Sculpting a masterpiece: synthesis and evolution of minimal yeast genomes. This project aims to better understand genome complexity by engineering minimal yeast genomes that have fewer genes, and are therefore easier to characterise and engineer. Yeast is a model organism and industrial food, fuel, and chemical producer. This project expects to increase our basic understanding of yeast genomes, and develop new tools for engineering whole genomes. Expected outcomes of this project include the eng ....Sculpting a masterpiece: synthesis and evolution of minimal yeast genomes. This project aims to better understand genome complexity by engineering minimal yeast genomes that have fewer genes, and are therefore easier to characterise and engineer. Yeast is a model organism and industrial food, fuel, and chemical producer. This project expects to increase our basic understanding of yeast genomes, and develop new tools for engineering whole genomes. Expected outcomes of this project include the engineering and characterisation of the world's first minimal yeast genome, and the development of novel industrial yeast strains. This will provide significant benefits for both fundamental genetics and biochemistry research, and the industrial use of yeast for bio-manufacturing of sustainable foods, fuels, and chemicals.Read moreRead less
Synthetic biology tools for integration into bacterial chromosomes. The aim of the project is to develop a set of versatile chromosomal integration tools for bacteria, enabling rapid development of novel biological outputs. A major goal in the emerging discipline of synthetic biology is to apply engineering principles to the design and construction of new biological entities such as proteins, genetic circuits and cells. Custom-designed genetic circuits, integrated in an appropriate host genome, ....Synthetic biology tools for integration into bacterial chromosomes. The aim of the project is to develop a set of versatile chromosomal integration tools for bacteria, enabling rapid development of novel biological outputs. A major goal in the emerging discipline of synthetic biology is to apply engineering principles to the design and construction of new biological entities such as proteins, genetic circuits and cells. Custom-designed genetic circuits, integrated in an appropriate host genome, hold enormous economic potential for applications ranging from biomedicine to biofuel production. This project aims to help synthetic biologists to embed made-to-order circuits in appropriate host cells to act as living factories, potentially replacing industrial processes which are currently environmentally and economically costly.Read moreRead less
Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolu ....Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolution crystal structures are being used to identify function. Intriguingly, preliminary data indicates that the mutations do not affect the native antibody structure, but rather influence dynamic states. The project plans to use a combination of mutagenesis, molecular dynamics simulation and deuterium exchange to study antibody dynamics.Read moreRead less
Structural studies of a reconstructed primordial antigen receptor. Antigen receptors (B- and T-cell receptor) form the basis of the adaptive immune system of humans and all other modern day vertebrates. These complex receptors are believed to have evolved from an extinct homodimeric (symmetrical) ancestor through a process of gene duplication and diversification. However, any molecular insights had so far remained elusive. Using laboratory evolution and X-ray crystallography this project demonst ....Structural studies of a reconstructed primordial antigen receptor. Antigen receptors (B- and T-cell receptor) form the basis of the adaptive immune system of humans and all other modern day vertebrates. These complex receptors are believed to have evolved from an extinct homodimeric (symmetrical) ancestor through a process of gene duplication and diversification. However, any molecular insights had so far remained elusive. Using laboratory evolution and X-ray crystallography this project demonstrates that such a primordial receptor can in principle be reconstructed and characterised. The project proposes to expand this work, which will provide intriguing insights into antigen receptor evolution. The reconstruction of basic recognition modules will also be highly beneficial for biosensor applications. Read moreRead less
Developing orthogonal synthetic signaling cascades. This project proposes a generic approach for the construction of molecular switches based on artificially autoinhibited proteases. The bottom-up design of protein-based signaling networks is a key goal of synthetic biology. Yet, this remains elusive due to our inability to tailor-make signal transducers and receptors that can be readily compiled into defined signaling networks. Using structure-guided design and directed protein evolution, a set ....Developing orthogonal synthetic signaling cascades. This project proposes a generic approach for the construction of molecular switches based on artificially autoinhibited proteases. The bottom-up design of protein-based signaling networks is a key goal of synthetic biology. Yet, this remains elusive due to our inability to tailor-make signal transducers and receptors that can be readily compiled into defined signaling networks. Using structure-guided design and directed protein evolution, a set of protease-based signal transducers and ligand activated allosteric receptors will be created. The developed components are intended to be used to construct artificial signaling networks in mammalian cells that are orthogonal to the endogenous signaling cascades.Read moreRead less
Artificially building the bacterial flagellar motor. This project will allow us to learn how nature’s most sophisticated rotary motor works and how to build these artificially, establishing a new field of research into man-made biological machines. This has potential applications for the emerging field of nanotechnology to make nanometre-scale devices that are powered by efficient biological machines.
