Discovery and development of new drugs for human use remains a slow, expensive and inefficient process. A critical point of failure in drug discovery programmes is the preclinical evaluation of drug candidates with only about 30% success rate. Consequently, new methodologies to increase success rate at the preclinical drug development stage are needed. This project aims to develop a new, environmentally sustainable, prototype device to allow for high-throughput in vitro characterisation of drugs pharmacokinetics (PK) coupled with in silico kinetic models to better predict drug performance in vivo. The gold-standard approach to investigate drugs PK involves using Positron Emission Tomography (PET) and microdosing techniques. However, these techniques can be expensive and often require a large number of animals. Importantly, although the use of animals can be useful to assess drug distribution, metabolism and therapeutic effects, species differences versus humans often decrease the translational success rate of a new drug. Therefore, there is a need to design more efficient drug discovery pipelines and to increase confidence on selection of the lead compounds at early stages of the process. To this regard, the recent development of the so called "body-on-chip" in vitro technology holds tremendous promise as a platform to predict drug responses in vivo. Recently, our team has developed a new "body-on-chip" prototype device, which has a number of important properties that position it uniquely in the "body-on-chip" arena, namely: Perfusion through the capillary system and organ compartments capable of mimicking the human circulatory system; Easy to use and versatile organ compartment inserts capable of housing a large number of cells, required for accurate quantification of concentration of drugs in cells by high throughput and mainstream chromatographic methods; Environmentally sustainable re-usable design, requiring only a simple clean protocol between experiments; Reduced cost of manufacturing as well as reduced maintenance costs, as the "body-on-chip" can be re-used and the associated peristaltic pump required to maintain flow through the device is commercially available off the shelf. Our new "body-on-chip" device has the potential to enable predictive PK studies in vitro as well as individual tissue drug exposure analysis and drug-target binding kinetics quantification, which currently cannot be accomplished with available "body-on-chip" devices.

Home and personal care products are often contained in bottles made of high-density polyethylene (HDPE) and about 150,000 tonnes of this packaging are produced annually. The resulting post-consumer plastic is then collected, sorted and mechanically recycled. This mechanical recycling process involves grinding, washing and then extruding to give pellets known as post-consumer resin (PCR). Less than 69,000 tonnes of HDPE PCR are produced annually, which means that more than half of the plastic packaging is going to landfill rather than being recycled. PCR can be incorporated into HDPE packaging to replace virgin plastic which saves on waste and is also more efficient in terms of carbon emissions. However, one of the major issues with using PCR in packaging is that it is a variable material. It may contain different grades of plastic, it can be contaminated with other materials and the recycling process itself can lead to degradation of the plastic. This means that incorporation of PCR into bottles tends to result in reduction in performance of the packaging. The variability in PCR makes it harder for companies to use PCR in packaging, it increases the cost of using PCR and ultimately places an economic penalty on the increased use of PCR. There is currently insufficient scientific understanding of the changes that occur to HDPE during recycling which means that it is challenging to address issues with the inconsistency of PCR. This means there is an urgent need to understand the quality-performance linkage for PCR in packaging. This ambitious project brings together an interdisciplinary team from the University of Liverpool and University of Manchester to improve the mechanical recycling of HDPE. We will enable rapid delivery towards the goals of the Plastic Pact for this important waste stream, and reduce plastic waste and increase recycling by 2025, by making use of existing plastics and infrastructure. We will generate a detailed understanding of the chemistry and property relationship of PCR. This new knowledge will allow PCRs to be produced with improved performance in packaging and also to prevent degradation in recycling. Simultaneously, we will understand how this disruption within the supply and demand for PCR will impact supply chain. This understanding will allow interventions to be selected that deliver the greatest economic, social and environmental benefits. This research will therefore facilitate improving the quality of PCR in packaging, increasing the value of PCR which will then drive greater investment in plastics recycling.

A clinical trial run by an established UK company has identified two natural plant molecules that inhibit skin inflammation. Unfortunately, the amount of these molecules from the source plant is very low and therefore extraction from the source plant is not feasible on an industrial scale. A potential solution to this problem is to use cultured plant cells, which can been grown on a large scale in multi-tonne bioreactors and optimised for the production of these target plant natural products. Significantly, by employing non-GM genetic approaches, the yield of these target molecules will be significantly increased in these cultured plant cells. This approach will also enable new insights into the biochemical regulation of these molecules within the source plant, potentially leading to further improvements in yield. The target natural products isolated from the generated plant cell lines will also be tested and compared to the same molecules extracted from the source plant in a large number of biomedical-based assays. It is anticipated this work will show the molecules produced from the generated plant cell lines are functionally equivalent to those extracted from the source plant. Once confirmed, and beyond the scale of this particular research project, the company will scale-up the growth of the generated plant cells and isolate the target molecules for their introduction into commercial products.

