The GibsonGroup, in collaboration with the Sosso Group (chemistry) are investigating how small molecules can inhibit ice recrystallisation - a property more commonly associated with macromolecules, such as ice binding proteins or some polymers. The challenge of the macromolecules is that sequential modification is challenging, and hence structure-property relationships are often missing. Here the team show that phenyl alanine can inhibit ice recrystallisation and that modulation of the hydrophobic face impacts the magnitude of the activity. This work shows that ’small molecule’ approaches can be taken to probe the complex ice/water interface, with the long term goal of finding new molecules to control ice growth.

Read the paper here.

This work answers the mystery surrounding when in evolution did a key class of membrane remodelling factors arise. The collaborative team comprising Balasubramanian (Warwick), Baum (Cambridge), Lowe (Cambridge), Robinson (Lancaster), and Ettema (Wageningen, Netherlands) worked on proteins encoded by Heimdall archaea, thought to be most related to eukaryotes. They found that, contrary to existing dogma, a complex eukaryote-like ESCRT family of membrane remodelling factors were present in archaea and are therefore not eukaryotic inventions. Warwick post-doctoral fellow and first author Hatano “reconstituted” key steps of the process using purified components helping arrive at the conclusions.
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Research from the University of Warwick sheds new light on a key cause of cancer formation during cell division (or mitosis), and points towards potential solutions for preventing it from occurring.

When we think about embryo growth, we often focus on tissue growth. However, this is not always the case: for example, the nervous system actually shrinks during parts of development. How do tissues condense in size while maintaining mechanical integrity? In recent work from the Saunders lab, with Spanish collaborators Enrique Martin-Blanco and Jose Munoz, they show that the Drosophila nervous system condenses through alternating waves of contraction from the anterior and posterior ends of the embryo. Further, they use the power of Drosophila genetics to reveal that the glial cells provide an essential mechanical support, effectively acting like a compression sock during condensation. This work opens up new avenues to study the mechanobiology of tissues that shrink – such tissues display behaviour very much distinct from growing tissues. Read the paper here.

The formation of a clathrin-coated vesicle is a major membrane remodeling process that is crucial for membrane traffic in cells. Besides clathrin, these vesicles contain at least 100 different proteins although it is unclear how many are essential for the formation of the vesicle. Here, we show that intracellular clathrin-coated formation can be induced in living cells using minimal machinery and that it can be achieved on various membranes, including the mitochondrial outer membrane. Chemical heterodimerization was used to inducibly attach a clathrin-binding fragment "hook" to an "anchor" protein targeted to a specific membrane. Endogenous clathrin assembled to form coated pits on the mitochondria, termed MitoPits, within seconds of induction. MitoPits are double-membraned invaginations that form preferentially on high curvature regions of the mitochondrion. Upon induction, all stages of CCV formation - initiation, invagination, and even fission - were faithfully reconstituted. We found no evidence for the functional involvement of accessory proteins in this process. In addition, fission of MitoPit-derived vesicles was independent of known scission factors including dynamins and dynamin-related protein 1 (Drp1), suggesting that the clathrin cage generates sufficient force to bud intracellular vesicles. Our results suggest that, following its recruitment, clathrin alone is sufficient for intracellular clathrin-coated vesicle formation.

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The GibsonGroup, working with the Sosso Group in chemistry have demonstrated that simple amino acids can slow the recrystallisation of ice. Ice recrystallisation inhibition (IRI) is normally associated with ice binding proteins, but the team show that amino acids can also achieve this. Using a combination of experiments and modelling the importance of the structure of the amino acid is explored, and the relative role of ice binding investigated.

Read the paper here.

The GibsonGroup, working with colleagues at UHCW, have demonstrated the detection of SARS-COV-2 virus using liquid samples. The team, in 2020, discovered that SARS-COV-2 spike protein could bind sialic acids (specialised sugars) and developed this for lateral-flow detection. In this present work, the team show a solution-phase assay which can be conducted in multiwell plates and is hence suitable for automation. The key design of this was rod-shaped gold nanoparticles, with a synthetic polymer tether connecting the sugars.

Read the paper here

A project to improve the efficiency of our medicines using tiny particles at the University of Warwick has received funding to take it a step closer towards commercialisation.

During development, many organisms initially undergo multiple rounds of nuclei division before cellularisation occurs. Such systems are known as syncytia. Other processes such as muscle formation – which have multiple nuclei in a single cell – are similar.