IDENTIFYING CONTROL ELEMENTS IN CHLOROPLAST GENE EXPRESSION. Energy from sunlight is captured by photosynthesis in plants, providing the basis for the terrestrial food chain. This process takes place in chloroplasts, subcellular structures that derived from photosynthetic bacteria a billion years ago. Chloroplasts have their own DNA, containing genes encoding the most important photosynthetic proteins. This project aims to provide the world’s best resources for the study of chloroplast genes. In ....IDENTIFYING CONTROL ELEMENTS IN CHLOROPLAST GENE EXPRESSION. Energy from sunlight is captured by photosynthesis in plants, providing the basis for the terrestrial food chain. This process takes place in chloroplasts, subcellular structures that derived from photosynthetic bacteria a billion years ago. Chloroplasts have their own DNA, containing genes encoding the most important photosynthetic proteins. This project aims to provide the world’s best resources for the study of chloroplast genes. In the process, we will discover how these important genes are regulated to provide photosynthetic proteins in the right amounts, in the right cells, at the right time. The knowledge and resources gained will facilitate improvement of photosynthetic function in future agricultural crops.Read moreRead less
Remodelling encapsulin nanocages to help enhance plant carbon fixation. Nature has evolved mechanisms in microbial systems to improve photosynthetic efficiency by saturating the enzyme Rubisco with carbon dioxide. These carbon concentrating mechanisms are genetically complex, precluding successful introduction into crops. Our simpler approach is to use encapsulins, a new source of robust bacterial pore-containing nanocages made from a single gene. This project will optimise the development of sy ....Remodelling encapsulin nanocages to help enhance plant carbon fixation. Nature has evolved mechanisms in microbial systems to improve photosynthetic efficiency by saturating the enzyme Rubisco with carbon dioxide. These carbon concentrating mechanisms are genetically complex, precluding successful introduction into crops. Our simpler approach is to use encapsulins, a new source of robust bacterial pore-containing nanocages made from a single gene. This project will optimise the development of synthetic encapsulin-Rubisco carbon-fixing nanoreactors and transform them into leaf chloroplasts to test their impact on plant photosynthesis and growth. Our genetically simpler solution will aid ongoing global efforts to deliver overdue step change improvements in agricultural productivity.Read moreRead less
Phage display derived antibody fragments for membrane protein research. Membrane proteins are key components of all living organisms and represent more than 50 per cent of all drug targets. This project will redefine the way membrane proteins are studied and will be highly beneficial to basic research, human disease and the biotechnology industry.
Investigating Wnt signaling during human nephron commitment and patterning. Aims: To use gene edited stem cell lines that display cell location, identity and cell state to map human kidney tissue formation in the laboratory. By monitoring how each cell responds to those around it across time and space, we will for the first time map the formation of kidney tissue in the dish.
Significance: Understanding how stem cells form a tissue will help us to improve and control the process. This is key to ....Investigating Wnt signaling during human nephron commitment and patterning. Aims: To use gene edited stem cell lines that display cell location, identity and cell state to map human kidney tissue formation in the laboratory. By monitoring how each cell responds to those around it across time and space, we will for the first time map the formation of kidney tissue in the dish.
Significance: Understanding how stem cells form a tissue will help us to improve and control the process. This is key to advancing tissue engineering.
Expected outcomes: The proposal will pioneer state-of-the-art imaging, gene editing and machine learning approaches, generating models of human development that are currently unavailable.
Benefits: This understanding will guide the development of novel approaches to tissue engineering.
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