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Exploring the Molecular Mechanism of Novel Mitochondrial Neurotoxins identified through a Machine Learning Approach


   Medical Research Council Toxicology Unit

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  Dr L Miguel Martins, Dr Emmanouil Metzakopian  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Mitochondrial inhibition is an important ‘OFF-target’ mechanism of drug-induced toxicity in the clinic, contributing to drug attrition in clinical trials and drug withdrawal following approval because of severe adverse events 1. We have recently developed metabolic shift assays to screen antipsychotic drugs for off-target mitochondrial toxicity (Hardy, manuscript in preparation).

In this project, we will use machine learning algorithms 2,3 to discover mitochondrial liabilities, inherent in neuroactive compounds. The student will then focus on characterising these drugs - representing different structural classes - for evaluating mitotoxicity in cultured human neurons. We will train a neural network on a curated list of chemical inhibitors (~200 compounds) of mitochondrial respiratory complexes. The trained neural network will be then used to identify novel mitochondrial toxins in drug libraries such as the Prestwick chemical library. Using a suite of cellular and cell-free biochemical assays, we will then explore the molecular mechanisms underlying the mitochondrial toxicity. For selected targets, we will use thermal proteome profiling 4,5 to identify mitochondrial drug targets followed by in silico docking to define chemical binding properties. As mitochondrial toxicity is involved in Parkinson’s disease and Frontotemporal dementia, we will screen for adverse effect of these drugs in human neurons and glial cells, as co-culture and/or organoids derived from induced pluripotent stem cells (iPSCs). The collaboration with bit.bio will offer access to a range of mature CNS cell types derived with consistent quality from wild-type or disease mutation-bearing isogenic iPSC lines by applying controlled cellular reprogramming (opti-ox™). On another hand, while there is emerging evidence on the impact of mtDNA variants on human iPSC biology and applications6,7, the project will further include the exploration of heteroplasmy and its consequences on hiPSC differentiation and their use as neurotoxic models. This part of the project will be run in close collaboration with the bit.bio research team and could include the development of QC assays and mitochondria targeted interventions towards the improvement of iPSC based in vitro models.

The project will provide the student with training in a wide range of innovative wet lab approaches and importantly an opportunity to integrate experimental laboratory skills with ‘in silico’-based approaches.

The Medical Research Council (MRC) Toxicology Unit is a leading International Research Institute within the School of Biological Sciences, University of Cambridge. The Unit delivers mechanistic toxicology research, pursuing hypothesis-driven toxicological questions with a particular focus on the study of the causal links between exposure to endogenous and exogenous toxicants, molecular initiating events and adverse outcome pathways. The Unit's overall aims are to carry out pioneering research which leads to improved health and to train and mentor the next generation of toxicologists.

The Unit provides a supportive learning environment designed to meet the scientific and transferable skills required for an internationally competitive career. Our PhD Programme aims to train the scientific leaders of the future, giving them rewarding research projects with access to world-class facilities and expertise. Students receive toxicology-specific training in the Unit and through the Integrated Toxicology Training Partnership (ITTP).

Students are registered for their PhD with the Graduate School of Life Sciences at the University of Cambridge and have membership of a University of Cambridge College. 

The ideal candidate will have excellent academic abilities (a good 2.1 honours degree or equivalent undergraduate degree) combined with strong communication and team working skills in order to make the most of interdisciplinary training opportunities.

To apply please visit the Toxicology Unit website and follow the instructions provided: Applications | MRC Toxicology Unit (cam.ac.uk)


Funding Notes

This is a four year PhD commencing Lent 2023 and comes with funding for tuition fees (at Home rate) and a maintenance stipend of £17,500 per annum.
To be eligible for full funding candidates will need to demonstrate they have Home fee status.
Candidates of any nationality/residency can also apply and will be considered for a fees-only (at Home rate) award. Candidates would therefore need to secure additional funds from other sources to cover the higher tuition fee and their maintenance stipend. The most current estimates of costs can be found on the Graduate Admissions fees page.

References

1 Dykens, J. A. & Will, Y. The significance of mitochondrial toxicity testing in drug development. Drug Discov Today 12, 777-785, doi:10.1016/j.drudis.2007.07.013 (2007).
2 Allen, T. E. H. et al. Neural network activation similarity: a new measure to assist decision making in chemical toxicology. Chem Sci 11, 7335-7348, doi:10.1039/d0sc01637c (2020).
3 Periwal, V. et al. Bioactivity assessment of natural compounds using machine learning models based on drug target similarity. bioRxiv, 2020.2011.2006.371112, doi:10.1101/2020.11.06.371112 (2021).
4 Savitski, M. M. et al. Tracking cancer drugs in living cells by thermal profiling of the proteome. Science 346, 1255784, doi:10.1126/science.1255784 (2014).
5 Perrin, J. et al. Identifying drug targets in tissues and whole blood with thermal-shift profiling. Nat Biotechnol 38, 303-308, doi:10.1038/s41587-019-0388-4 (2020).
6 Palombo, F. et al. The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs. Stem Cell Reports 16, 1953-1967, doi:10.1016/j.stemcr.2021.06.016 (2021).
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