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.
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.
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.
Stem-cell based models make the early precursors to germ cells
The cells that will eventually give rise to germ cells, sperm and egg, are originally made by the embryo early on in its development. These cells, called Primordial Germ Cells or PGCs, are an exciting group of cells to study because we still know relatively little about how they are first generated, how they move around the early embryo, and how they start to mature and eventually produce sperm or egg cells. However, current technology to make PGCs in the laboratory uses large, disorganised culture systems alongside specific chemicals to 'bias' the cells towards becoming PGCs. Instead of doing this, we have shown that mouse stem cells can be cultured in a controlled, 3D system that mirrors certain elements of the early mouse embryo.
In this work, the researchers show that these structures, called 'gastruloids', also contain PGCs, and that these cells not only appear in these structures, but that they interact with the other cells in the gastruloid in a manner that is very similar to the way they develop in the actual embryo. They also show that the gastruloid PGCs reach a more mature stage of development (at about the stage of a 13-15 days old mouse embryo) compared to traditional culture methods (that only reach day 9-10). This shows that not only can we make PGCs in a new way that might reveal new insights about these specific cells, but it also highlights the value of embryo-like models, including gastruloids, to generate rare cell types that might otherwise be difficult to access.
Does infection or vaccination induce nasal neutralising antibodies to SARS-CoV-2 variants? The Covid Surveillance Unit has developed a fast, easy method to test if antibodies in nasal mucosa stop SARS-CoV-2 replicating in cells in swabs from participants in the UCLH-Crick Legacy study. Both vaccination and infection boosted antibody levels in nasal mucus, and repeated vaccinations could enhance this. Importantly, the range of nasal antibodies differs from that in blood, which means current vaccines may not stop infections with new antigenically different variants. The methodology used in the study will make it easy to evaluate next generation vaccines, including mucosal vaccines.
Vaccine monitoring crucial as SARS-CoV-2 variants continue to evolve
Researchers at the Francis Crick Institute and the National Institute for Health and Care Research Biomedical Research Centre at UCLH have highlighted the importance of continued surveillance of emerging SARS-CoV-2 variants and vaccine performance as the virus continues to evolve. The research, part of the Legacy study, compared the newer monovalent COVID vaccine with older bivalent vaccines used in the Autumn 2023 booster campaign, finding that both vaccines generated neutralising antibodies against the most recent strain of Omicron, BA.2.86. However the new monovalent vaccine generated higher levels of antibodies against a range of other Omicron variants. This highlights the importance of careful vaccine updates and continuing to complement a vaccination programme with the development of antibody drugs that work against all variants, as some more vulnerable people don’t respond well to vaccines.
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. 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. 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.
Research reveals man born thousands of miles to the east travelled to Cambridgeshire 2,000 years ago
Scientists from the Francis Crick Institute, Durham University, and MOLA Headland Infrastructure have discovered that a man who lived between AD 126-228 during the Roman period did not originally come from a rural farmstead near where he was buried, but likely thousands of miles away, possibly outside of the Roman Empire. In research published in Current Biology, the researchers revealed this man carried ancestry related to people in the Caucasus and Sarmatian individuals. The Sarmatians, Iranian-speaking nomadic peoples, were renowned horse riders who mainly lived in an area around modern-day southern Russia and Ukraine. The man, known as Offord Cluny 203645, was buried by himself without any personal possessions in a trackway ditch, so this analysis gave archaeologists a glimpse into his life.
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.
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.
Researchers identify new PKCε target as key to successful cell division
Researchers in the Parker lab have unpicked the action of protein kinase C (PKC) in modulating cell growth and division. The team developed a novel trap for proteins regulated by PKC by engineering UV-photocrosslinkable amino acids into PKCε to produce a sort of molecular flypaper. They captured a previously unknown PKCε target, the RNA-binding protein SERBP1, and showed that SERBP1 was required for successful chromosome segregation and cell division. Their work provides a new insight into how cells protect their genome during division and also which regulatory processes could play a key role when cells become cancerous.
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 method to understand protein biomarkers in plasma
In recent years, the Ralser lab have developed new methods to understand proteins in plasma – the liquid part of the blood – with the hope of discovering new protein biomarkers, which are indicators for a wide range of diseases.
However, the structure and function of proteins is highly influenced by chemical modifications. One such modification – glycosylation – happens to lots of different proteins in plasma and is known to be altered in diseases such as cancer. Currently, methods to study protein glycosylation in plasma are relatively limited, generally requiring additional handling steps. The team developed a method capable of quantifying over a thousand glycopeptide features from human plasma without any extra steps, making it compatible to understanding data from large clinical trials.
They then applied this method to a cohort of COVID-19 patients and healthy donors, finding changes in glycosylation of plasma proteins in response to increasingly severe COVID-19. They hope this method can be applied for larger epidemiological and clinical studies, both to better understand the underlying biology and develop new biomarkers.
Ed Tate and Wouter Kallemeijn in the Chemical Biology and Therapeutic Discovery Satellite Lab at the Francis Crick Institute and Imperial College London, in work led by Jesus Gil at the MRC-LMS (Laboratory of Medical Sciences) at Imperial College, have uncovered critical insights that can pave the way for novel therapeutic approaches to tackle cancer, fibrosis, and many age-related conditions. Ed and Wouter identified and patented NMT inhibitors to selectively kill senescent cells, which have stopped growing but can drive inflammation in cancer and fibrosis. Crick/Imperial spin-out Myricx Bio is now developing NMT inhibitors as potential senolytic drugs.
Researchers uncover protein interactions controlling fertility in female mice
Researchers at the Francis Crick Institute have shed light on the proteins controlling the development of ovaries in mice before and after birth. They found that a protein called FOXL2, which sits on top of specific regions in DNA ('enhancers') and influences whether and how other target genes are read, plays a role during embryonic development, but has the most impact after birth. Using chromatic proteomics to fish out' all of the other proteins that interact with FOXL2 when bound to DNA, they found that a number of protein interactions drastically increased in ovaries after birth. They believe another protein called USP7 is needed to stabilise FOXL2 on top of DNA as removing the Usp7 gene from female mice made them infertile. As FOXL2 and USP7 share some common roles in humans, this research could inform causes of female infertility.
Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation
This work reveals that amino acids, rather than fructose 1,6-bisphosphate, are the relevant cellular regulators of pyruvate kinase M2 (PKM2), a critical node in cancer metabolism. It further elucidates the molecular mechanism of PKM2 regulation by amino acids with a new algorithm that predicts allosteric pathways in proteins, a major and difficult problem in structural biology.
New insights into signalling enzyme in inflammatory response
A study from the Svejstrup lab has uncovered new insights into the enzyme cGAS, a key component of the innate immune system, showing that cGAS also senses dysfunctional protein production. They present an unexpected mechanism of cGAS activation by ribosome collision, which could inform our understanding of inflammatory responses to viral infection.
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.
The Briscoe lab has used single cell mRNA sequencing to study the developing human spinal cord during gestational weeks 4 to 7. The team compared their results with the ones obtained in mice and found similarities as well as human-specific differences. This data is available as an open resource and will prove useful for future studies into sensory and motor control systems.
A new study led by postdoc Martina Hallegger and the Ule lab describes what happens when the RNA binding protein TDP-43 is mutated and its condensation properties change. The protein is often mutated in the rare neurological disease, amyotrophic lateral sclerosis (ALS).
A study from the Briscoe lab has developed methods to quantify so-called Waddington landscapes, a description of cellular differentiation. The team have constructed a dynamical geometric model that can predict cell fate.
