the same time.
Unlike most insects, which lay eggs, pregnant tsetse flies (Glossina sp.) give birth to a single larva that rapidly burrows into the soil to pupate. In nature, pupae are often found clustered together, and laboratory-based studies suggest that pregnant tsetse females are attracted to suitable larviposition sites - places to give birth - by pupae-released pheromones. However, this effect could not be reproduced when tested in the flies' natural environment. So how do tsetse mothers recognise appropriate larviposition sites?
To resolve the discrepancy in the data, we designed laboratory experiments that mimicked the natural situation as closely as possible. Our results show that under these conditions, females strongly prefer leaf litter-covered sand over bare sand, whereas the presence of pupae or pupal pheromones does not affect female choice. This indicates that larviposition site selection is not guided by pupal pheromones; rather, the type of ground cover (e.g. leaf litter) is the predominant cue used by pregnant females to select birthing sites. Our study highlights the importance of taking the animal's ecology and natural environment into account when designing laboratory experiments.
Published in Proceedings of the Royal Society B: Biological Sciences
Published
Researchers show genetic basis of facial changes in Down Syndrome
Researchers at the Francis Crick Institute, King’s College London and University College London have shed light on the genetics behind changes in the structure and shape of the face and head in a mouse model of Down Syndrome. The researchers found that having a third copy of the gene Dyrk1a and at least three other genes were responsible for these changes taking place in development – called craniofacial dysmorphology – which involve shortened back-to-front length and widened diameter of the head. Because Dyrk1a is so key for craniofacial dysmorphology, it's highly likely it's involved in other changes in Down Syndrome too, like heart conditions and cognitive impairment.
Mutations in ARPC5 gene linked to immune defects and early death
The shape, interactions, and function of every cell in our bodies depends on an internal skeleton formed of 'filaments' or strands of a molecule called actin. How actin filaments come together and interact within each cell is controlled by a protein called the Arp2/3 complex, which has seven parts. The Arp2/3 complex, however, comes in eight different “flavours” each with distinct parts and properties.
Genetic analysis of patients and work in mice by researchers at the Francis Crick Institute in collaboration with clinicians in Albert-Ludwigs-University of Freiburg, Germany has provided new insights into the role of Arp2/3 complexes containing a part called ARPC5. The scientists uncovered that mutations in ARPC5 result in defects in heart development and function of the immune system that can cause early death. This study demonstrates that the ARPC5 gene should now be included in genetic testing for families with dysfunctional immune systems early in life, or death in infants.
How DNA repair proteins structurally organise themselves at sites of DNA damage
The DNA in our cells constantly accumulates different forms of damage. This damage can be caused by factors outside the cell such as UV light but also from the by-products that the cell produces during natural processes such as metabolism. One particular form of DNA damage, called a DNA double-strand break, occurs when both strands of the DNA double-helix are broken close to each other. A large number of proteins in the cell work to recognise and repair this type of DNA damage.
In this work, we developed a microscopy method to study how these DNA repair proteins structurally organise themselves at a DNA double-strand break. This new technique uses magnetic fields to apply forces onto DNA while simultaneously measuring the binding of proteins that assemble at the DNA damage site. Our experiments revealed how some of the key human proteins involved in DNA repair are able to stabilise DNA double-strand breaks. These results give us a new understanding of the basic mechanisms of how these proteins function, which may aid in the development of drugs which target DNA repair proteins in cancer therapy.
Published in Proceedings of the National Academy of Sciences of USA
Published
Molecular mechanism of antigen retention in immune response unveiled
Research led by UCL and the Francis Crick Institute has identified the biological mechanisms by which antigens are captured, stored and replaced in lymph nodes after vaccination and how they regulate B cell and antibody responses.
The findings, published in Nature Immunology, provide valuable insight into human immune responses and point the way to understanding how the immune system could become better equipped to recognise and eliminate specific pathogens - leading to more efficient and targeted immune responses and vaccine design.
