Research Assistant

A central component of the project is the identification of therapeutic candidates for HD. The post-holder will conduct medium- to high-throughput screens to identify agents that suppress somatic expansion or phenocopy MSH3 loss. Validated hits will be characterised mechanistically to support therapeutic target prioritisation, integrating functional genomics with translational screening in patient-derived iPSC and neuronal models.

Candidates must hold a BSc in Biochemistry, Cell Biology, Molecular Biology, Genetics, or a related discipline (PhD not required). A strong practical background in cell and molecular biology is essential, including PCR/qPCR, Western blotting, DNA/RNA/protein extraction, and basic cloning, together with proficiency in mammalian tissue culture. Experience with CRISPR-based workflows - gRNA or pegRNA design, lentiviral transduction, and functional screening - is required. Hands-on experience of human iPSC culture under feeder-free conditions is highly desirable, as iPSC-derived neuronal models will be central to the project.
Experience with repeat instability or DNA repair assays - fragment analysis or small-pool PCR of repeat tracts, amplicon deep sequencing, yH2AX/53BP1 immunofluorescence, or flow cytometry-based cell cycle analysis - would be advantageous. Familiarity with interpreting output bioinformatic analyses of screen and editing data (e.g. MAGeCK, CRISPResso2) or transcriptomic datasets is desirable but not essential, as training will be provided. Experience with ASO or siRNA delivery and knockdown validation would also be of value.
The role requires excellent organisation skills, rigorous record-keeping, and the ability to work both independently and collaboratively. The post-holder will manage their experimental programme, contribute to laboratory operations and compliance, and generate data suitable for publication and progress reporting. Close interaction with Balmus Lab members and collaborators across the UKDRI and wider Cambridge community is expected.

A Research Assistant position is available in the group of Prof. Gabriel Balmus at the UK Dementia Research Institute (UKDRI), Department of Clinical Neurosciences, University of Cambridge. The project applies prime editing-based functional screening to the biology of MSH3, the leading genetic modifier of somatic CAG repeat expansion, with the goal of identifying therapeutic strategies for Huntington's disease (HD) and other repeat expansion disorders. The post-holder will map how MSH3 sequence variation, protein levels, and partner interactions determine repeat instability at the expanded HTT locus in disease-relevant human cellular models.
Somatic expansion of the CAG tract in HTT is now recognised as a principal driver of age at onset and disease progression, and human genetic modifier studies converge on the mismatch repair machinery - MSH3, FAN1, MLH1, PMS1 and LIG1 - as the pathway that sets the pace of expansion. MSH3 is a particularly compelling target: loss-of-function alleles are tolerated in humans yet strongly suppress expansion, providing rare pre-validated genetic support for therapeutic modulation. Substantial gaps remain, however, in defining which residues, domains and protein-protein interfaces are required for MSH3-driven instability, and which are dispensable. The project aims to resolve this by combining saturation prime editing across the MSH3 coding sequence with quantitative measurement of repeat dynamics and DNA repair activity at the endogenous expanded locus.