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.
Changes in circulating immune cells may be able to reveal the presence of breast cancer
Research led by a team of scientists at Francis Crick Institute and clinicians at Imperial College London investigated whether changes in certain circulating immune cells (neutrophils) were detectable in newly diagnosed patients with breast cancer. The team recruited women that, after routine mammograms and subsequent biopsy, were diagnosed with breast cancer. Their disease was very early stage and asymptomatic. The researchers collected blood before treatment, isolated and analysed circulating neutrophils (one of the more abundant immune cells in blood) and compared it to neutrophils from age matched healthy volunteers.
The results showed that different cancer specific activities in the cells were detectable in circulating neutrophils from early cancer patients compared to healthy volunteers. These activities were not detected in patients with benign breast disease. This study only included a limited number of patients, but it represents proof-of-concept evidence suggesting that disruption to neutrophils occurs very early in the disease. Defining these disruptions could represent not only a way to understand how they contribute to tumour progression, but also could be exploited as biomarkers for early disease.
During development, multicellular organisms undergo stereotypical patterns of tissue growth in space and time, but how this is orchestrated remains unclear, largely due to the difficulty of observing and quantitating this process in a living organism. The Tapon and Salbreux labs used live imaging and computational methods to quantitatively analyse developmental growth in the fruit fly adult abdominal epidermis. Abdominal growth is initiated by degradation of the basement membrane to which the epidermal progenitor cells are attached and is terminated by rapid exit from the cell cycle, rather than a gradual slowdown, as occurs in some other tissues. Different developing tissues can therefore achieve their final size using distinct growth termination strategies.
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. 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.
Focusing on a class of genes called cancer drivers, 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.
Accelerating developmental biology research with deep learning
Zebrafish are often used in biological research due to their transparent embryos and rapid development, allowing scientists to easily observe and study their growth processes. This makes them particularly valuable for understanding human biology and diseases. Sometimes, these fish can experience developmental delays due to genetic issues or experimental treatments. Traditionally, scientists have manually checked the fish's growth against standard charts, a slow and not always precise method.
Researchers at the Crick developed KimmelNet, an artificial intelligence tool, to make this process quicker, less subjective and more reproducible. KimmelNet analyzes standard microscope images of zebrafish embryos to determine their growth stage and can reliably spot developmental delays, requiring just a small number of images to do so confidently. Furthermore, the tool adapts well to new data, and its performance can be even further enhanced with some additional fine-tuning.
This innovation could significantly speed up research involving zebrafish, making studies more efficient and reliable. Plus, the approach has the potential to be applied to other organisms as well, broadening its utility in the field of biological research.
Microbial communities are composed of cells of varying metabolic capacity, and regularly include auxotrophs that lack essential metabolic pathways, whose usefulness to the community is therefore puzzling. A study from the Ralser lab revealed that metabolic changes in auxotrophs enrich the microbial community exometabolome—the mixture of secreted extracellular metabolites—and increase drug resistance. The findings could help the development of more effective antimicrobial treatments.
New software to detect and track individual cells growing in colonies
Cell biology techniques are creating more and more images that need to be analysed. In this work we present software, DM3D, that we developed to detect and track individual cells growing within small colonies. Each colony is between 10 and 30 cells that have been imaged with an advanced microscopy technique, which allows us to record movies of growing cells for long periods of time. The resulting 3D timelapse movies need to be analysed. Our software provides an interactive environment to combine two powerful techniques for cell segmentation: active contours (a way to find the outline of an object in an image) and neural networks (a series of computer algorithms used to understand relationships in data).
The software lets a user open a movie and called a 3D mesh – a type of model which defines the surface of an object with triangles – that represents a cell or a nucleus, then the mesh can be deformed by an active contours algorithm to improve the representation. It provides an interactive way for somebody to create 3D representations of their data, which are then used to train a neural network. The neural network is used to analyse large numbers of cells and colonies over long periods of time.
This work is important because it looks at how can we get the most out of neural networks, and merges two techniques to counteract their individual weaknesses. Neural networks are susceptible to a training history and it can be difficult to interact with the output to tune or verify it. Active contours require an initialisation step and need to be explicitly "told" to avoid artifacts – an output which has been generated by the training process. Combining the two techniques leads to fast and accurate results.
Mechanism of action of the anti-tuberculosis drug pyrazinamide
Pyrazinamide is one of the standard quartet of antibiotics used to treat TB, but its mechanism of action has been unclear. In this study, the Gutierrez lab used a novel dual live-imaging approach to show that the drug works through disrupting the ability of M. tuberculosis to maintain intrabacterial pH irrespective of the environment in the cell it has infected.
Using theory from engineering to understand how different cells are generated in a tissue
Researchers at the Crick have proposed a new way to analyse how signals control patterns of gene expression during embryonic development. In many developing tissues, signals known as morphogens form gradients across tissues. The current view, the “French Flag” model, suggested that cells simply read morphogen concentrations directly to determine their fate. However, in many tissues, morphogen levels change dynamically over time, concentration does not correlate with position and the duration of signalling influences patterning.
