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Four ground-breaking new projects set to expand the frontiers of bioscience knowledge

Today, the UKRI Biotechnology and Biological Sciences Research Council (UKRI-BBSRC) has awarded £14 million to four exceptional teams of investigators in the UK to carry out long-term, large-scale and highly interdisciplinary research programmes with the ambitious goal of discovering new rules of life.

UKRI-BBSRC,s Executive Chair, Professor Melanie Welham, said, "The projects we have announced funding for today are at the cutting edge of bioscience. Researchers are looking at the very fundamentals of the rules of life. By pushing forward the boundaries of knowledge, we can often make surprising and potentially world changing discoveries. This investment from BBSRC underlines our long-standing commitment to excellence in discovery research."

Investing in excellent, curiosity-driven, discovery research in the UK remains the best strategy for delivering the adaptable knowledge that will be necessary to ensure healthy, prosperous and sustainable living, no matter what challenges the future brings. The investigator teams leading these four strategic Longer and Larger (sLoLa) research programmes will assemble the people, skills and cutting-edge tools and technologies necessary push back the frontiers of bioscience knowledge and to answer some of life’s most persistent riddles. These include how life first arose from abiotic precursors, how plants integrate and respond to environmental cues without a nervous system, how animals sense and adapt to mechanical forces, and how disordered proteins can be useful for a cell.

Read on to see how some of the UK’s top scientific minds intend to answer these questions:

Origins of Biology: How energy flow structures metabolism and heredity at the origin of life

How did life arise from abiotic precursors? Because life seems to have little to say about the time before its own emergence, the study of abiogenesis demands an examination of prebiotic chemistry and the naturally occurring conditions under which modern carbon-based biochemistry could have emerged. Building on the 'metabolism-first' theory that energy flow in the form of dynamic proton gradients across inorganic barriers could ultimately yield complex organics including the first polymers and proto-membranes, this project seeks to integrate computational modelling and experimental chemistry to systematically test conditions that could favour the emergence of life, including those similar to hydrothermal vents. The fundamental discoveries made here have broad range of potential long-term influence in other fields including in the design and manufacture of synthetic protocells and the development of metabolomic biomarkers of health across the lifecourse.

This project is a collaboration between four Divisions at University College London, and Birkbeck College and is led by Professor Nick Lane (UCL). Professor Lane said "The origin of life is one of the biggest questions in all of science, yet until recently the biosciences have had surprisingly little input - an important gap. We are delighted that the BBSRC is backing this ambitious project to understand the fundamental driving forces that gave rise to cells and still shape how organisms function today."

SUMOcode: deciphering how SUMOylation enables plants to adapt to their environment

Cell specific expression of a Green Fluorescent Protein tagged SUMO target in Arabidopsis roots. Photograph from Srivastava et al, Current Biol. 2020. Cell specific expression of a Green Fluorescent Protein tagged SUMO target in Arabidopsis roots
Photograph from Srivastava et al, Current Biol.

Without nervous systems, plants rely on post-translational modifications (PTMs) to integrate their growth and development with environmental signals. PTMs modify an organism’s protein machinery, altering cell function. This allows plants to adapt to their environment (water availability, salt, pathogens, etc) and enhances their ability to survive and flourish. One important type of PTM is SUMOylation, however its mechanism is currently not well defined. This project will help uncover how SUMO converts environmental signals into a physiological response. This will help to understand fundamental ‘rules of life’ regulating processes from plant development to disease resistance.

  This project is a collaboration between Durham University, University of Liverpool, University of Cambridge, and University of Nottingham and is led by Professor Ari Sadanandom (Durham U). Professor Sadanandom said "This investment will allow us to decipher the ‘SUMO code ’and determine how it programs cellular processes to adapt plant growth and development to different environmental stresses including water availability, salt and pathogens."


Regulation of epithelial and endothelial cell-cell junctions by mechanical forces

 An image of an airway bronchoconstricting, compressive forces from an asthma attack damage the airway barrier. Image by Dr Dustin Bagley. An image of an airway bronchoconstricting.
Image by Dr Dustin Bagley.

How do animals sense and adapt to mechanical forces?  Every day, cells in our bodies are stretched, compressed, and sheared through exposure to a barrage of external (e.g. pressure on the skin) and internal (e.g. blood pressure) forces.  We know that there are specialized proteins on cell surfaces that hold cells together and can recognize different types of mechanical forces, but how exactly do they work together with each other and other players to trigger an appropriate response?  This project aims to develop an integrated understanding of mechanobiology through the meticulous experimental analysis of single molecules, cells, tissues and ultimately whole organisms under a variety of different conditions using a cutting-edge combination of techniques including 3D tissue culture, optogenetics and novel DNA-based mechanosensors.  New knowledge generated here has the potential to influence our understanding of every physiological process mediated by mechanical forces from the expansion of our lungs when we breathe to the hardening of arteries as we age.

This project is a collaboration between the University of Bristol, King’s College London and University College London and is led by Professor Anne Ridley (U. Bristol).  Professor Ridley said "Understanding how our bodies sense and respond to mechanical forces requires the many different skills of our team, from physics to chemistry and biology and from single molecules in cells to cell and tissue imaging".

Deciphering the function of intrinsically disordered protein regions in a cellular context

Composite overlay of known Aurora-A/IDR partner structures (PDB ID: 5G1X, N-MYC in purple, PDB ID: 5ODT, TACC3 in orange, PDB ID: 1OL5 TPX2 in dark blue, with Aurora A Kinase in cyan). Image from Prof. Richard Bayliss. Composite overlay of known Aurora-A/IDR partner structures.
Image from Prof. Richard Bayliss

While most proteins have a fixed shape, many have regions with no fixed shape, called intrinsically disordered regions (IDRs). These 'shape-shifting' regions allow proteins to perform different jobs under different conditions, enabling cells to respond to their environment. Our understanding of protein shape, structure and function has been enormously useful in furthering our molecular understanding of life, leading to successful drug-discovery efforts, methods to improve crop production and other applications with economic and societal benefits. This project aims to accelerate the development of tools for the study of IDRs, which will open-up new areas of research to understand human and animal health. In the longer term, the ability to manipulate "shape-shifting" proteins will open up a new route to developing medicines to treat a wide range of diseases.

This project is a collaboration between the University of Leeds and University of Oxford and led by Professor Andrew Wilson (U. Leeds).  Professor Wilson said: "I am enormously excited to have the opportunity to work together with my co-investigators and collaborators on this challenge. Understanding for the first time how multiple intrinsically disordered regions simultaneously regulate a kinase could lead to unprecedented insight into to other systems of IDRs for which there is enormous interest and worldwide activity".

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