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Public summaries of proof of concept funding

Reference number: POCE3B002
Project title: Enhancing plant metal uptake & nanoparticle deposition for recovery of platinum group metals & gold
Lead academic partner: Neil Bruce, University of York
Industrial partner: Chandresh Malde, Emily Summerton and Felicity Massingberg-Mundy, Johnson Matthey

Public summary: Reserves of platinum group metals and gold, essential for industrial and hi-tech applications, are dwindling. Significant amounts are present in mine tailings, a mining process waste product. We have shown that plants can take-up and store palladium and gold as nanoparticles. In a previous BBSRC NIBB-funded PoC, we demonstrated that expression of synthetic peptides enhances deposition of toxic gold metal ions into nanoparticles in plants. This biomass can be used as a biocatalyst, or manipulated to release valuable building-block chemicals (so-called platform molecules), which are then used to make higher-value products. We have identified a plant transporter for palladium and gold, COPT2, and have characterised over-expression and knock-out COPT2 lines. We want to combine the synthetic peptide and transporter mechanisms to increase uptake, and alleviate phytotoxicity of these metals. Ultimately, this research will contribute to the re-vegetation of environmentally-damaged mining regions and sustainability of finite metal resources.

Reference number: POCE3B011
Project title: Enhancing iron-sulfur cluster functionality in synthetic biology applications
Lead academic partner: Tobias von der Haar, University of Kent
Industrial partner: Hans Genee, Biosyntia ApS

Public summary: Engineering host cells to express recombinant enzymes is used in industrial biotechnology to produce high-value biochemicals like flavours, fragrances, vitamins and other compounds. Some particularly useful enzymes require the introduction of chemical co-factors to be active. Limiting activity in one such co-factor, a chemical entity comprised of iron and sulfur atoms called an iron- sulfur cluster, is known to be the reason for the failure of a number of otherwise promising enzyme pathways. This project will build on our recent discovery of an unusual iron sulfur protein from an anaerobic microbe, which can enhance the activity of other iron-sulfur cluster enzymes when introduced into target cells frequently used in industrial biotechnology. We aim to test the usefulness of this accessory protein as a general tool for enhancing limiting iron-sulfur cluster formation in industrial applications.

Reference number: POCE3B012
Project title: Selection of rare earth elements through uptake by methylotrophs (SERUM)
Lead academic partner: Simon Gregory, British Geological Survey
Industrial partner: Edward Loye, E-Tech Metals

Public summary: Rare earth elements (REE) are required for many hi-tech and green technologies. Separation of individual REE is a major challenge to the extraction and processing industry. Bacteria have been shown to selectively enrich certain REE by various mechanisms. Methylotrophs (bacteria that consume single-carbon compounds i.e. methane, methanol or methylated compounds) have been shown to selectively take up light REE into their cells. In this project we isolate methylotrophs from acid environments and test them alongside existing lab strains for their ability to selectively uptake REE and produce enrichments of certain REE that are of value to industry. Firstly, we will test methylotroph isolates to optimise the removal of REE from solutions to enrich REEs, either in biomass or in solution. Secondly, we will take the most effective isolates and test their ability to selectively leach and uptake REE from monazites which are an important ore for REE extraction

Reference number: POCE3B014
Project title: Robust SARS-CoV-2 detection for COVID-19 diagnosis: Enhancing loop-mediated isothermal amplification (LAMP) with single-strand DNA binding proteins
Lead academic partner: Emke Pohl, Durham University
Industrial partner: Bernd Ketelsen Striberny, Arctizymes

Public summary: With development of vaccines against SARS-CoV-2 expected to take at least 12-18 months, and the development of new drugs taking considerably longer, improving and extending testing is acknowledged to be an immediate crucial priority. While currently, reverse transcription (RT) PCR is the standard method of viral testing, we propose to develop RT loop-mediated isothermal amplification (LAMP) technology, which allows testing using a single-step assay which does not require the expensive laboratory equipment needed for RT-PCR.  While RT-LAMP technology has already been successfully applied to other viral RNA detection, we have shown that the unique viral single strand DNA binding proteins (SBB) from the Virus-X consortium significantly increase speed and sensitivity of the assay. In this project we aim to optimise the RT LAMP assay for COVID-19 diagnosis by identifying the best conditions for SSB production, storage and usage in the assay.  This optimisation will focus on the stabilising effect of divalent metals for DNA (Mg2+) and SSBs(Zn2+). The overall goal of this project is to produce a lower cost, reliable SARS-CoV-2 RNA detection assay based on RT-LAMP technology with potential to increase the availability, speed, accuracy and accessibility of viral testing both in developed nations and across the developing world.

