Independence Accelerator Award

Who are you?
My scientific life began in Australia, and has since taken me to the UK, the US, and now to Heidelberg, Germany. Over time, I have developed a strong interest in how genetic material is organised inside cells. A big part of my work now is about using structural biology and biophysics to understand the mechanisms behind this. In my PhD, I studied the molecular mechanisms of genome packaging in DNA viruses by X-ray crystallography, NMR, single-particle cryo-EM and single-molecule localisation microscopy. In my postdoc now at the European Molecular Biology Laboratory in Heidelberg, I am using cryo-electron tomography (cryo-ET) as a means to study molecular structures inside cells, with a focus on ribosomal DNA transcription and the architecture of the nucleolus. To help this work, I am also developing methods to streamline and automate the preparation of thin lamella specimens for cryo-correlative electron tomography, as a means to target specific structures inside the cell for imaging.

What project do you plan to work on while being supported by the award money?
In my future research, I would like to capture the structure of chromatin inside cells by cryo-ET, and elucidate how phase separation contributes to genome structure and function. A current major limitation of cryo-ET is that it is difficult to identify molecules in the observed cellular landscape, unless the molecule has a known shape and a certain size (e.g. ribosomes). This poses a particular challenge for the study of flexible, disordered molecules known to be key in driving liquid-liquid phase separation. With the support of this award, I would like to overcome this limitation by developing a new localisation method based on genetically encoded multimeric nanoparticles (GEMs) — self-assembling protein structures with a defined size and shape that would be easily detectable by cryo-ET. The main challenge ahead will be to identify a GEM protein that will robustly form particles and can be efficiently imported into the nucleus for the tagging of nuclear proteins. In the Mahamid lab, and in collaboration with the Cüylen lab, I plan to tackle this by screening a selection of proteins and testing their potential for protein tagging in the nucleolus of human cells.