Dr Gabrielle Rudenko, University of Texas 20/04/21
'The competitive world of ‘Synaptic Organizers’ – cell surface molecules implicated in neuropsychiatric disease.'
Abstract: My laboratory focuses on proteins that mediate synapse development, especially the growing class of so-called ‘synaptic organizers’. Many synaptic organizers are implicated in neuropsychiatric disorders such as autism spectrum disorder, schizophrenia, and bipolar disorder. Typically, these proteins form trans-synaptic bridges that span the synaptic cleft, the space between two neurons connected by a synapse. There they mediate adhesion between the presynaptic and postsynaptic membranes, working to facilitate proper neural connections and connect groups of select neurons into discrete neural circuits. Specific synaptic organizers also play a critical role in developing and maintaining excitatory versus inhibitory synapses which are crucial for the excitation/inhibition balance that regulates overall neuronal excitability and communication through neural circuits. While previously, synaptic organizers were thought to simply promote cell adhesion, we now know that they guide the formation of complex protein interaction networks in the synaptic cleft and work as scaffolds to organize macromolecular assemblies that modulate synaptic function. Our laboratory is using a combination of structural biology, biochemical and biophysical methods, and proteomics, to study a portfolio of different synaptic organizers implicated in neuropsychiatric disease. By elucidating structure-function relationships of key molecules that selectively guide synapse development and uniquely impact specific neural circuits, we hope to identify novel therapeutic targets that can be leveraged to design better treatments for brain disorders in future.
Dr Emilia Santos, University of Cambridge 13/04/21
'On the mechanistic basis of morphological change'
Abstract: The evolution of novel morphologies is a key component of organismal diversification, yet the genetic mechanisms and adaptive significance underlying their evolution remain understudied. We address this question in two highly diverse model systems: pigmentation patterns in cichlid fishes and cuticle structures in water striders.
Prof Helen Walden, University of Glasgow 16/03/21
"Regulation of DNA repair by monoubiquitin signals"
Abstract: The Fanconi Anemia DNA repair pathway is needed to fix DNA inter-strand crosslinks. At the heart of the pathway is a single monoubiquitin signal which is attached to two homologous proteins, FANCD2 and FANCI. Both the assembly and the removal of the signal are required for completion of inter-strand crosslink repair. My lab focusses on understanding the mechanisms of assembly, functional consequence, and removal of specific ubiquitin signals. I will present our biochemical and structural data defining each of these steps, from how a single site is targeted for modification, what the addition of ubiquitin does to the ID2 complex, how each ubiquitin signal has a distinct function, and how the signal is removed from a specific site.
Dr Vincent Lynch, University at Buffalo 09/03/21
"On the (im)possibility of elephants"
Abstract: The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Through comparative genomics we identified a duplicate SOD1 gene Proboscideans that we functionally characterize and show may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.
Prof Ehab Abouheif, University of McGill 02/03/21
"How Ants and Bacteria Became One"
Abstract: Obligate endosymbiosis, in which distantly related species integrate to form a single replicating individual, represents a major evolutionary transition in individuality. Although such transitions are thought to increase biological complexity, the evolutionary and developmental steps that lead to integration remain poorly understood. Here we show that obligate endosymbiosis between the bacteria Blochmannia and the hyperdiverse ant tribe Camponotini originated and also elaborated through radical alterations in embryonic development, as compared to other insects. The Hox genes Abdominal A (abdA) and Ultrabithorax (Ubx)—which, in arthropods, normally function to differentiate abdominal and thoracic segments after they form—were rewired to also regulate germline genes early in development. Consequently, the mRNAs and proteins of these Hox genes are expressed maternally and colocalize at a subcellular level with those of germline genes in the germplasm and three novel locations in the freshly laid egg. Blochmannia bacteria then selectively regulate these mRNAs and proteins to make each of these four locations functionally distinct, creating a system of coordinates in the embryo in which each location performs a different function to integrate Blochmannia into the Camponotini. Finally, we show that the capacity to localize mRNAs and proteins to new locations in the embryo evolved before obligate endosymbiosis and was subsequently co-opted by Blochmannia and Camponotini. This pre-existing molecular capacity converged with a pre-existing ecological mutualism to facilitate both the horizontal transfer and developmental integration of Blochmannia into Camponotini. Therefore, the convergence of pre-existing molecular capacities and ecological interactions—as well as the rewiring of highly conserved gene networks—may be a general feature that facilitates the origin and elaboration of major transitions in individuality.