Reference number: POCE3B015
Project title: GLYCOVID-19: Investigating the modulatory effect of metal ions upon the interaction of polyanionic heparin with the SARS-CoV- Spike protein
Lead academic partner: Mark Skidmore, Keele University
Industrial partner: Ruth Yates, Anglo-Italian Chemometrics

Public summary: COVID-19 is a severe disease affecting lungs and airways caused by SARS-CoV-2 coronavirus. We were first to show that pharmaceutical heparin (a widely used anticoagulant pharmaceutical) interacts with the latest coronavirus (DOI:10.1101/2020.02.29.971093) and protects host cells from viral infection (DOI:10.1101/2020.04.28.066761). Furthermore, heparin alleviates blood clotting and inflammation, which are linked to COVID-19 deaths. Heparin is a natural, biological product with high negative charge and must always accompany metal ions and these modulate its activity. Indeed, pharmaceutical heparin is biomanufactured with selected cations (e.g. Na, Ca and Li) to maximise their benefits. By understanding these interactions, favourable biological activities can be selected, while at the same time, reducing side-effects. As there are no approved drugs to treat COVID-19, this information will be useful to produce heparin and heparin sub-fractions with improved activity in different cation forms to treat the current COVID-19 outbreak.

Reference number: POCE3B020
Project title: FLAVH2: Establishing Feasibility for a Metalloenzyme System for Dihydrogen-Driven Flavin Recycling for Chemical Synthesis in Industrial Biotechnology
Lead academic partner: Kylie Vincent, University of Oxford
Industrial partner: Beatriz Dominguez, Johnson Matthey

Public summary: Industrial biotechnology taps into the wealth of chemistry available in natural systems. The enormous range of chemical reactions conducted in living cells can be extended further by isolating and manipulating nature’s key machines, enzymes. This project exploits a newly discovered, non-natural reactivity from an enzyme called hydrogenase. Hydrogenase is a metal- containing enzyme which uses a nickel / iron cluster to split apart hydrogen gas, and clusters of iron atoms to conduct electrons. In nature, hydrogenase allows cells to store energy from hydrogen, but we have shown, unexpectedly, that hydrogenase can recharge an important biological chemical called ‘flavin’. Enzymes which depend on flavin are potentially valuable in biotechnology as ‘machines’ for performing difficult chemical reactions in an environmentally- friendly way. However, barriers to recharging flavin mean they have not been used industrially. Our technology solves that by providing a simple way to recharge flavin with H2 gas, propelling flavin-dependent enzymes into biotechnology.

Reference number: POCE3B021
Project title: Conserving the position of rare codons for the optimised production of commercially-important, cofactor-containing enzymes
Lead academic partner: Ciarán Kelly, Northumbria University
Industrial partner: Simon Charnock, Prozomix

Public summary: Many enzymes used in the food, pharmaceutical and chemicals industries require metal cofactors. Proteins consist of amino acids; each encoded by a triplet of nucleotides (codon). Rare codons, codons that are less commonly found in that particular organism, are often replaced with abundant codons to maximise protein production in new organisms. The location of rare codons is conserved in some proteins. Replacing them with more common ones can adversely impact protein activity and stability. These rare codons may be important for cofactor incorporation. We aim to identify conserved rare codon clusters in iron-containing proteins used in industry. We will build a tool to rank each codon in a protein-coding sequence from most common to least common in the original host organism. The tool will then replicate this pattern, generating a sequence for use in the new host organism. These sequences will be tested for improved protein folding and cofactor incorporation.

Reference number: POCE3B024
Project title: Development of a biotechnological protocol for extracting and recovering nickel from pyrrhotite waste and generating an environmentally-benign solid residue
Lead academic partner: Barrie Johnson, Bangor University
Industrial partner: Julie Coffin, Sudbury Integrated Nickel Operations (Glencore), Canada

Public summary: Mining of metals has underpinned civilisations for millennia, but this most-established human activity has always produced waste by-products. Mining waste is an increasing environmental issue due to the expansion in scale of mining and the range of metals extracted to meet industrial and domestic demands in recent decades. Mine spoils can generate extremely hazardous (acidic and metal-rich) liquors that can migrate into the wider environment and cause serious pollution and ecosystem destruction. Historic waste deposits can also, however, contain significant amounts of residual valuable metals. Biomining technologies offer environmentally-benign approaches for extracting and recovering residual valuable metals from wastes, and to generate more secure and less hazardous secondary products. The proposed project will develop and demonstrate an indirect bio-processing protocol to recover nickel from historic mine wastes in Ontario which will, uniquely, incorporate a technique that limits acid production by generating elemental sulfur as a secondary marketable product.