Their findings showed that the structure and arrangement of the follicular dendritic network - a specialised network of cells within the lymph node - made a difference in how antigens were captured and used. The team identified that only the cells in the centre of the network functioned as an antigen reservoir, whereas those on the periphery did not, and the molecular mechanisms underpinning this. This discovery has implications for the potential development of more efficient vaccines.
Thanks to continuous advances in human stem cell research, studies using embryo models are progressing quickly, including research happening at the Crick. Embryo models offer a scientific and ethical addition to the use of embryos from fertilised human eggs in research, but ethical guidelines sometimes have to play catch-up with scientific progress.
The challenge is to know how we would decide when an embryo model is ‘similar enough’ to an embryo as to fall under the same restrictions, since research keeps pushing the technology forward.
Naomi Moris, Group Leader of the Developmental Models Laboratory at the Crick, worked with an international group of biologists and ethicists to propose a refined definition of the human embryo, as a group of cells which have the potential to form a fetus, focusing on what the embryo can become rather than its origin. The group identified ‘tipping points’, where embryo models would stray into the territory of an embryo.
Excessive DNA damage found in Motor Neuron Disease
Amyotrophic lateral sclerosis (ALS), also known as Motor Neuron Disease, is a devastating neurological disease that causes motor neurons to die, leading to muscle weakness and ultimately death. It has been challenging to access motor neurons to identify the underlying causes of the disease, due to high risk of complications that come with a biopsy of the fragile spinal cord. Researchers have turned to studying motor neurons derived from induced pluripotent stem cells (iPSC) to better understand ALS. However, previous iPSC studies were limited to small numbers of patients, and there is no consensus on how ALS develops.
In this study, researchers combined iPSC-derived motor neurons and post-mortem spinal cord tissue data into a large resource, to identify changes that cause motor neuron death in ALS. They found that ALS leads to an accumulation of somatic mutations and a heightened DNA damage response. Although these changes were observed in various types of ALS, they were most notable in cases where the nuclear protein, TDP-43, was relocated to the cytoplasm. This study highlights genome instability as a hallmark of ALS and could help in the development of new therapies.
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 we 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. We 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.
Uncovering cancer-immune system interactions could inform how patients respond to immunotherapy
Researchers at the Francis Crick Institute and King’s College London have revealed the complex interactions between cancer and the immune cells that surround a tumour, with the potential to inform how patients will respond to immunotherapy.
In the study, published in the journal Genome Medicine, the researchers analysed thousands of samples across 32 types of cancer to examine the way that cancer dynamically interacts with the tumour immune microenvironment (TIME), allowing the disease to flourish.
The researchers focused on a class of genes called cancer drivers because, when altered, they help drive cancer. They identified 477 of these cancer drivers that interact with multiple features of the TIME, suggesting that they drive the formation of cancer by disrupting biological processes within the cell as well as interfering with the immune system.
Autophagosomes—the waste disposal units of the cell—are formed by a process whereby a cup-shaped membrane structure closes around a part of the cytoplasm or a particular cargo. Autophagosome biogenesis is catalysed by the autophagy-related (ATG) proteins but how this works is unclear. Sharon Tooze and collaborators have used machine learning analysis, molecular dynamics simulations and live cell imaging to explore the function of the ATG3 protein. They find that ATG3 contains special structures called amphipathic α helices (AH) that help it associate with membranes, leading to the membrane remodeling required for the formation of autophagosomes. Intriguingly, AH structures are present in other ATG proteins and may have similar functions.
Cohesin protein complexes are central players in most processes involving unwinding of DNA, moving on the DNA and extruding DNA loops. Understanding the mechanical forces involved is an important aspect of cohesin research. The Molodtsov lab measured mechanical forces generated by shape changes in single cohesin molecules and found that force is created in two ways: one is from a bending motion caused by random thermal fluctuations, and the other involves using energy from ATP molecules. They propose that mechanical forces generated by these so-called conformational changes have roles in the initiation and elongation phases of the loop extrusion process.