In syncytia, nuclei distribute in a regular pattern. Yet, how does this occur? Answering this question is important for understanding how life developments and muscles form. In recent work from the Saunders lab, in collaboration with the Telley lab at the Gulbenkian Institute in Portugal, they used quantitative measurements to unravel how the nuclei regularly position in the fruit fly syncytium. They took advantage of explants – whereby material is removed from the egg and imaged – to reveal that are repulsive interactions between microtubules (rod like structures) in the syncytia. They used modelling and experimental tests to show that these repulsive interactions drive the ordering of the nuclei.

Read the paper here.

In collaboration with groups at UMass Med School, Smith College and Morehouse University, we have developed a reporter mouse generated by modification of a widely expressed and highly rhythmic gene encoding D-site albumin promoter binding protein (Dbp). In this line of mice, firefly luciferase is expressed from the Dbp locus in a Cre recombinase-dependent manner, allowing assessment of bioluminescence rhythms in specific cellular populations. Our studies reveal cell-type-specific characteristics of rhythms among neuronal populations and liver cells. Our model allowed assessment of the rate of recovery from circadian misalignment once animals were provided with food ad libitum. These studies confirm the previously demonstrated circadian misalignment following environmental perturbations and reveal the utility of this model for minimally invasive, longitudinal monitoring of rhythmicity from specific mouse tissues.

Read the paper here.

The Perrier Lab have just published a new study in Angewandte Chemie which shows how polymeric nanotubes can be designed to switch their fluorescence on as they deliver a commercial anticancer drug (doxorubicin), thereby permitting the in-situ visualization of drug release. By this method, we can both treat a cancer tumour and show where the tumour is located. These theranostic systems (from therapeutic and diagnostic) form a new approach to drug delivery.

Read the paper here.

The Medical Schools Council has released its report into how university research contributed during the COVID-19 pandemic. Work undertaken by the GibsonGroup is featured in this report.

Chromosome mis-segregation during mitosis leads to aneuploidy, which is a hallmark of cancer and linked to cancer genome evolution. Errors can manifest as ‘‘lagging chromosomes’’ in anaphase, although their mechanistic origins and likelihood of correction are incompletely understood. Here, we combine lattice light-sheet microscopy, endogenous protein labeling, and computational analysis to define the life history of >104 kinetochores. By defining the ‘‘laziness’’ of kinetochores in anaphase, we reveal that chromosomes are at a considerable risk of mis-segregation. We show that the majority of lazy kinetochores are corrected rapidly in anaphase by Aurora B; if uncorrected, they result in a higher rate of micronuclei formation. Quantitative analyses of the kinetochore life histories reveal a dynamic signature of metaphase kinetochore oscillations that forecasts their anaphase fate. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with an additional layer of anaphase error correction required for stable karyotype propagation. Read the paper here

The GibsonGroup, working with the Sagona group in SLS and Cytivia (who host Prof Gibson as a Royal Society Industry fellow) have investigated how polymers can be used to cryopreserve bacteriophages. Methods to freeze cells have attracted huge interest of late, for application in cell based therapies and biotechnology. However, virus storage is less explored. The team showed that a simple commodity polymer could (surprisingly) protect phage and offers a new approach for banking, or even storing cocktails of phages for future use in therapy or diagnostics.

Read the paper here

The GibsonGroup and their Industrial partners Iceni Diagnostics have been collaborating on new tools for Lateral Flow Diagnostics(LFDs). In particular, on replacing antibodies as the recognition units with glycans (sugars). Here the team show the first example of a complete LFD which uses glycans as both the mobile and stationary phase, providing complete proof-of-concept that a lateral flow diagnostic can be achieved without antibodies. This is demonstrated for the sensitive detection of lectins and could be applied to a range of biological targets, spanning toxins, viruses and more.

Read the paper here

The GibsonGroup with their industry partner Iceni Diagnostics have demonstrated a new approach to make ’test lines’ in lateral flow diagnostics. Current methods to make a test line involve immobilising antibodies, or using high molecular weight proteins with chemical modifications to display binding ligands. In this work, the team showed that a synthetic polymer can be used instead, which could dramatically simply the process of making a new test line, and using ’small molecule ligands’ as the targets, shown here with a glycan and biotin.

Read the paper here

The COVID-19 pandemic has brought health inequalities into sharp focus on an international scale. Vulnerability to and mortality from acute COVID-19 infection is higher in men, whereas, Long COVID disproportionately affects women. Why?

Read the paper here

Dr Joanne Muter and Professor Jan Brosens collaborated with researchers in Chicago and Buffalo, USA, in a study that used comparative transcriptomics to reconstruct the evolutionary history of gene expression in the pregnant endometrium. The study identified hundreds of genes that were gained or lost in the womb lining of primate and human lineages. Genes that evolved to be expressed at the maternal-fetal interface in the human lineage were enriched for immune functions and diseases, such as preterm birth and pre-eclampsia. Read the paper here

We're delighted to announce that Dr Rob Howes, the Director of the Rosalind Franklin Laboratory, has been appointed as an honorary Professor at WMS.