Dr Pauline Scanlan, University College Cork, Ireland 23/02/21
"Antagonistic Coevolution between bacteria and phages - from in vitro models to the human gut"
Abstract: Antagonistic coevolution (AC) between bacteria and bacteriophages plays a key role in driving and maintaining microbial diversity. Consequently, AC is predicted to affect all levels of biological organisation, from the individual to ecosystem scales. Nonetheless, we know nothing about bacteria–bacteriophage AC in perhaps the most important and clinically relevant microbial ecosystem known to humankind – the human gut microbiome.
To address this gap in our knowledge I track patterns of resistance and infectivity in naturally occurring populations of bacteria and phages isolated from the human gut, together with modelling their interactions in vitro. In this talk I will focus on emerging data from our in vitro models, which suggest that the dynamics of AC may be constrained by mutation supply and costs of resistance, and that other mechanisms such as phase variation may help explain the coexistence of bacteria and phages in complex environments such as the human gut.
Prof Anna Blom, University of Lund, Sweden. 16/02/21
'Major complement evasion strategy: binding of complement inhibitors to bacterial pathogens'
Abstract: The complement system is a pivotal component of innate immunity. Composed of over 30 plasma proteins and several cellular receptors, complement aims at destruction of invading pathogens. Therefore, the majority of bacterial pathogens developed strategies aiming at inhibition of complement.
We have found that binding of human complement inhibitor C4b-binding protein is a major evasion strategy of Gram-positive Streptococcus pyogenes. Further, this binding is also crucial for development of serum resistance in Gram-negative Neisseria gonorrhoeae. Importantly, N. gonorrhoeae are highly resistant to antibiotics.
Since N. gonorrhoeae evades killing by human serum through binding of C4BP, we previously created a chimeric protein that links the first two domains of C4BP, which bind to gonococci, with Fc domain of IgM (C4BP-IgM) to enhance complement-mediated killing of bacteria. Our findings indicate that C4BP-IgM fusion protein acts as a membrane perturbing agent through complement activation on microbial surface. The rapid and intense complement deposition triggered by C4BP-IgM generates membrane attack complex (MAC) pores, which facilitate the access of antibiotics to their intracellular targets. Consequently, gonococci become more susceptible to antibiotics, which results in an accelerated and enhanced killing. Thus, our data provide insights for the use of complement activators such as C4BP-IgM fusion protein as adjuvant for antibiotic treatment of gonorrhea.
Prof Arwen Pearson, (University of Hamburg) 02/02/21
'Time-resolved structural biology - the next revolution?'
Abstract: With the arrival of ultra-bright free electron X-ray laser sources, diffraction limited synchrotron storage rings, massive automation and the resolution revolution in cryo-electron microscopy structural biology is arguably in a golden age. But even with the large numbers of macromolecules structurally characterised to date, open question remain about how exactly structure is linked to function. Attention is now shifting to adding dynamics to our understanding of structure-function relationships, but time-resolved experiments remain technically challenging and thus are often viewed as a niche technique, where a few specialist groups investigate a subset of well-behaved proteins. In this seminar I will present some of the newest methods and tools for such experiments and show how time-resolved structural studies are becoming within reach of the broader community of structural biologist and molecular cell biologists interested in mechanism.
