Centre Seminar Series

Title:  Ask the ancestors: resurrecting and re-evolving the bacterial flagellar motor

Speaker: Matt Baker (Scientia Associate Professor , School of Biotechnology and Biomolecular Science UNSW Sydney)

Time: 9.30am - 10.30am

Format: In person

Host:  Teuta Pilizota (School of Biological Sciences)

Abstract: A/Prof Matthew Baker works on two systems of biophysical interest: 1) the bacterial flagellar motor, a rotary electric nanomachine which powers most bacterial swimming, and 2) using de novo DNA nanotechnology to control and shape lipid membranes. The flagellar motor is one of the canonical molecular complexes, ~40 nm in diameter but capable of rotating at 1000 Hz, self-assembling in the membrane and changing rotational direction in milliseconds. His team's recent work on the flagellar motor used directed evolution to monitor the adaptation of the stator units, the engine which drives rotation, in changing environments to explore what constrains the operation and evolution of the motor. The structure of the stator was recently solved, hinting that the stators themselves are an even tinier rotating nanomachine! Furthermore, strong structural homology with other ion powered rotary motors has opened new avenues for considering the common origin of these complexes. These new structures changed our approaches to stator engineering, as well as revolutionised the study of motor biophysics, where many tiny ‘wheels’ in turn engage the larger rotor and ultimately the bacterial filament which enables cellular propulsion. Our most recent work consists of examining chimeric constructs of the separate components of the stator to examine what can possibly drive function, as well as rationally stabilising the central stalk (the B-unit) to examine what impact this has on function.

At the other end of the scale, from the in vitro bottom-up perspective, we look at how to build multi-compartment interacting systems out of simple DNA and lipid components. Our work on DNA nanostructures, in collaboration with Dr Shelley Wickham's team at Sydney University, has characterised the best way to connect DNA to lipids via cholesterol. We recently demonstrated that more cholesterols are not necessarily better and explored the most suitable linkage chemistry to allow strand displacement, the basis of all reaction and interaction in DNA nanotechnology.

Biography: Matt grew up in Dunedin, New Zealand and finished an Hons in Chemistry at the Australian National University studying Fluctuation Theorems before completing his DPhil in Physics at the University of Oxford as a John Monash Scholar looking at the molecular motor that makes many bacteria swim. He finished a postdoc on protein transport in the Department of Biochemistry and then returned to study structural biology at the Victor Chang Cardiac Research Institute in Sydney, Australia. Matt focused primarily on how simple subunit interactions govern assembly of complex architectures, including the rotor and filament of the bacterial flagellar motor. Matt’s group at UNSW Sydney continue to study the flagellar motor, focusing on ion selectivity changes using directed evolution and ancestral reconstruction (Mol Micro 2019, Front. Microbiol. 2020, Microlife 2023) to examine the evolutionary landscape that constrains the adaptation of the motor (Science Advances 2022). We then use this knowledge to examine other potential applications of the flagellar motor (Journal of Bacteriology 2021, Biomicrofluidics 2020, Biomicrofluidics 2023). 

Matt’s team also investigate force sensitive proteins reconstituted in synthetic lipid bilayers (Channels 2019). In collaboration with Dr Shelley Wickham, we probe membrane dynamics and interactions using novel DNA nanotechnology (Nanoscale 2019, NAR 2021), with the ultimate goal to control membrane communication using de novo DNA nanotechnology. 

Matt loves radio: he was a Top 5 Under 40 Scientist in Residence at the Australian Broadcasting Corporation in 2015 and appears regularly on Saturday Morning with Kim Hill on Radio New Zealand, with an audience of roughly 1 million. 

