A Multimodal, ultra-sensitive microscope combining molecular printing and hyperspectral imaging of labelled and unlabelled single molecules

The hallmark of life, is that it is both complex and animate. A typical human cell has around 10,000 different kinds of proteins, often interacting with each other at specific locations for mere seconds or less. For example, the process of endocytosis by which cells internalise extracellular components involves ~60 proteins that act in a defined sequence at precise relative locations to each other in order to orchestrate this biological function.

The purpose of this application is to unravel the precise details of the molecular ballet underlying a number of other fundamental processes of life, and how this dance is affected in diseases. For instance, we plan to understand how cells divide, how the cell's inner compartments can be specifically enriched with certain molecules, then move at the right place at the right time, or how our brain develops during embryogenesis, but also in pathologies, in particular neurodegenerative diseases.

To achieve this, we propose to assemble a unique novel microscope, which has been specifically designed to shed light on the spatio-temporal nature of biological processes.

This microscope will be the first of its kind to combine multiple imaging modalities into a single instrument controlled by a single software. In particular, the microscope will be extremely sensitive and fast, meaning that it will be able to resolve the very quick events that are characteristic of biology, while at the same time having the ability to resolve single molecules.

Furthermore, while most microscopes can only image three proteins, biological processes often involve more than three key players. This dramatically limits our understanding of biological processes, because we only get a partial view of the phenomenon, without all the factors at play. To alleviate this issue, the microscope will uniquely be able to image up to height proteins at the same time.

Last, the microscope will be able to "print" proteins onto biologically-relevant substrates, the same way a computer printer prints ink onto paper (just orders of magnitude smaller). This can be used to precisely control the position of proteins in cells, thereby providing spatial control over the biological phenomena we want to study. In other words, while with conventional microscopes, scientists have to look for the specific process they want to image, and so more often than not, miss it.

But with this new instrument, we will be able control where things are happening, so we can make sure it happens where we look.