Dr Mark Webber (Quadram Institute, UK) 12/01/21
“How to understand and predict routes to antimicrobial resistance”
The development of antimicrobial resistance by bacteria remains one of the great challenges to global health. Development of resistance usually involves a change to the DNA content of the strain in question. Development of resistance can however result in a change to the fitness of the organism and the ultimate fate of a resistant organism is dictated by more than just its ability to survive exposure to an antibiotic. Our research is interested in understanding how resistance emerges and evolves under pressure over time. We aim to identify the wider complement of genes involved in defining susceptibility to a stress and studying how development of resistance impacts bacterial fitness. This talk will describe how we have developed a biofilm evolution model to study these issues.
Dr Sarah Coulthurst, (University of Dundee) 08/12/20
"How to kill your rivals: microbial warfare mediated by the Type VI secretion system”
Protein secretion systems are specialised macromolecular machines used to translocate specific proteins out of the bacterial cell, where they can be either released to the external environment or injected into other cells. Secretion systems, and the diverse proteins they secrete, mediate the interaction of bacterial cells with the environment, eukaryotic cells or other bacteria. The Type VI secretion system (T6SS) is a key weapon in the competitiveness and virulence of very many Gram-negative bacteria. Whilst some T6SSs are ‘anti-eukaryotic’, used to target host cells as classical virulence factors, the majority appear to be ‘anti-bacterial’, used to efficiently kill rival bacterial cells and provide a competitive advantage in a variety of polymicrobial niches. T6SSs deliver multiple, diverse toxins (‘effectors’) directly into target cells by a contraction-based firing mechanism. We have used the potent anti-bacterial T6SS of the opportunistic pathogen Serratia marcescens as a model to study the mechanisms and consequences of T6SS effector delivery into competitors. This has revealed a varied portfolio of effector toxins and cognate immunity proteins, used for several forms of inter-microbial competition. In particular, we have characterised several new anti-bacterial effectors and also discovered that the S. marcescens T6SS not only targets bacterial competitors, but can also deploy anti-fungal effector proteins against microbial fungi. Our findings have contributed to the growing appreciation that the role of the T6SS in shaping polymicrobial communities is both important and broad.
Dr Daniel Hebenstreit, (University of Warwick) 01/12/20
"Does RNA polymerase obey lockdown? Spatial and temporal dynamics of Pol2"
Transcription is central to all life, but many things remain unclear. In particular, RNA polymerase II (Pol2) mediated transcription of mRNAs in mammalian systems is characterized by relatively complex, enigmatic phenomena; transcripts are made in burst-like fashion rather than at a constant rate, Pol2 appears to cluster at transcriptional hotspots, and the genome is subject to 3D interactions.
Using a broad range of techniques including next gen sequencing, genome-wide analyses, single molecule imaging, and modelling approaches, we investigated how these observations can be integrated into a consistent overall picture of transcription.
Our results reveal mechanistic links between Pol2 localization, transcriptional dynamics and nuclear topology.
Prof Edel O'Toole, (Queen Mary University of London) 24/11/20
"Insights into cell biology from rare skin diseases"
Edel O’Toole is a clinical academic at Barts and the London School of Medicine and Dentistry with an active research group working on rare genetic skin disease biology. She trained in Medicine at University College, Galway, Ireland, followed by general medical and dermatology training in Dublin and London. She was a Howard Hughes Medical Institute Post-Doctoral Fellow with David Woodley at Northwestern University in Chicago from 1994-1998. Her main clinical interests are ichthyosis and palmoplantar keratodermas. She is the current clinical lead for the British Association of Dermatologists Dermatology and Genetic Medicine network. She is also on the steering committee of Pachyonychia Project and is actively involved in 100K Genomes, a gene discovery project within the NHS. In her talk, Professor O'Toole discussed 2 current areas of research interest in her lab: 1) How loss of basement membrane type VII collagen leads to aggressive skin cancer in the rare blistering disorder recessive dystrophic epidermolysis bullosa. 2) Identification of novel therapeutic targets in one of the most severe disorders of the skin barrier, harlequin ichthyosis.