The GibsonGroup, working with UHCW and Iceni Diagnostics have shown that glycans (sugars) can be used in place of antibodies to detect SARS-COV-2. Last year the team identified that SARS-COV-2 spike protein could bind certain glycans, and in this work they incorporate the glycan onto gold nanoparticles to make a ‘flow through’ (similar to lateral flow) device. The methods allowed detection of infection and was shown to retain binding to several variants of concern. The underpinning principle can now be applied to a range of infections or biosensing challenges. The work was large collaboration with Chemistry, WMS (including the Straube-Group from our division), Physics, Industry and the hospital.

Read the paper - Glycan-Based Flow-Through Device for the Detection of SARS-COV-2 

Within species, there can be very large differences in animal size. Perhaps the most striking example is in domestic dogs; e.g. compare a Chihuahua with an English Mastiff. Despite being genetically very similar, their internal organs are correctly positioned and sized for their particularly body size, i.e. the organ size scales with the organism size. How does such scaling occur? There has been extensive analysis of scaling of external organs, such as insect wings, due to their accessibility for imaging. However, how internal organs scale and adjust for changes in system size remains poorly understood. In recent work, the Saunders lab utilised a genetic trick to generate smaller Drosophila embryos that could be live imaged. From live imaging of heart, hindgut and nervous system formation, they have provided the first quantitative dynamic analysis of internal organ scaling during development. Interestingly, the initial heart vessel scales precisely with embryo size (see figure). However, the developing nervous system appears to have a lower bound on its size, regardless of how reduced in size the embryo is. These results suggest that organs adapt to changes in embryo size through different mechanisms. Hopefully further work, including in vertebrate systems, will uncover the genetic and biophysical mechanisms driving internal organ scaling.

Glycans (sugars) dictate a huge range of biological recognition processes, which can be replicated by presenting the sugars onto polymers (or other materials). However, whilst these almost always have high affinity, these materials are non-selective and can bind a wide range of targets, limiting their use. In a Perspective article, Dr Sarah-Jane Richards and Prof. Matthew Gibson discuss synthetic tools to enable selectivity to be engineered into glycomaterials, to help translate them into applications including biosensing.

Read the article now here 

Our understanding of the etiology and pathophysiology of endometriosis remains limited. Disease modelling in the field is problematic as many versions of induced mouse models of endometriosis exist. We integrated bioluminescent imaging of ‘lesions’ generated using luciferase-expressing donor mice. We compared longitudinal bioluminescence and histology of lesions, sensory behavior of mice with induced endometriosis and the impact of the GnRH antagonist Cetrorelix on lesion regression and sensory behavior. Four models of endometriosis were tested. We found that the nature of the donor uterine material was a key determinant of how chronic the lesions were as well as their cellular composition. The severity of pain-like behavior also varied across models. Whilst Cetrorelix significantly reduced lesion bioluminescence in all models, it had varying impacts on pain-like behavior. Collectively, our results demonstrate key differences in the progression of the ‘disease’ across different mouse models of endometriosis. We propose that validation and testing in multiple models, each of which may be representative of the different subtypes / heterogeneity observed in women should become a standard approach to discovery science in the field of endometriosis. Read the paper here

With the support of the Wellcome-Translational Partnership, the teams of Dr Meera Unnikrishnan and Professor Sebastien Perrier have developed a new family of nanoparticles for the treatment of TB infection which address the main shortfall of current therapies, poor penetration to mycobacterium containing niches such as macrophages.

The team has designed mannose-decorated nanoparticles loaded with a well-established TB drug, which can degrade and deliver their payload at lysosomal pH. Fluorescence uptake studies showed preferential endocytosis of mannosylated particles via sugar-lectin interactions, and the particles were also shown to be effective at killing intracellular M. bovis BCG bacteria in THP-1 macrophages. Taken together these results show that in vitro, such macrophage-targeted particles increase intracellular isoniazid concentration, showing an increased antimicrobial activity against intracellular mycobacteria. Read the paper here

This paper was the result of a collaboration between Saravanan Palani (now at IISC Bangalore), Darius Köster and Mohan Balasubramanian. Here we show that the extended CH domain of IQGAP proteins such as Rng2 or IQGAP1 can bend usually straight actin filaments into tight rings when tethered to a lipid membrane. That observation was quite unexpected as no other protein is known to do this! It was a control experiment that allowed us to make this fascinating observation… read more here