Reference number: POCE3B025
Project title: Development of site specific conjugation of alkaline phosphatase via metal mediated His-tag complexation for biomanufacturing of diagnostic and biotherapeutic reagents
Lead academic partner: Mark Smales, University of Kent
Industrial partner: Charlotte Williams, CSIRO Manufacturing, Australia; Paul Bennett, Sekisui Diagnostics

Public summary: An increasing number of protein biotherapeutics used to treat disease or used as diagnostics require the linking of a protein to other molecules for their application. To link a protein molecule to a target molecule during biomanufacturing, specialised linker molecules are usually employed that results in variable attachment in a non-site specific manner. We will investigate a novel alkaline phosphatase (AP) metalloenzyme used in diagnostics that is biomanufactured with a tag of multiple histidine amino acid residues that some metal ions can interact with and act as a bridge between the tag and another molecule. We will demonstrate we can use this approach to site specifically link the AP (biological resource) to a model biotherapeutic antibody and determine the functionality of the product, showing this biomanufacturing approach offers advantages over non-site specific labelling approaches and the generation of new diagnostic products/materials, thus also addressing the BBSRC remit in industrial biotechnology.

Reference number: POCE3B028
Project title: Development of a biotechnological protocol for extracting and recovering nickel from pyrrhotite waste and generating an environmentally-benign solid residue
Lead academic partner: Liz Rylott, University of York
Industrial partners: Martin Atkins, Green Lizard Technologies; Konstantina Stamouli, Kew Technology

Public summary: Cost-effective technologies that can recapture polluting metals for re-use and land remediation, are urgently needed. This proposal will investigate nickel uptake in the biomass crop willow. Nickel is catalytically active which means we can produce value-added chemicals during processing of the harvested willow, then recover the relatively high value nickel. But rates of nickel uptake and accumulation are still relatively low. The research examines ways to mobilize more nickel into the aerial tissues, and has four components: 1. Combining cyanogenic and plant-growth-promoting bacteria to increase plant Ni uptake. 2. A transcriptomics experiment to identify key Ni-response genes for breeding. 3. Measuring partitioning of Ni between leaf and stem. 4. Production of Ni-rich biomass to pyrolysis testing. Together, this research aims to provide robust supporting data for industrial take-up: the nickel phytoremediation capacity of selected willow lines, methods to potentially increase metal uptake, and metal-rich biomass.

Reference number: POCE3B029
Project title: Sustainable bioleaching of platinum group metals from spent automotive catalytic converters
Lead academic partner: Eva Pakostova, Coventry University
Industrial partner: Neil Rowson, Bunting Europe

The demand for platinum-group metals (PGMs) is growing due to the increasing need for next-generation batteries in electric vehicles. Spent automotive catalytic converters (SACCs) are a valuable PGM source, but environment-friendly recycling needs to be developed. We propose to use a designed consortia of acidophilic bacteria to remove inhibiting base metals from SACCs, followed by optimised PGM biorecovery using organic acid-producing fungi. Such sequential bioleaching will minimize microbial inhibition and waste generation, and maximize SACC loads and metal recovery. The main novelties are magnetic pre-separation of SACCs and the use of closed-loop bioleaching for efficient base-metal removal. The proposed approach reduces the use of hazardous substances, is suitable for scale-up, and can be optimized for other source materials (e.g. printed circuit boards). Ultimately, this research will contribute to the UK Net Zero target, providing an alternative metal supply while addressing waste management challenges.