Dr Peter Oliver, (MRC Harwell Institute) 10/03/2020
"Investigating the dual role of TLDc proteins in neurodevelopment, neurodegeneration and neuroprotection"
There is still a great deal to learn regarding the molecular mechanisms that underlie neuronal cell death and dysfunction in disease, in particular the selective vulnerability of cells in the brain - a common theme across many major neurological disorders. Cells have evolved a range of endogenous detection and defence mechanisms against stressful events, and there is hope that these pathways could be exploited in the future for therapeutic benefit.
Oxidation resistance 1 (OXR1) was originally identified from a screen for genes that could prevent oxidative DNA damage, and most recently, disruption of OXR1 has been implicated in human neurodevelopmental disorders characterised by epilepsy and cerebellar ataxia. We have demonstrated that over-expression of Oxr1 can effectively protect against oxidative stress-induced cell death in neuronal cells, while expressing higher levels of Oxr1 in vivo is able to reduce and delay neurodegeneration and neuroinflammation in two independent mouse model of amyotrophic lateral sclerosis (ALS). Conversely, disruption of Oxr1 in the mouse leads to region-specific neurodegeneration and ataxia, as observed in patients. Interestingly, many fundamental properties of this protein appear to be conserved in evolution, from mammals to flies and plants.
Oxr1 contains the TLDc domain, a motif present in a family of proteins including TBC1 domain family member 24 (TBC1D24), a protein mutated in a range of disorders characterised by seizures, hearing loss and neurodegeneration. The TLDc domain itself is highly conserved across species, although the structure-function relationship is unknown. To understand the role of this domain in the stress response and disease, we are carrying out systematic functional analysis of TLDc domain-containing proteins as well as continuing to investigate their neuroprotective properties in mouse models of neurodegeneration. We have also revealed for the first time the essential role of the epilepsy-associated TLDc family member TBC1D24 at the mammalian synapse and are now focussing on a new function for TLDc proteins in vesicular trafficking, combining electrophysiology and three-dimensional structural studies of the synapse with cell biology and biochemical approaches.
Peter graduated from the University of Bath in 1996 (Biochemistry), followed by a PhD at the MRC National Institute for Medical Research and post-doctoral positions in the MRC Functional Genomics Unit, Oxford. In 2013 Peter was awarded a European Research Council Consolidator Grant to establish his own independent group in the Department of Physiology, Anatomy and Genetics at The University of Oxford, and in 2018 moved his group to the MRC Harwell Institute.
Professor Eshwar Mahenthiralingam, (University of Cardiff) 03/03/2020
"Burkholderia bacteria: the ugly, the bad and now the good?"
Burkholderia are a diverse group of antimicrobial resistant Gram-negative bacteria. This talk will cover their ugly and bad traits as transmissible and virulent lung infections in people with cystic fibrosis, plant pathogens, and as problematic contaminants for industrial manufacture. This will be contrasted to the good side of Burkholderia bacteria that within the natural environment can protect plants and insects from attack by fungal pathogens, degrade a range of man-made pollutants, and more recently have been harnessed as producers of novel antibiotics. Further information on the contrasting roles of Burholderia as potential biopesticides versus opportunistic pathogens can be obtained from a recent blog (https://naturemicrobiologycommunity.nature.com/users/207716-eshwar-mahenthiralingam/posts/43397-natural-bacterial-biopesticides-weighing-up-the-risk-of-pathogenic-versus-beneficial-properties)
Professor Ana Caicedo, (University of Massachusetts Amherst) 25/02/2020
"Crops, weeds and wild plants: leveraging the agricultural environment for insight into plant adaptation."
Dr Ellie Harrison, (University of Sheffield) 18/02/2020
"Living with bacteriophages - lessons from the lab and from the wild."
Bacteria exist in hugely diverse communities and engage in interactions not just with other species - but also with a menagerie of genetic elements, like plasmids and phages, which infect, kill, benefit and manipulate their bacterial hosts. Interactions between these elements and their bacterial hosts play an important part in shaping the ecology of microbial communities and driving bacterial evolution. A key tool for understanding these interactions has been the use of experimental evolution; understanding evolutionary dynamics in simplified, highly controlled communities but limitations on what we can learn from 'abstract' experimental systems is driving a shift to expand this approach into complex, (more) natural microbial communities. I will present my work showing how genetic elements can alter the outcome of bacterial evolution in the lab, as well as introduce new work to understand bacterial - genetic element interactions in the wild.
