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

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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.

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Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

Aberrant protein-lipid interactions occur in neurodegeneration, although their role is unclear. We show how the protein α-synuclein interacts with lipids to drive a form of cell death, ferroptosis. As α-synuclein aggregates, oligomeric species with hydrophobic domains incorporate into the plasmalemmal membrane, leading to altered membrane conductance and abnormal calcium influx following glutamatergic and dopaminergic stimuli. Aggregates induce iron dependent generation of free radicals, and peroxidation of polyunsaturated fatty acids, which underlies the incorporation of aggregates into the membranes. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling in human neurons, highlighting a new causative role for lipid homeostasis in Parkinson’s disease.

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Published in Cell Death and Differentiation

Published

Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population

Stem cell numbers in the hippocampus of young adults stabilise due to coordinated changes in stem cell behaviour which ensures lifelong hippocampal neurogenesis, according to new research from the Guillemot lab.

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Published in Cell Stem Cell

Published

High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

The immune system is increasingly acknowledged to be integrated with general physiology, but the genetic pathways underpinning those are largely unknown. This study demonstrated that high-content immunophenotyping could be accomplished at scale, compatible with a genetic screen and in so doing identified 80 novel immunoregulators (“hits”) and established striking correlations of immunological traits with blood biochemistry markers such as cholesterol and sodium. The paper formed a basis for the successful and rapid application of high-content high-throughput profiling to COVID-IP and to cancer immunomonitoring, and has spawned mechanistic follow-up studies of several of the hits.

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Published in Nature Immunology

Published

A COVID-19 virus particle

A dynamic COVID-19 immune signature includes associations with poor prognosis

SARS-CoV-2 infection and life-threatening COVID-19 caused the world’s most severe infectious disease pandemic in 100 years. An immediate priority was to decipher what was happening to patients’ immune systems. Rapidly deploying its skill-sets in high-content, high-throughput immunoprofiling, the Immunosurveillance Laboratory identified a dynamic, COVID-19 immune signature that blended textbook immunoprotection with examples of immune dysregulation that today’s textbooks do not describe. Among those, three molecules measured upon hospital admission seemingly predict a patient’s likelihood of deterioration over the next week; knowledge which can benefit health-care resource management, and offer novel therapeutic targets in COVID-19 and other inflammatory infectious diseases.

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Published in Nature Medicine

Published

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

Using a combination of structural biology, genome editing, and biochemistry, a new study from the Hill lab showed that Shprintzen–Goldberg syndrome is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, as previously predicted.

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Published in eLife

Published

Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development

This study describes the ubiquitome of several stages of the intra-erythrocytic development and extracellular stage of the malaria parasite in the blood stream. It highlights the remarkable changes in ubiquitylation that occur and a number of very interesting substrates. Using a chemical biology approach we show the importance of the first step in the pathway and the consequences of its inhibition during intra-erythrocytic development.

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Published in PLOS Pathogens

Published

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans

An example of our work on COVID-19 and of the flexible and collaborative nature of the Crick, involving several labs within the Crick and our collaborating universities and university hospitals. In this work, we described the discovery of pre-existing binding and neutralising antibodies against SARS-CoV-2 in uninfected and unexposed individuals. These antibodies, likely induced by exposure to seasonal coronaviruses, are present in a small percent of adults but in the majority of children, consistent with the relative sparing of the latter from the severe form of COVID-19

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Published in Science

Published

Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure

Children with intestinal failure cannot absorb the nutrients that are essential to be healthy. In the most severe cases, patients may require transplantation. However, there is a shortage of donor organs and complications can arise after surgery. We have shown how intestinal stem cells and intestinal tissues taken from patients can be used to grow functioning intestinal grafts in the laboratory, which could offer a safe and longer-lasting alternative to traditional donor transplants.

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Published in Nature Medicine

Published

Histology of gonads from patient showing bilateral dysgenetic testis.

Testis formation in XX individuals resulting from novel pathogenic variants in Wilms’ tumor 1 (WT1) gene

Through analysis of a large collection of clinical cases of Disorders of Sex Differentiation (DSDs), and a mouse model, we showed that unlike previous association of WT1 variants with XY female development, variants of the fourth zinc finger (ZF4) WT1 are a relatively common cause of XX male development, where the gonads are testes or ovotestes. This article is typical of our interaction with clinical geneticists, where our studies on the mouse, including generating models of human disorders, provide valuable insight into conditions affecting patients, as well as revealing novel insights into the underling mechanisms.

