Applications must be complete, including both references, by 14th January 2022 at 5pm
Applications must submit an online application: https://www.uclbbk-mrcdtp.ac.uk/apply
Parkinson’s disease (PD) is the second most common age-related disorder and the fastest growing neurological condition in the world, with no cure. PD is characterised by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to impaired movement such as tremors, stiffness and slowness of movements. In the UK, 1 in 37 people will be diagnosed with PD in their lifetime and there is an urgent need for new treatment options that address the underlying disease mechanisms and improve upon the current therapeutic approach managing symptoms. Recent advances in our understanding of the causes of PD have highlighted a central role for mitochondrial and lysosomal dysfunction in the development of the disease (Wallings et al. 2019).
The aim of this joint UCL/BenevolentAI PhD studentship is to identify novel genes involved in PD progression derived from hypothesis generation by Artificial Intelligence (AI) in the context of lysosomal and mitochondrial biology. Lysosomal and mitochondrial function is vital to neuron viability because of their involvement in recycling of waste material and energy production, respectively. PD, like other neurodegenerative diseases, is characterised by an accumulation of protein aggregates highlighting deficiencies in the clearance pathways. Genetic studies have established an important link between lysosomal and mitochondrial dysfunction and the pathogenesis of PD (Clark et al. 2021). A large number of autosomal dominant and recessive genes are associated with PD as well as several genetic risk factors which encode for key proteins involved in mitochondrial quality control and lysosomal activity, including PINK1 or GBA1. In healthy cells, damaged mitochondria are removed from cells by mitophagy, i.e., the capture of damaged mitochondria by autophagosomes with subsequent delivery to the lysosome. This process and successful degradation of damaged mitochondria by the lysosome is defective in many forms of PD. The main aim of the proposed research is to identify genes that can be manipulated to enhance mitophagy and lysosomal function and thus improve dopaminergic neuron survival.
Benevolent AI is a drug discovery company that employs AI-driven machine learning approaches to identify novel targets for a range of diseases. In the first part of the project, the successful student will have the opportunity to test a custom, AI-derived gene list in established functional mitophagy assays using siRNA- and CRISPR/Cas9-based screening (Ketteler lab at UCL; see Tsefou et al.2021). Secondly, hits identified from the mechanistic screening will be further validated for their disease relevance in neuronal cells derived from induced pluripotent stem cells (developed with BenevolentAI and UCL). The student will learn how to perform experiments on patient derived induced pluripotent stem cells (iPSC)-derived dopaminergic neurons in research labs at BenevolentAI, thus enabling the student to gain significant experience in working in an industry environment.
The successful student will be supported by a multidisciplinary team, combining the strengths in functional genomics and imaging-based screening (Ketteler lab) with target identification from AI and validation in neurodegenerative diseases (BenevolentAI).
The student will benefit from an excellent support structure at the LMCB, and close supervision in the Ketteler lab and at BenevolentAI. The Ketteler lab is based at the LMCB at UCL, a world-leading institute in cell biology, with excellent core facilities within the building. The LMCB provides outstanding training in an environment of scientific excellence. In addition the student will spend significant time in the Cambridge labs. Furthermore, the proximity of the BenevolentAI London offices to UCL, will allow the student to attend appropriate company events and meet London-based colleagues throughout the studentship. The student will have the opportunity to regularly update the BenevolentAI Parkinson’s deployment team on their progress and benefit from the feedback of this multidisciplinary team.