Reference number: POCE3B030
Project title: Bioprospecting for new metalloenzymes for the circular economy
Lead academic partner: Paul Walton, University of York

Enzymes are the catalysts of life. Enzymes are also the catalysts of death, a biological process in which organic matter is ultimately degraded. These ‘death’ enzymes have the capacity to turn large polymeric molecules found in dead biomass into useful smaller molecules that could be used in a sustainable economy, such as biofuels or plastics recycling. This project seeks to use a new method to search a vast but currently unavailable to the public database of the genomes and domain/module structures of organisms that can degrade ‘dead’ matter. The method — called signal strapping — searches genomes to find a specific group of enzymes that contain metal ions. These metalloenzymes offer great potential in breaking down biomass and polymer waste, since the metal is known to deliver particularly powerful chemistry that can attack even the most difficult materials, from which they can contribute to the circular economy.

Reference number: POCE3B031
Project title: Bioflocculants for metal removal and recovery
Lead academic partner: Helena Gomes, University of Nottingham
Industrial partner: Sumitesh Das, Tata Steel

Metals are essential in our daily lives and have a finite supply, but are also contaminants of concern. The current CO2 emissions and environmental impact of mining are untenable. We need to reclaim important resources like metals from wastes to meet present needs without compromising the need of future generations. This project aims to remove and recover metals from industrial wastewaters using natural polymers (large molecules) produced by bacteria, avoiding pollution and retrieving valuable critical materials. These polymers are non-toxic, biodegradable, and cheaper than the chemicals currently used, which degrade poorly and can be carcinogenic. We aim to isolate and characterise these polymers and demonstrate that they can be a low-cost, low-energy, environmentally friendly biotechnology capable of removing metals from wastewater. We will also study the metal selectivity of the polymers and their subsequent recovery for a circular economy and an alternative to mining natural resources.

Reference number: POCE3B032
Project title: The use of limpet-derived metal enzymes in sustainable biomanufacturing
Lead academic partner: Dariusz Gorecki, University of Portsmouth

The strongest known biomaterial is found in the teeth of the common limpet. This material has a tensile strength greater than spider silk, and is comparable to synthetic carbon fibre. It is a mixture of chitin (like insect shell) with additional reinforcement from crystals of iron oxide. We have replicated limpet tooth development in a Petri dish and made synthetic material using chitin scaffolds mineralised by secretions from lab-grown limpet cells. Our results established a platform for developing a novel limpet-tooth inspired biomaterial. Given that this material is both strong and elastic, it could replace plastics. Furthermore, it can be generated from waste material and is biodegradable, making it a carbon net-zero process. We propose to identify the composition of the cell secretions that enable chitin-scaffold mineralisation. This knowledge would allow generation of an entirely man-made mineralisation solution and therefore production of this biomaterial at a large scale.

Reference number: POCE3B033
Project title: Rare-earth element biorecovery using methylotrophs
Lead academic partner: Ying Zhang, University of Nottingham
Industrial partner: Andrew Goddard, Freeland Horticulture

Each year millions of tonnes of waste electrical and electronic equipment (WEEE) are generated in the EU, but only 30% is reported as properly collected and recycled, while the majority ends up in landfill. In turn, critical raw materials that are present within these WEEE, namely rare earth elements (REE), are also wasted. This represents an unnecessarily high cost to the economy, and a pressing need to develop cheap and sustainable REE recycling process. We propose to use methylotrophic bacteria to design a ‘one-pot bio-refining’ process, adopting combinatorial chemistry and synthetic biology approaches for novel REE recovery. This project will address the initial development of such a process. The proposed process will have a very low carbon footprint, as the carbon source for methylotrophic bacteria growth can be green methanol produced sustainably and renewably where renewable electricity splits water into oxygen and hydrogen, which is combined with carbon dioxide.

Reference number: POCE3B034
Project title: Scaling-up [FeFe]-hydrogenases to biocatalysis
Lead academic partner:Simone Morra, University of Nottingham
Industrial partner: Holly Reeve, HydRegen

This project aims to advance industrial biotechnology by exploiting metalloenzymes for the sustainable production of chemicals, contributing to net-zero manufacturing targets in the future. HydRegen pioneers a technology that enables slot-in biocatalytic alternatives to traditional precious-metal catalysts for hydrogenation reactions (representing 20% of all chemical reactions). The academic partner is an expert in metalloenzymes who is researching novel [FeFe]-hydrogenases that can boost industrial applications due to their improved activity, O2-tolerance and stability. We have recently shown that the HydRegen technologies can make use of these novel metalloenzymes in small scale processes (TRL2). This project will provide a step-change by assessing reaction parameters that are crucial for effective industrial exploitation and, if successful, scaling-up enzyme production allowing HydRegen to enhance its current best biocatalyst with a more active and scalable hydrogenase.