Professor Dek Woolfson, (University of Bristol)
"Peptide design and assembly in computers, test tubes, membranes and cells"
Dr Emilia Santos, (University of Cambridge)
"Colour pattern evolution in cichlid fishes"
Dr Sarah Coulthurst, (University of Dundee)
Seminar title - TBC
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.