TMEM106B: SARS-CoV-2’s secret entrance to the cell
SARS-CoV-2 is known to enter cells using the ACE2 receptor, but the virus can also infect cells that lack ACE2. The Cherepanov lab, together with Crick and international colleagues, have shown that a second protein, TMEM106B, can act as an alternative entry port for the SARS-CoV-2 virus. The E484D mutation in the virus spike enhances TMEM106B use, and antibodies against TMEM106B can stop viral entry, suggesting their potential as therapeutics. Structural studies looking at how TMEM106B and the virus interact showed that TMEM106B engages the spike precisely at its receptor binding motif. The results may explain how SARS-CoV-2 can spread to tissues outside of the respiratory tract and highlight the ability of the virus to switch to an alternative receptor.
Antibody levels vary according to vaccine type and previous infection with COVID-19
Two doses of the Oxford-AstraZeneca COVID-19 vaccine induce lower levels of antibodies that are able to recognise and fight the SARS-CoV-2 Delta variant (B.1.617.2) than against other strains.
COVID-19 vaccine booster provides good antibody protection against Omicron
As part of the CAPTURE study, researchers in collaboration with the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre found that antibodies generated in people who had received only two doses of either the Oxford/AstraZeneca vaccine or the Pfizer/BioNTech vaccine were less able to neutralise the Omicron variant as compared to the Alpha and Delta variants. They also found that antibody levels dropped off in the first three months following the second dose but that a third ‘booster’ dose raised levels of antibodies that effectively neutralise the Omicron variant.
Patients with blood cancer found to have lower protection against SARS-CoV-2
As part of the largest study to comprehensively evaluate the response of patients with cancer to COVID-19 vaccines, researchers in the Turajlic lab monitored the immune response of 585 patients with different types of cancer after receiving a first and second dose of the COVID-19 vaccine. They found that patients with blood cancer were less likely to have antibodies than individuals of a similar age without cancer or with solid cancer, and when they did have antibodies, the levels were lower against all variants.
Researchers identify role of key gene in embryonic development
A zebrafish study by researchers in the Hill lab has provided new insights into the role of the SMAD4 protein in vertebrate embryo development. Very early in development, SMAD4 was thought to be required to transmit signals from two closely related members of the TGF-β protein family, BMP and Nodal, which are responsible for organising different parts of the body plan of an embryo. Surprisingly, when the Smad4 gene was deleted in zebrafish, the parts of the embryo patterned by BMP signalling were severely disrupted, but those for which Nodal was responsible were far less affected. SMAD4 is thus differentially required for signalling by different TGF-β family members, which has implications for diseases such as cancer where it is mutated or deleted.
Bone marrow backup needed to tackle respiratory infections
Researchers in the Reis e Sousa lab have found how the immune system triggers an ‘emergency’ dendritic cell response during infection. Dendritic cells have an important role in the immune system, detecting infectious bacteria, fungi or viruses that have entered the body and alerting T cells which recognise and attack the invader. However, there are few dendritic cells in healthy tissue like the lungs which means that, on infection, their numbers need to be boosted. In their study, the team monitored dendritic cells in mice infected with flu virus and found that, after infection, new dendritic cells are released from the bone marrow in response to a chemokine ‘distress’ signal which directs them to the site of infection.
Gene-editing used to create single sex mice litters
Researchers in the Turner lab, in collaboration with the University of Kent, used gene editing technology to create female-only and male-only mice litters with 100% efficiency. Targeting the Top1 gene, which is essential to DNA replication and repair, their method uses CRISPR-Cas9 to induce sex-linked lethality before embryo implantation, allowing only the desired sex to develop. This proof of principle study demonstrates how the technology could be used to improve animal welfare in scientific research and perhaps also agriculture.
New tool to control of fruit fly gene expression using light
Researchers in the Vincent Lab, , in collaboration with the group of Yohanns Bellaiche at Institut Curie in Paris, have developed a new tool for robust control of gene expression in Drosophila using light. They successfully used the new method to activate key genes in different tissues and at various developmental stages and demonstrated gain and loss-of-function phenotypes at animal, organ, and cellular levels. Their work provides developmental biologists with the ability to control gene expression with high temporal and spatial resolution, a valuable addition to the Drosophila genetic toolkit.