Professor Sally Ward, (University of Southampton) 11/02/2020
"Targeting subcellular trafficking behaviour for the design of therapeutic antibodies"
The central role of FcRn in regulating IgG persistence and transport provides opportunities for targeting this receptor in multiple different diagnostic and therapeutic situations. The engineering of IgGs with higher affinity for FcRn can be used to produce antibodies with longer in vivo half-lives due to increased recycling within cells, but only if the pH dependence of the IgG-FcRn interaction is retained. Conversely, engineered IgGs with higher affinity for FcRn at both acidic and near neutral pH act as potent inhibitors of FcRn and drive wild type IgG into lysosomes. Consequently, such antibodies (‘Abdegs’, for antibodies that enhance IgG degradation) can lower the levels of endogenous IgG, providing a pathway for the treatment of antibody-mediated autoimmunity. In addition, we have recently generated engineered Fc-antigen fusions that selectively deliver antigen-specific antibodies into lysosomes (called ‘Seldegs’, for selective degradation).
We have also generated engineered, tumour-specific antibodies with altered endosomal trafficking behaviour. Following conjugation to cytotoxic drugs to form antibody-drug conjugates (ADCs), these antibodies are more effective in delivering their toxic payload to target cells, resulting in a potential strategy to circumvent the dose-limiting toxicities that frequently reduce the therapeutic efficacy of current ADCs.
Professor Katie Peichel (University of Bern) 04/02/2020
"Genetics of adaptation: the roles of pleiotropy and linkage"
Despite recent progress, relatively little is known about the specific genetic and molecular changes that underlie adaptation to new environments. Stickleback fish have been at the forefront of research to uncover the genetic and molecular architecture that underlies adaptation and speciation. A wealth of quantitative trait locus (QTL) mapping studies in sticklebacks has provided insight into the distribution of effect sizes during adaptation and has also revealed that several regions of the genome contain more loci than expected for traits involved in adaptation. It is unknown whether these trait clusters result from tight physical linkage of multiple genetic changes responsible for different traits, or from a single genetic change with pleiotropic effects. I will discuss recent research in my group that is focused on disentangling the roles of pleiotropy and linkage in adaptation, using both genome-wide approaches and more focused studies of specific loci with a major effect on adaptation.
Professor Deborah Mackay, (University of Southampton) 10/12/2019
"Genetic Epigenetics: Lessons from Imprinting Disorders"
Prof. Mackay's work has lead to the discovery of novel (epi)genetic disorders that have informed our understanding of the mechanisms underlying imprinted gene expression. Prof. Mackay is Professor of Medical Epigenetics within Medicine at the University of Southampton, and laboratory lead of the Wessex Imprinting Group at Salisbury NHS Trust.
Dr Ronald Jenner, (Natural History Museum) 05/11/2019
"Of complex cocktails and borrowed bullets: the evolution of centipede venom composition"
Venoms have evolved many times in the animal kingdom. Centipedes are one of the oldest groups of venomous land animals. They have a pair of claw-like appendages bearing venom glands, and they use their powerful venoms for predation and defense. Although all centipedes are venomous, our understanding of centipede venoms is based almost exclusively upon a handful of species from 1 of the 5 centipede orders. In this talk I present our research on the evolution of this toxic weapon based on proteotranscriptomic data from all 5 orders. Two of our most surprising findings are that centipedes have evolved complex venoms in parallel multiple times, and that horizontal gene transfer seems to have made important contributions to these toxic arsenals.