The researchers at the Crick used tools from optimal control theory to determine signalling strategies that optimally drive cells to their correct identity. They found that cells exploit the underlying behaviour of gene networks to make cell fate decisions. The signalling adapts over time, providing a large push early on but then backing off as the cell approaches its target state. This offers insight into the principles that produce cell fate decisions during embryonic development, explaining how the right type of cells are produced in the correct positions.
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.
A study led by Lucia Prieto-Godino has investigated evolutionary changes in ligand preference that occur in a family of olfactory receptors. The work found that different receptors’ odour preferences are linked to particular protein mutations. Some of these mutations appear at the same position over evolutionary distances, highlighting of a “hot-spot” that has a major role in determining ligand preference.
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, the researchers 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. The 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
Ancient viruses aid lung cancer cell survival
Endogenous retroviruses (ERVs) are a specific group of viruses that altered human evolution by inserting themselves into our DNA. Often these alterations do not cause any changes in human health and disease, however in some cases they may impact the way a disease progresses by changing the way our genes function. This happens because ERVs can help to generate new versions of proteins. In this paper, the aim was to explore whether the calcium regulatory protein calbindin influenced lung cancer cells when present in the ERV-altered form (ERV-calbindin).
Lung cancer cell growth and inflammation was compared in the presence and absence of ERV-calbindin. The results indicated that ERV-calbindin aided lung cancer cell survival and tumour-promoting inflammation. On the other hand, ERV-calbindin deficient lung cancer cells grew slower, initiated the recruitment of immune cells called neutrophils and released the inflammatory marker interleukin-8. This creates an interplay between pro and anti-tumour immune reactions. Altogether the reduction in growth and increase in inflammation observed in the absence of ERV-calbindin is a phenomenon called “senescence”. These results imply that the presence of the ERV altered form of calbindin aids cancer cell growth and survival and could potentially pose as a future target for therapies.
A heartbeat in a dish – growing specialised heart cells
Researchers at the Crick have now developed a way to grow specialised left ventricular heart muscle cells from stem cells, opening up new opportunities for research into heart disease, drug screening, and potentially the development of new treatments.
Their methods are published today in Cell Reports Methods and have also been licensed to Axol Bioscience to commercialise the protocol for the generation and sale of cardiomyocytes for R&D and the provision of contract research services, especially in field of drug screening and cardiotoxicity assays.
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.
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.
The shape, function, and movement of cells in our body depends on a branched skeleton made of actin filaments. This dynamic skeleton is stabilized by cortactin, a protein that is known to promote the spread of cancer. Researchers from Birkbeck College and the Crick have now determined how cortactin stabilizes actin branches by determining its structure using cryo-electron microscopy. The structure which overturns previous models has provided important new molecular insights into how cortactin binds actin branches and will help in the design of drugs/inhibitors that inhibit its function.
Published in Nature Structural and Molecular Biology
Published
New insight into how Toxoplasma exits host cells
The processes governing host cell exit by the intracellular parasite Toxoplasma gondii are regulated by several signalling pathways, but how these pathways are connected remains largely unknown. Researchers in the Treeck lab have used a combination of phosphoproteomics, lipidomics, reverse genetics and biochemical assays to demonstrate the presence of a feedback loop linking calcium signalling with the upstream cyclic nucleotide and phospholipid signalling pathways to enhance signalling during Toxoplasma egress. The work improves understanding of how the parasite integrates various signalling inputs to a single phenotypic outcome.
Diversity of stem cells and selective maintenance of descendent cells in the mouse pituitary gland
In organs with a high cell turnover, stem cells often generate new cells to maintain cell numbers and organ function. In contrast, in organs with a low cell turnover, such as the pituitary gland, stem cells are quiescent (i.e. dormant) and only generate new endocrine cells in exceptional circumstances. For example, upon removal of a pituitary target organ, such as the adrenals, stem cells are activated and some give rise to new corticotrophs, the endocrine cell type that normally regulates these glands.
In this study, the researchers explored quiescent and activated pituitary stem cells using single cell technologies, uncovering subtypes of stem cells in different regions of the gland. They unexpectedly observed that activated stem cells generate a wide range of endocrine cell types in addition to those regulating the removed organ. Analysing these new stem cell-derived cells at different times and with different tools, they found that only required cells, such as corticotrophs after adrenal removal, are maintained. This system provides a good model to characterise stem cell activity and how both emergence and maintenance of new cells is regulated.
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.
Random cell fate switching revealed in early embryonic development
How complex organisms are constructed from far simpler embryos is a central problem of biology. During embryonic development, pluripotent cells are guided to a variety of cell fates by a series of decision-making processes involving gradients of chemical and mechanical signals. A concentration gradient of the Nodal protein has long been thought to specify endodermal and mesodermal cell fates, depending on how much Nodal a cell is exposed to. However, this model is too simple, as neighbouring cells in the embryo can adopt different fates despite being exposed to similar concentrations of Nodal. The Hill lab has demonstrated that rather than pushing cells down a particular path, a gradient of Nodal signalling establishes a window of competency in which cells can switch to an endodermal fate. Those that don’t switch become mesoderm. Switching is a random event, the likelihood of which is modulated by signalling from another protein, Fgf. This imprecise mechanism is honed at later stages to produce clearly defined endoderm.
