Publication highlights

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Explore a selection of research cases studies from the past five years.

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Intro

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.

Highlights

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Neutrophils (shown in brown) a type of immune cells helping breast cancer cells to grow in the lung.

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.

Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes

Published in Breast Cancer Research

Published

Targeting the interplay between HIF and mTOR in kidney cancer

The HIF and mTOR signalling pathways are frequently dysregulated in cancer. In the most common kidney cancer, clear cell renal carcinoma, HIF is upregulated, and mTOR is hyperactivated, but their interplay is poorly understood, in part because of difficulties in simultaneous measurement of global and mRNA-specific translation. Yoichiro Sugimoto and Peter Ratcliffe describe a new method, high-resolution polysome profiling followed by sequencing of the 5′ ends of mRNAs (HP5), that addresses this challenge, and use it to analyse the interplay of HIF and mTOR in kidney cancer cell lines. They show that specific classes of HIF1A and HIF2A target genes have different sensitivity to mTOR, in a manner that suggests combined use of HIF2A and mTOR inhibitors is a rational therapeutic strategy for kidney cancer.

Isoform-resolved mRNA profiling of ribosome load defines interplay of HIF and mTOR dysregulation in kidney cancer

Published in Nature Structural and Molecular Biology

Published

Modelling and enhancing migration of hiPSC-derived myogenic progenitors

Cell therapies to treat severe muscular dystrophies are inefficient. Major hurdles include the limited ability to expand mature myogenic cells in vitro, as well as the minimal migration capacity of myogenic cells upon transplantation, which inhibits dispersal into affected tissues. Researchers in the Tedesco lab have used directed iPSC differentiation, single-cell profiling, microfluidics and 3D tissue engineering to show that hiPSC-derived muscle satellite stem cells, which may be useful in cell therapies for muscular dystrophy, can have their in-vivo migration enhanced through activating the NOTCH and PDGF pathways, via treatment with DLL4 and PDGF-BB.

Assessing and enhancing migration of human myogenic progenitors using directed iPS cell differentiation and advanced tissue modelling

Published in EMBO Molecular Medicine

Published

Mechanical disengagement of the cohesin ring

Mechanical disengagement of the cohesin ring

In healthy cell division, the replicated DNA forms sister chromatids that must remain connected until separation later in the process. It’s only then that X-shaped chromosomes must be segregated symmetrically: each sister chromatid (one half of the X) is pulled to the opposite edges of the dividing cell by microtubules - protein filaments that generate force – to give rise to two daughter cells with an equal amount of genetic material. A ring-shaped protein called cohesin physically links sister chromatids and, like an elastic band, resists the forces generated by microtubules. Not only is the absence of cohesion lethal, but mutations in it can lead to cancer and incurable developmental disorders.

In this research by the Molodtsov and Uhlmann groups, the force that the cohesin complex can withstand is revealed. Using optical tweezers, the researchers pulled apart the DNA molecules tied by cohesin, showing that one cohesin ring is capable of embracing two DNAs and can resist up to 20 piconewtons of force, and when it breaks, it always opens at its weakest point: the hinge domain. These findings reveal that 40 cohesins are sufficient to oppose the tension generated in mitosis, whilst larger forces release the sisters. For the first time, this work lifts the veil on cohesin’s physical properties, bringing us closer to understanding how it is dysregulated in disease.

Mechanical disengagement of the cohesin ring

Published in Nature Structural and Molecular Biology

Published

Bone marrow micro-environment in leukemia

A study led by the Bonnet lab looks at how acute myeloid leukemia cells interact with and alter bone marrow. The team has produced an omics repository of potential biomarkers for different bone marrow cell populations.

Integrated OMICs unveil the bone-marrow microenvironment in human leukemia

Published in Cell Reports

Published

An asymmetric pattern of PAR proteins

Going with the flow: how to polarise a cell

Cell polarisation is a fundamentally important ordering process that breaks the internal symmetry of a cell by establishing a preferential axis. The Goehring lab used the nematode worm C. elegans to study why the polarity protein PAR-3 needs to aggregate to efficiently move to the front of the worm embryo. Contrary to previous theories, they found that the size of molecule aggregates did not directly affect PAR-3 movement. Instead, what matters is how tightly these molecules stick to the membrane. This discovery challenges existing ideas about cell transport mechanisms and highlights the role of membrane stability in cellular processes. Defects in cell polarisation can disrupt numerous processes, so developing a systems-level understanding may enable new therapies for developmental defects and cancer.

Design principles for selective polarization of PAR proteins by cortical flows

Published in The Journal of Cell Biology

Published

Watching tissues developing in real time

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.

ECM degradation in the Drosophila abdominal epidermis initiates tissue growth that ceases with rapid cell-cycle exit

Published in Current Biology

Published

Ciccarelli banner

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.

Mechanistic insights into the interactions between cancer drivers and the tumour immune microenvironment

Published in Genome Medicine

Published

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.

