Available
Project number:
2025_A03
Start date:
October 2025
Project themes:
Main supervisor:
Reader in Bioinformatics
Co-supervisor:
Shi-Yan Ng, PhD (A*STAR joint-first supervisor)
Senior Principal Scientist I, IMCB A*STAR
Alan Hodgkinson, PhD (second internal academic supervisor)
Senior lecturer, King’s College London
A comprehensive investigation of the role of mitochondrial variation in Amyotrophic Lateral Sclerosis utilising large scale genomics and stem cell models
Background Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive paralysis, leading to death from respiratory failure within 2-5 years. Mitochondria are essential cellular organelles responsible for regulating a number of key processes, and their malfunctioning is one of the earliest pathophysiological in ALS. Mitochondria possess their own DNA distinct from the nuclear genome, and despite their central role in ALS, efforts in investigating mitochondrial DNA variation in the context of ALS have been very limited. Novelty & Importance This project proposes a novel comprehensive approach to study the role of mitochondrial variants in the pathogenesis of ALS, which has potential to discover new insight into the biological basis of this disease and to highlight new treatment avenues. Aims & Objectives This project aims to elucidate the role of mitochondrial DNA variation in the pathogenesis of ALS. We will achieve this by 1) utilising large-scale genomics datasets of thousands of people with ALS and controls, to identify mitochondrial mutations associated with disease risk or distinct clinical outcomes. 2) We will then utilise in-silico methods such as APOGEE, and modelled using molecular dynamics simulations, for the characterisation of their functional effect, and 3) study their mechanism of action in cell models of the disease. Mitochondrial variants will be created in pluripotent stem cell (PSC) lines using the cybrid technology. PSCs will be differentiated into spinal motor neurons, and phenotypic analyses will be carried out by immunostaining and metabolic profiling assays. Aims 1-2 will take place at KCL in year 1-2, and aim 3 will take place at A*STAR in Singapore in year 3-4. References: [1] Battle, Stephanie L., et al. ""A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data."" NAR Genomics and Bioinformatics 4.2 (2022): lqac034. [2] Bianco, Salvatore Daniele, et al. ""APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants."" Nature Communications 14.1 (2023): 5058. [3] Harvey, Calum, et al. ""Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis."" Heliyon 10.3 (2024). [4] Hor, Jin-Hui, et al. ""ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation."" Cell Death & Differentiation 28.4 (2021): 1379-1397. "
We are now accepting applications for 1 October 2025
How to apply - A*STAR projects
Candidates should possess or be expected to achieve a 1st or upper 2nd class degree in a relevant subject including the biosciences, computer science, mathematics, statistics, data science, chemistry, physics, and be enthusiastic about combining their expertise with other disciplines in the field of healthcare.
Important information for International Students:
It is the responsibility of the student to apply for their Student Visa. Please note that the EPSRC DRIVE-Health studentship does not cover the visa application fees or the Immigration Health Surcharge (IHS) required for access to the National Health Service. The IHS is mandatory for anyone entering the UK on a Student Visa and is currently £776 per year for each year of study. Further detail can be found under the International Students tab below.
Key dates - A*STAR projects
- Applications submitted by the closing date of Thursday 30 January 2025 will be considered by the CDT. We will contact shortlisted applicants with information about this part of the recruitment process.
- Candidates will be invited to attend interview(s). Interviews are projected to take place in March 2025.
- Project selection will be through a panel interview chaired by CDT Directors at EPSRC DRIVE-Health and relevant supervisors from A*STAR Institute followed by informal discussion with prospective supervisors.
- Successful candidates are required to accept their conditional places by 14 April 2025.
- If you have any questions related to the specific project you are applying for, please contact the main supervisor of the project directly.
For any other questions about the recruitment process, please email us at drive-health-cdt@kcl.ac.uk.