Title: Cellular navigation in non-stationary environments

Speaker: Aneta Koseska  (MaxPlanck Institute)

Time: 9.30am - 10.30am

Format: In person

Host:   Andrew Goryachev (School of Biological Sciences)

Abstract: A fundamental characteristic of living systems is sensing and subsequent robust response to continuously varying environmental signals. Even seemingly “simple” systems, such as single cells or single-cell organisms, reveal higher-order computational capabilities that go beyond simple stimulus-response association.  We have identified experimentally that cells utilize dynamic ghost states as a form of a cellular working memory to integrate information from time-varying signals, and thereby navigate in continuously changing environments. We show that these dynamic states are an emergent feature of cell-surface receptor networks organized at criticality, and uniquely enable cells to maintain directed migration when signals are disrupted or noisy, while still being responsive to spatial-temporal changes of the chemotactic cues. Developing a theoretical framework to characterize semi-stability in dynamical systems, we further analyze model responses to dynamic cues and show the importance of long non-asymptotic transients and non-autonomy for cellular computations in general.  

 https://mpinb.mpg.de/en/research-groups/groups/cellular-computations-and-learning/ccl-group-leader-de.html

Title: A general theoretical framework to study holistic models of growing cells

Speaker: Hugo Dourado (Heinrich Heine University, Dusseldorf)

Time: 9.30am - 10.30am

Format: In person

Host:  Andrea Weisse (School of Biological Sciences/Informatics)

Abstract: Mathematical models are an important tool for understanding and predicting the complex behavior of biological cells. For unicellular organisms, this behavior is driven by natural selection through fitness maximization under nonlinear physical constraints that cannot be fully captured in most current modeling frameworks, which rely on simplified linear optimizations and phenomenological assumptions about cell biomass composition. Importantly, the critical trade-off between cell resource investments in reactants and catalysts of biochemical reactions can only be fully captured by models that incorporate nonlinear kinetic rate laws. When these kinetic models also account for the necessary production of proteins to catalyze their biochemical reactions, the limited cell density, and the dilution of all components by growth, they become holistic models capable of explaining the entire cell composition and behavior as a result of a nonlinear optimization problem. While this problem cannot be solved efficiently numerically for large models with thousands of reactions, we present here an alternative analytical approach to study holistic cell models of any size, leading to fundamental quantitative principles relevant to all cells at steady state growth. These analytical principles can be used as tools to independently predict the composition and behavior of cellular subsystems. We show how these predictions are in good agreement with experimental measurements of E. coli enzyme and metabolite composition at steady state growth, and ribosome allocation at different steady state growth rates for both E. coli and S. cerevisiae. We also present our recent result on the necessary analytical conditions for optimal dynamic allocation of cell resources in changing environments, and show how it predicts the same qualitative behavior observed experimentally for ribosome allocation and specific growth rate in E. coli.

Title: Surface tension: an engineered bladder microtissue model reveals a fierce battle for supremacy during urinary tract infection

Speaker: Jenny Rohn (Head of the Centre for Urological Biology, Division of Medicine, University College London)

Time: 9.30am - 10.30am

Format: In person

Host:   Meriem el Karoui (School of Biological Sciences)

Abstract: to follow

Title: Systems biology for increasing chemical production in cyanobacteria

Speaker: Paul Hudson (Head of Division of Systems Biology, KTH Royal Institute of Technology, Sweden)

Time: 9.30am - 10.30am

Format: In person

Host:   Alistair McCormick (School of Biological Sciences)

Abstract: I will describe our approaches toward optimizing photoautotrophic cyanobacteria for synthesis of chemicals from carbon dioxide. This includes first the use of CRISPR interference genetic screens to identify useful regulation points to divert fixed carbon away from growth and instead toward chemical production. Such screens have also been useful for mapping gene fitness in cyanobacteria in various growth conditions and informing on function of hypothetical genes. In a second track, we have adapted chemoproteomics methods to identify metabolite-protein interactions in the proteomes of cyanobacteria and chloroplasts, with the motivation that accumulating metabolites in genetically modified producer strains may negatively affect enzyme activity. These techniques allow us to map metabolite-protein binding surfaces. In an initial application, we found widespread interaction of tested metabolites with enzymes in central carbon metabolism, but only a fraction of these interactions affect catalysis. Finally, I will describe efforts in mutagenizing enzymes to reduce sensitivity to metabolite regulation, by high-throughput screening of the effect of enzyme mutation on both cell growth and product synthesis rates.