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Published in Proceedings of the National Academy of Sciences

Published

SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27-null mice

Tumour development depends on cell intrinsic dysfunction, but extrinsic factors can also be important drivers. Deletion of p27, which is downregulated in many tumours, predominantly gives pituitary tumours in mice. Sox2, which is transcriptionally derepressed in the absence of P27, is also important for tumorigenesis in this and other systems. Using various approaches, we establish the regulatory interaction in vivo of SOX2 and p27 and show that SOX2 is required independently, both cell-autonomously in the endocrine cells that form the tumours and non-cell-autonomously, in adjacent pituitary stem cells, to orchestrate tumorigenesis in the absence of P27.

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Published in Proceedings of the National Academy of Sciences of USA

Published

A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

New research from the McDonald lab combined crystallography and cryo-electron microscopy to reveal how the RET receptor, tyrosine kinase, recognises different GDNF family ligand/co-receptor pairs.

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Published in Structure

Published

IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche

In this work we mined this database to refine hESC culture conditions. These data will be a powerful resource for the community and will lead to changes in how hESCs are cultured in the future. Building on these data, we demonstrated that IGF1-receptor/PI3K/AKT, but not FGF receptor, signalling is required for hESC self-renewal. We built a searchable website that includes a compendium of human embryo gene expression analysis and compiled a list of all possible ligand and receptor interactions.

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Published in Nature Communications

Published

Initiation of a conserved trophectoderm program in human, cow and mouse embryos

We discovered that the mechanism underlying the first lineage decision in human embryos is mediated via cell-cell contact, triggering a cascade of broadly evolutionarily conserved molecular events that initiates a switch to a placental progenitor programme. We believe that our study will have clinical impact given that the timing of this decision coincides with the stage when most human embryos arrest.

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Published in Nature

Published

Frequent loss-of-heterozygosity in CRISPR-Cas9–edited
early human embryos

Crick researchers, including Kathy Niakan and James Turner, have revealed that CRISPR-Cas9 genome editing can lead to unintended mutations at the targeted section of DNA in early human embryos. The work highlights the need for greater awareness of and further research into the effects of CRISPR-Cas9 genome editing, especially when used to edit human DNA in laboratory research.

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Published in Proceedings of the National Academy of Sciences of USA

Published

The hydrophobic patch directs cyclin B to centrosomes to promote global CDK phosphorylation at mitosis

Disruption of a hydrophobic patch in the Cdc13 B-cyclin prevents localisation of CDK at the centrosomal spindle pole body, blocks mitosis, and compromises phosphorylation of the weakest CDK substrates. We propose this mechanism contributes to CDK substrate regulation.

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Published in Current Biology

Published

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

An important factor in determining the outcome of M. tuberculosis infection was identified in new research from the O’Garra lab. The team found that the cytokine type I interferon-induced neutrophil extracellular trap (NET) formation promotes bacterial growth and disease severity.

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Published in Nature Communications

Published

ESCRT-III/Vps4 controls heterochromatin-nuclear envelope attachments

Here we show that the inner nuclear membrane Lem2-Nur1 complex serves a substrate for the nuclear ESCRT-III/Vps4 machinery and explain how the dynamic tethering of chromosomes to this complex during interphase is linked to the establishment of nuclear compartmentalization following mitosis.

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Published in Developmental Cell

Published

Credit: Yuuki Obata and Álvaro Castaño, The Francis Crick Institute. Neuronal fibres labelled with rainbow fluorescence proteins.

Neuronal programming by microbiota regulates intestinal physiology

In this paper we explore the molecular mechanisms used by enteric neurons to monitor the luminal environment of the gut. In particular, we demonstrate that the transcription factor AhR functions as a biosensor of intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen.

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Published in Nature

Published

The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

The paper unravels the cell cycle dependent input to PKCe engagement and its proximal action through AuroraB. The non-apoptotic M-Phase role of caspase7 in cleaving a chromatin-associated pool of PKCe, alongside the site switching mechanism that plays out in the control of Topo2A by AuroraB are unusual and distinctive features of this cell cycle programme. The mechanistic insights into this transformation-associated pathway provide a specific steer to intervention oppportunities in cancer.

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Published in Nature Communications

Published

Astrocytes

Reactive astrocytes in ALS display diminished intron retention

A study led by Rickie Patani has identified the trigger of a key cellular change in amyotrophic lateral sclerosis (ALS), a type of motor neurone disease. The findings could help develop new treatments for many neurological diseases with the same change, including Parkinson’s and Alzheimer’s.

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Published in Nucleic Acids Research

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.