CRISPR-Cas9 effectors facilitate generation of single-sex litters and sex-specific phenotypes

Published in Nature Communications

Published

Polarity in dividing cells

Coupling cell division and polarity to keep cells organised

The vast majority of cells exhibit ‘cell polarity’ – they typically must distinguish their tops from their bottoms and their front from their backs. In complex organisms like animals or humans, cell polarity must be coordinated between cells to generate functional tissues and organs. Such coordination poses a challenge during embryonic development or in regenerating tissues as cells are continuously growing and dividing. To ensure cells are oriented correctly with respect to one another, cell polarity and cell division must be coupled.

When a cell divides, it generates a flow of material towards its centre, which aids the process of cell division and contributes to the forming boundary between what will become the two new daughter cells. Here the researchers show that this flow of material also transports a key molecule, PAR-3, into this forming boundary. The local flow-dependent accumulation of PAR-3 breaks the internal symmetry of the daughter cells and ensures that the polarity of each daughter cell is oriented properly with respect to its sister. This simple physical mechanism for coupling cell division and polarity may be a general method for keeping cells organised in actively dividing tissues.

Cleavage furrow-directed cortical flows bias PAR polarization pathways to link cell polarity to cell division

Published in Current Biology

Published

Synthetic sugars

Molecular decision making in glycosaminoglycan synthesis

Cell-surface and secreted proteins play critical roles in human development, growth factor signalling, and cell adhesion. Proteoglycans are an important subset of these proteins and are modified with long chains of sugar molecules called Glycosaminoglycans (GAGs) such as heparan sulphate (HS) or chondroitin sulphate (CS), but they all start with the same four sugars – only after the addition of the fifth sugar is the fate of the growing chain sealed.

While protein and DNA synthesis are template-driven, from DNA or RNA, synthesis of the proteoglycan GAG chains are not. In a collaboration between the Crick and Imperial, the researchers devised a synthesis system to allow precise control of eight of the enzymes in the biosynthesis pathway. They discovered that chrondroitin sulphate is the “default” modification, and that the enzyme responsible for priming chrondroitin sulphate synthesis modifies all sites equally. They also found that the enzyme responsible for priming heparan sulphate synthesis (EXTL3) has a positively charged patch that interacts with negatively charged amino acids near the attachment site and will only modify certain substrates. This will help to predict how mutations surrounding the glycosaminoglycan attachment sites could be implicated in diseases like cancer or developmental conditions.

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

Published in Nature Communications

Published

Zebrafish embryo stages

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.

Automated staging of zebrafish embryos with deep learning

Published in Life Science Alliance

Published

Rogue plasma cells within a germinal center.

The genetic architecture of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects women and those of an Afro-Caribbean ethnicity. In its severest form, it can cause organ failure - like kidney failure - leading to poor patient outcomes. SLE is also highly variable, which means people are affected differently in terms of the symptoms they have, organs involved and how they respond to treatment. This makes it very difficult to manage. Current therapies for SLE indiscriminately suppress the immune system with many side effects; as yet there is no cure.

There is a strong genetic contribution to SLE. This review integrates the many genetic variants currently understood to cause or be associated with SLE. It highlights rare, ultra-rare and novel causal variants that have been identified in humans and shown in animal models to cause an SLE- like disease. It also evaluates the common variants that may be associated with SLE, identified by large population studies, and the cell types that most highly express these genes. This highlights an important role for age-associated B cells in the development of the disease, already shown to be consistently associated with SLE related kidney disease, which may prove an attractive target for therapeutics.

Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants

Published in Nature Reviews Nephrology

Published

New insights into HIV infection

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.

HIV-1 requires capsid remodelling at the nuclear pore for nuclear entry and integration

Published in PLOS Pathogens

Published

Gamma delta T cells monitor tissue health

Although distress signals from microbes and tissue damage have long been appreciated as instigators of immunity, how surface tissue (epithelial) health is monitored remains poorly understood. Work from the Hayday lab has identified how gamma delta T cells, a population of specialised immune cells, sense the body’s status quo, enabling them to assess the health of surface tissues and protect against UVR-induced DNA damage and inflammation, two cancer-disposing factors.

Normality sensing licenses local T cells for innate-like tissue surveillance

Published in Nature Immunology

Published

Diagram showing evolutionary branches.

Research outlines how sex differences have evolved

Researchers at the Francis Crick Institute and Heidelberg University in Germany have shown that sex differences in animals vary dramatically across species, organs and developmental stages, and evolve quickly at the gene level but slowly at the cell type level. The researchers analysed the activity of genes in males and females over time in humans and four species (mice, rats, rabbits, opossums and chickens), covering the development of five organs (brain, cerebellum, heart, kidney and liver), into adulthood in the animals and up to birth in humans.

They discovered that organs which are different between the sexes vary across species, and in all animals and humans, few sex differences occurred while organs were developing, instead increasing sharply around sexual maturity. Only a very small number of sex-biased genes were shared across species, suggesting that sex differences have evolved quickly, but the same type of cells are sexually dimorphic across species.

Sex-biased gene expression across mammalian organ development and evolution

Published in Science

Published

Cryo-electron microscopy structure of coractin

How cortactin stabilises actin branches

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.

Cortactin stabilizes actin branches by bridging activated Arp2/3 to its nucleated actin filament

Published in Nature Structural and Molecular Biology

Published

A therapeutic target for two diseases

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.

Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation

Published in The EMBO Journal

Published