Biophysics

Organoids are assemblies of cells that recapitulate organ shape and function. Organoids are currently revolutionizing many aspects of cellular biology, as they allow for the study of disease-relevant processes outside the body. However, technical challenges have long prevented cellular dynamics from being quantified from time-lapse movies. Over the past years, we have developed AI-driven analysis methods to track all cells within organoids as they grow, divide, move, differentiate into different functional cell types, and ultimately die.

This tool shows the truly fascinating ways in which all these systems self-organize into functional tissues. For instance, we have shown that highly dynamic cross-cellular actin structures detect mechanically weak cells to extrude them from the intestinal epithelium, and that cellular identity choices are not governed by a spatial gradient of signaling molecules but rather by a timer mechanism that starts ticking when two key cell types dissociate from each other. This approach can be broadly applied to different organ cell types, organ systems, but also immune cells, which we are also exploring. We do our organoid work together with AMOLF colleague Jeroen van Zon.

Polysomes are RNA messages decorated by ribosomes, as well as the proteins they produce and other cofactors. While known for decades, their functional purpose has long remained unclear. Recent work by us and others now suggest that polysomes enable cooperation between ribosomes. We mainly use single-molecule tools to mechanistically understand this cooperation. We also exploit RNA sequencing methods to characterize it across the proteome in cells, in collaboration with the Bukau-Kramer lab in Heidelberg.

For instance, we have shown how two ribosomes are physically linked via the proteins they are synthesizing, and hence jointly produce protein dimers. Strikingly, such nascent chain interactions can suppress misfolding. These and other findings indicate a wealth of dynamics and regulation occurring within polysomes, which we are exploring. These processes may be relevant to all major cellular processes, as well as to mRNA vaccines and AI-generated protein design.