Title: Orchestrated localisation and translation of functionally related mRNAs to translation factories: roles in glycolytic regulation, inheritance of the translation machinery and protein complex assembly

Speaker: Mark Ashe (Professor of Cell Biology, University of Manchester)

Time: 3pm - 4pm

Format: In person

Host:   Edward Wallace (School of Biological Sciences)

Abstract: Across many biological systems, mRNA localisation and translation form part of a strategy allowing polarised protein production. However, recent research in our laboratory shows that mRNAs encoding proteins that are not necessarily thought of as polarised are also translated at discrete sites within the cell. For instance, functionally related mRNAs such as the glycolytic and translation factor mRNAs are co-localised and translated at such sites. We and others have termed such sites translation factories,

Such co-ordinated localisation and translation of mRNAs could have a range of potential functions. Our recent published data suggests roles in the regulation of metabolic pathways and the inheritance of key proteins.  It is also possible that co-localisation of mRNAs to translation factories could have implications in the formation of protein complexes since individual components of protein complexes would not need to locate each other within a sea of macromolecules.  We have developed a proteomic approach to isolate nascent chains and their associated proteins and identify signatures of co-translational assembly. This screen identifies most of the known examples of co-translational assembly in yeast, as well as highlighting numerous other potential examples with functions across cell biology. Understanding the requirements for forming translation factories and the extent of co-translational complex production within them could therefore provide vital information regarding protein complex activity and the influences of inappropriate formation of protein aggregates.

Title: Building and exploiting synthetic yeast genomes

Speaker: Benjamin Blount ((Assistant Professor, Faculty of Medicine & Health Sciences, University of Nottingham)

Time: 9.30am - 10.30am

Format: In person

Host:  Giovanni Stracquadanio (School of Biological Sciences)

Abstract: The international Sc2.0 project is building the first synthetic eukaryotic genome. By designing, assembling and debugging DNA on a genomic scale, we have refined our understanding of how genomes work, developed new technologies and imbued cells with new abilities. The most prominent of these abilities is SCRaMbLE, a system that rearranges synthetic chromosomes on-demand. Using SCRaMbLE, we can generate a massive amount of genotypic and phenotypic diversity from which individuals with enhanced characteristics can be identified.

In this talk I will discuss the process of building an Sc2.0 synthetic chromosome (synXI); the convoluted and at times surprising ordeal of debugging synXI; steps towards building the next generation of synthetic chromosomes; and the use of SCRaMbLE to rapidly generate strains with improved production of high value compounds, growth in new carbon sources and tolerances to a range of different stresses.  

Title: Engineering and Safeguarding synthetic genomes

Speaker: Professor Patrick Yizhi Cai, Chair of Synthetic Genomics, The University of Manchester 

Time: 2pm - 3pm

Format: In person

Host:  Susan Rosser (School of Biological Sciences)

Abstract: Over the last 10 years, my lab has been building synthetic yeast chromosomes from scratch. I will discuss our efforts in developing transformational technologies in design, assembly and characterise synthetic chromosomes, including a tRNA neochromosome. These synthetic yeast cells are engineered to allow genome-wide directed evolution with a system call SCRaMbLE . In this talk I will focus on the applications of SCRaMbLE in various areas including dissection of aneuploidy phenotype. Finally, I will also discuss the progress of developing safety mechanisms for synthetic genomes.

Bio: Professor Patrick Cai (PC, Manchester) is Prof. in Synthetic Genomics and a world-leading expert in synthetic chromosomes, with a highly interdisciplinary research group. PC is the international coordinator for the (Sc2.0) Consortium, which is composed of over 10 top universities from 4 continents aiming to synthesize the world’s first synthetic eukaryotic genome. PC co-founded Edinburgh Genome Foundry, which is the largest automated DNA synthesis and assembly facility in academia today. PC regularly provides advice and consultancies to the Cabinet office, the Foreign Office and the Prime Minister’s Council for Science and Technologies. PC holds prestigious visiting professorships with MIT (US), MRC LMB at Cambridge (UK), Hong Kong University and Chinese Academy of Sciences (China). In 2022, PC was awarded a 5 year EPSRC fellowship to work on biosecurity and biosafety mechanisms for synthetic genomes. In 2023, PC was awarded an ERC Consolidator Award to engineer non-coding RNAs using a synthetic genomics approach.