WOrM Drug Models: Whole Organism Metabolomic Drug Models to improve holistic understanding of therapeutic performance

CDT theme alignment: Predictive Pharmaceutical Sciences, Pharmaceutical Process Engineering and Complex Product Characterisation

This project will aim to establish Caenorhabditis elegans as a model system to determine the influence of pharmaceuticals on global shifts in Whole Organism Metabolomics, to improve therapeutic performance.
BACKGROUND: Metabolomics is considered as the functional readout of the physiological state and phenotype of an organism, which can be significantly transformed by drug treatment. Effective modelling of metabolomics in humans is challenging. This is because humans are large complex animals, which are not completely understood and can be both scientifically and socio-economically challenging to characterise. Therefore, there is a strong international drive to replace, reduce and refine the use of animals in research so that this precious resource is reserved for the strongest therapeutic candidates, whilst also providing a mechanism to improve those therapeutics that fail at early-stage development. Bearing this in mind there is a need to develop innovative solutions or repurpose existing models that can provide key insights into therapeutic performance. An excellent example of a potential solution is the model organism C. elegans.
C. elegans, a free-living nematode, is the most completely understood animal on the planet. This is due to its small size (<1 mm), short generation time (<3 days), optical transparency, availability of genetic variants and exclusion from Home Office animal regulations. To date, the complete genome, proteome and connectome for C. elegans have been mapped. However, currently there is no readily available metabolic information on C. elegans.
METHOD: This project will fill the important knowledge gaps in whole organism metabolomics in response to drugs by harnessing the School of Pharmacy's & University of Nottingham's world leading analytical facilities of the Centre for Analytical Bioscience (CAB) and Nanoscale & Microscale Research Centre (nmRC).
The CAB is home to a high-resolution ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). UHPLC-MS/MS will be used to decipher metabolomic profiles of nematode homogenates challenged to widely used pharmaceuticals, with well-established literature on influence on physiological state (atenolol, acetaminophen, fluoxetine, omeprazole and simvastatin). This will provide a calibrated metabolomic outcome to therapeutics with known pharmaceutical activity. Nematodes will also be challenged to next generation therapeutics, "reverse prodrugs," which self-polymerise through the introduction of electrical activity to stop cancer growth. The metabolome of the calibrated drug samples will provide an important insight to the physiological state of next-gen therapies and provide pathways to improve performance.
The nmRC hosts the world's only academically situated 3D-OrbiSIMS, capable of high spatial and chemical resolution three-dimensional mass spectrometry. The key metabolomic shifts identified from LC-MS will be spatially coordinated with 3D-OrbiSIMS. This scientific first will be used to produce a "Google street view" of Whole Organism Metabolomics for C. elegans. This will be a valuable resource for researchers to improve their understanding of the physiological state of WOrMs and those furthering the knowledge of C. elegans as a model for complex mammalian biochemistry.
IMPACT: This multidisciplinary project will improve the understanding of the influence of therapeutics on metabolic pathways and will contribute to the production of new and improved drugs to prevent and treat diseases, such as cancer. It will also provide diverse training opportunities for the PhD candidate. With support form the experienced supervisory team the research conducted will pave-the-way towards establishing new and improved models and analytics for drug delivery.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.