Most genes produce multiple protein isoforms with distinct functions. We study what these isoforms do, how their misregulation drives neurodegeneration and cancer, and how they could be selectively targeted. Our major focus is ALS, where we ask how disrupted RNA processing leaves motor neurons vulnerable.
Who we are
The Weatheritt Lab is a multidisciplinary RNA biology group at the Garvan Institute of Medical Research and UNSW Sydney, and part of EMBL Australia.
Our work asks how cells expand biological function beyond the information encoded in genes. We focus on alternative RNA processing, protein isoforms and biomolecular condensates, and we build computational and long-read methods to measure them at the level of whole transcripts and single cells.
Motor neuron disease is a major focus of the lab. We apply these isoform-level approaches to ALS, asking how disrupted RNA processing changes the protein landscape of vulnerable neurons and where it might be corrected.
Research program
We connect transcript-level changes to protein behaviour and cellular phenotype, combining discovery-scale approaches with focused mechanistic experiments.
We use long-read sequencing of patient stem cell-derived motor neurons, including SOD1-ALS and TDP-43 models, to ask how disrupted splicing, polyadenylation and cryptic exons change the proteins vulnerable neurons make, and why ALS differs between men and women. We pair this with drug screens to search for compounds that selectively correct disease-associated isoforms.
Most human genes make several protein isoforms. We map how alternative exons and promoters rewire protein interactions and localisation, and how isoform-specific therapies could exploit those differences.
We combine CRISPR perturbation with single-cell and long-read sequencing to test what individual isoforms and alternative promoters do, including how they shape cancer cell responses to drugs, and to resolve allele-specific expression such as X chromosome inactivation.
We profile what P-bodies and stress granules hold and how their contents shift under stress, including the accumulation of oncogenic mRNAs, linking RNA compartments to translation, cancer and the stress granule pathology seen in ALS.
How we work
The questions determine the method. Our program joins quantitative discovery with experiments that resolve function at isoform and single-cell level.
Selected publications
Lab head
EMBL Australia Group Leader, Viertel Senior Medical Research Fellow, and ARC Future Fellow.
Robert trained in computational biology and neuroscience before completing his doctorate at EMBL and Heidelberg University. His postdoctoral work at the MRC Laboratory of Molecular Biology and the University of Toronto established a research program at the interface of RNA regulation, proteomics and cellular organisation. He founded the Weatheritt Lab in Sydney in 2018.
His work has helped show how alternative splicing rewires protein interaction networks and higher-order assemblies, including work defining a conserved program of neuronal microexons and the development of Whippet for fast splicing analysis. The lab now aims to move from cataloguing RNA variation to explaining what individual isoforms do.
People
Join and collaborate
We welcome students and researchers who want to connect computational discovery with molecular and cellular mechanism.
Projects span RNA processing and drug screening in patient stem cell-derived motor neurons, long-read and single-cell analysis, and isoform function in human cells. We particularly welcome applicants from neurodegeneration, neuroscience or stem cell backgrounds. Students enrol through UNSW Sydney.
We are glad to discuss positions and to support fellowship applications in RNA biology, functional genomics and computational biology.
Send a CV and a few lines on which question interests you and why. Collaborators are welcome to reach out directly.