Dr Alex Brand (University of Exeter) 29/10/2019
"Understanding the enemy: new perspectives in the pathogenic fungus, Candida albicans"
Candida albicans is a commensal yeast that is carried asymptomatically by most people. However, C. albicans can cause mucosal infections in women of child-bearing age, the elderly, neonates and AIDS patients. Although not life-threatening, billions of people worldwide suffer these irritating infections. In patients undergoing immunosuppressive treatments, C. albicans causes around 200,000 life-threatening bloodstream infections a year, with up to 40 % mortality. In both types of disease, the transformation of yeast to the filamentous hyphal form is a key virulence trait. Blood-born hyphae can invade virtually any human body site to cause inflammation, sepsis and organ failure. My research focuses on the regulation of hyphal growth at the molecular level, and how this translates into defined responses to the physical environment. We combine genetic manipulation and live-cell imaging with a number of applied physical stimuli, such as electric fields and microfabricated topographies, to understand how hyphae detect and respond to their environment. We have identified a key role for a Ras-like GTPase, Rsr1 (human RAP1) in the spatial organisation of apical dominance and cell directionality in hyphae and we have shown that Rsr1 and a Paxillin-like protein are required for contact-dependent behavioural responses. These responses require calcium influx and we have recently developed the first live-cell calcium reporter in C. albicans. This has shown that pH, osmotic and oxidative stress elicit specific signalling and recovery signatures. Together, these approaches are revealing cell processes and behaviours that are important for fungal cell integrity and invasive hyphal growth.
Dr Ian Henderson, (University of Cambridge) 22/10/2019
"Genetic and Epigenetic Control of Recombination in Plant Genomes"
The majority of plants, animals and fungi reproduce via meiosis, which has a profound effect on genetic diversity and adaptation. During meiosis homologous chromosomes pair and recombine, which creates new combinations of alleles. Interestingly, the rate of recombination is highly variable along chromosomes, with hotspots and coldspots. We are interested in defining the mechanisms that cause variation in recombination frequency and the implications this has for genome evolution. I will present our research investigating the roles of genetic and epigenetic factors that shape recombination in plant genomes. This will include discussion of both the role of chromatin in shaping recombination, and mechanisms by which genetic variation can feedback onto the recombination process. Ultimately, I hope that our work will shed light on the enigmatic role of recombination in genome and species evolution.
Dr Roger Williams (University of Cambridge) 08/10/2019
"Structural mechanisms of regulation of enzymes in nutritional sensing"
Eukaryotic cells balance anabolic and catabolic pathways in order to survive in changing environments. The eIF2alpha kinase GCN2 is activated by amino acid starvation, while the protein kinase mTORC1 is activated when amino acids are replete. These nutrition-sensing pathways are linked through their influences on autophagy and endocytic traffic, two broad sorting pathways that are dependent on signalling by lipid second messengers. Our work on GCN2, mTORC1 and the lipid kinase VPS34 is aimed at understanding how these enzymes are regulated in control of growth, pathogenesis and cancer. We have applied a synthesis of hydrogen/deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography, single particle electron cryo-microscopy (Cryo-EM) and electron cryo-tomography (cryo-ET) to understand these mechanisms.
The complex mTORC1 controls cell proliferation by integrating growth factor signals with nutritional availability. Regulation of mTORC1 is controlled by two types of switch-like G-proteins that associate with it, the Rag heterodimers and RHEB. Structures and dynamics of a complex of mTORC1 with active Rags and RHEB explain how oncogenic mutants activate the complex by recruiting it to lysosomes and by allosteric changes in its conformation. An enzyme complex containing phosphatidylinositol 3-kinase (PI3K) VPS34 is also part of the mechanism of mTORC1 activation. Cryo-ET and HDX-MS have helped illuminate the role of another switch-like G-protein, Rab5, in stimulating a VPS34-containing complex involved in endocytic sorting.
While mTORC1 is activated by amino acid abundance and promotes protein translation, nutrient stress activates GCN2, which initiates the Integrated Stress Response (ISR) and inhibits general translation. Human GCN2 is potently stimulated by ribosomes, and using HDX-MS we showed that GCN2 recognises domain II of the uL10 subunit of the ribosomal P-stalk.