Understanding and designing molecular structure is core to science and technology. Electron microscopy (EM) enables high-resolution imaging of biological samples to see molecules at the atomic level and visualize them in 3D in of cells and organs. To keep the Netherlands at the forefront of this revolutionary field, we will create a national infrastructure integrating the latest innovations in cryo-EM and volume EM. The infrastructure will offer users tools for cutting-edge sample preparation, data acquisition and analysis, train and expand the EM community in the Netherlands, and pave the way for new discoveries and scientific advances in medicine and technology.

The timing of light exposure, physical activity, and food intake are important cues for synchronising the biological clock. Disruption of the biological clock is a clear threat to both public health and vulnerable ecosystems. Especially in a highly industrialised country such as The Netherlands there is a mismatch between biological clocks and social demands. However, these cues have drastically – and abruptly - changed in our modern society due to the widespread use of artificial light and the round-the-clock demand for goods and services. Fundamental research has shown that precisely these conditions cause desynchrony among clock cells.

Glucosylceramide (GlcCer) is a ubiquitous cellular building block that fulfils important, but in some aspects little appreciated, roles in health and disease. We aim to obtain fundamental insight in GlcCer metabolism in its broadest sense and generate new biomarkers and diagnostics, and ultimately new therapeutics. Well-known GlcCer metabolites are complex glycosphingolipids implicated in signaling processes. Their excess is associated with Metabolic Syndrome. A less studied GlcCer metabolite is glucosylsphingosine, recently shown to induce Multiple Myeloma. Additional GlcCer metabolites are glucosylated sterols and other glucosylated metabolites that emerge after transfer of glucose from GlcCer. During inherited deficiency of glucosylceramidase GBA1 (Gaucher disease, a multi-organ lysosomal storage disease), GlcCer and its metabolites accumulate. Impaired GBA1 constitutes a known but unexplained risk for Parkinsonism. Pathological consequences of excessive glucosylation of sterols and other metabolites warrant elucidation. We plan to identify glucosylated metabolites of GlcCer and obtain structural and spatio-temporal insight in GlcCer metabolism by glycosidases. The aim is to understand the cellular consequences of GlcCer metabolites as a first step towards manipulating the associated diseases. Assembled is an interdisciplinary platform with input from synthetic organic chemistry, cell biology, structural biology, medical biochemistry and industry to dissect GlcCer metabolism from various angles.

A struggle for control - The localization and activity of cellular proteins is regulated by so-called dynamic post-translational modifications. It turns out these modifications are also modified themselves, leading to a novel hidden layer of control. The researchers aim to develop chemical tools to study these complex processes in detail.