The recent advances in high through-put data generation for DNA/RNA, proteins and metabolites has resulted in a paradigm shift in how we seek to answer some of the fundamental questions of biology. Over the past decade, significant amounts of these large data sets encompassing resident microbial communities (microbiome), specific host responses and environmental conditions have been generated. To date the integration and exploitation of these complex datasets in a structured way has been highly problematic. However recent advancements in in-silico methodologies can for the first time help to unlock the full potential of these data, facilitating improved understanding of and discovery of novel interventions for host-microbiome interactions. With the advent of these technologies it has become apparent that interactions between environmental, host and microbial factors give rise to the various changes in skin homeostasis that result in cosmetic conditions such as dry skin and dandruff. Dandruff and dry skin are widespread conditions impacting over 50% of the world's population affecting quality of life including self/body confidence and their treatment is the basis of a sector worth over 10bn Euros annually. In this study, in collaboration with our industrial partners, Unilever, we will investigate the physiological changes of normal, dry skin and dandruff through unique integration of computational biology and modelling with microbiology. We will develop a computational and experimental platform for skin host-microbiome interactions to reveal the microbial mechanisms involved in different skin states. Using this approach, we will identify and evaluate new therapeutic targets as well as reveal the underlying physiological events in skin homeostasis. Using a combination of skin samples collected by tape strips from normal, dry skin and dandruff, as well as data generated from reconstituted skin models and keratinocyte monolayers, we will generate data that accurately describes skin-microbe interactions. we will also identify the key species and strains of Malassezia, Staphylococcus and Cutibacterium associated with different skin states. In parallel by using the available multi-omics data from Unilever and the public domain, we will generate computational models for microbes and host skin tissue and cells. Having both in-silico and in-vitro set ups, we will investigate the impact of key metabolites and anti-metabolites on the relationship between the skin and key microbes and microbial communities. Finally, we will explore the impact of key host factors, such as cytokines (e.g. IL-36, IL-1, IL-17, IL-20 family) and antimicrobial peptides (e.g. beta-defensins, S100, LL-37) on the resident microbial communities. We will then categorize these therapies based on their mode of action on skin-microbiomes interactions. The new therapeutic targets generated and validated through this combination of both computational and experimental techniques can then be tested for host toxicity and efficacy. This cutting-edge integrative platform could be easily extended to identify new targets or drugs for different microbial constituents in human body, their association with a range of hosts and pathologies. As such it will delineate an entirely novel approach to investigating host-microbiome interactions that will have broad applicability across a wide range of sectors, including medical, veterinary, cosmetic and agricultural.

A wide range of household products as diverse as foodstuffs, cleaning materials and personal care products, rely on the ability to modify starting materials on an industrial scale to generate products with the desired properties. One key requirement in many cases is the introduction of charged groups, to bestow the desired characteristics such as the ability to gel, to bind other materials or to behave as detergents. This can often be achieved by the addition of charged groups and one key way to do this is to add a sulfate group. The problem is that this is done currently using toxic and environmentally damaging chemicals. The global market for such household products is huge and growing, for example, for personal care products is $ 7.35 Bn with annual growth of 7%. Our industrial collaborator, Unilever, with whom we have a long and well-established working relationship, is a major global player, with around 50% of the market share. Consumer sensitivity to environmental concerns, particularly with existing petroleum-based products and the use of harsh chemicals, arising from their resistance to biological degradation, the generation of greenhouse gases and other environmental issues during their production or disposal, has culminated in commercial pressure to develop sustainable alternatives. The current method of achieving sulfation industrially, involving aggressive chemicals which show poor selectivity and are environmentally damaging, needs to be replaced with a one employing renewable resources without damaging the environment. Together with Unilever, we aim to develop methods by which sulfation can be achieved using enzymes, thereby avoiding these problems. The route we propose - engineering enzymes to carry out this modification - offers both better control of the process and, crucially, enables environmentally responsible production of biodegradable products and waste. Until now, the application of enzymes to these areas has been hindered by the problems of readily detecting the modifications that have been made and, owing to the cost of some of the materials involved, also of developing a commercially feasible method of adding sulfate groups. Now, however, as a result the combination of preliminary work carried out by ourselves and Unilever, as well as other technological advances, both of these problems can be solved. This project will exploit these improved technologies, together with our established expertise in enzyme production to achieve two principal aims: (i) to assemble the technology (termed the high throughput enzyme-engineering platform) with which to produce and optimise enzymes that will be suitable for application to a wide range of enzyme-driven processes of industrial relevance and, (ii) to illustrate the use of this platform to select and optimise suitable enzymes, using a class of enzymes that can add sulfate groups to naturally-occurring and renewable starting materials such as complex sugars (polysaccharides) and lipids (glycolipids) from plants. The potential for industrial application of these sulfated products will then be assessed by Unilever, a major global company with a developed sustainability agenda that, in the future, will enable delivery of clean, renewable products.