Discovering Therapeutic Targets for ALS Using CRISPR-dCas9 Single-Cell Perturb-Seq in Patient-Derived Motor Neurons

About the Project

Project Description

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective cure. Although several causal mutations (e.g. SOD1, C9orf72) have been identified, why some mutation carriers remain symptom-free while others develop severe disease remains unknown. This suggests the existence of genetic and epigenetic modifiers that determine neuronal vulnerability.

This PhD project will combine CRISPR-dCas9 single-cell Perturb-Seq screening with motor neurons derived from ALS patient iPSCs to systematically identify genes and regulatory elements that modify disease progression. Using single-cell transcriptomics (10x Genomics) and long-read nanopore sequencing, the student will map the molecular networks that promote or suppress ALS pathology at isoform-level resolution.

By integrating computational and experimental approaches, this project aims to discover novel therapeutic targets and pathways for isoform-specific RNA and gene therapy development. The successful candidate will help build a first-of-its-kind atlas of ALS modifier mechanisms in human neurons.

Training and Environment

The student will join the Neurotranscriptomics Laboratory led by A/Prof Robert Weatheritt at the Garvan Institute of Medical Research (Sydney, Australia), affiliated with UNSW Sydney and EMBL Australia.

The Garvan Institute hosts world-class facilities in genomics, imaging, and computational biology. Students will gain hands-on experience in:

• CRISPR-dCas9 Perturb-Seq screening
• iPSC culture and motor neuron differentiation
• Single-cell and long-read (Nanopore) transcriptomics
• Computational analysis and machine learning for network biology

The candidate will be embedded in an interdisciplinary team spanning computational biology, neurogenetics, and RNA therapeutics, with opportunities for collaboration across EMBL Australia and international partners (e.g. King’s College London, CRG Barcelona).

Candidate Requirements

• Academic background: Honours (First Class) or Master’s degree in bioinformatics, computational biology, molecular biology, or neuroscience.
• Essential skills: Strong bioinformatics or data-science experience (e.g. single-cell or nanopore transcriptomics).
• Desirable skills: Experience in CRISPR screens, RNA biology, or neurodegenerative disease.
• Eligibility: Applicants should hold a degree from a top-200 ranked university to be competitive for international scholarships (UNSW, RTP, or EMBL Australia).
• Publications or demonstrable research output are advantageous.

Funding Notes

This project is eligible for support under UNSW or EMBL Australia PhD Scholarships. Competitive applicants will receive full tuition coverage and a living stipend (approximately AUD $37,000 – $43,000 per year).

Prospective candidates are encouraged to contact the supervisor early to discuss scholarship applications and project fit.

How to Apply

Email A/Prof Robert Weatheritt (r.weatheritt@garvan.org.au) with:

1. A current CV
2. Academic transcripts
3. A short statement of research interests and motivation

Shortlisted applicants will be invited for interview and supported to apply for competitive international scholarships through UNSW Sydney or EMBL Australia.