Novel Chemo-Optogenetic Systems Offer Spatiotemporal Precision

A research team at Umeå University has developed advanced light-controlled tools that enable real-time regulation of proteins within living cells. This pioneering work opens new possibilities for studying intricate cellular processes and could drive breakthroughs in medicine and synthetic biology.

"Cellular processes are complex and constantly change depending on when and where they occur within a cell. Our new chemical tool, equipped with light switches, will make it easier to control these processes and study how cells function in real-time. We can also regulate these processes with micrometer-level precision within a cell or tissue."

— Yaowen Wu, Professor and SciLifeLab Group Leader, Umeå University

The intricate interplay of cellular events depends on the precise distribution and interaction of proteins across time and space. Regulating protein or gene function is a fundamental challenge in modern biological research.

However, conventional genetic methods like CRISPR-Cas9 often operate on longer time scales, allowing cells to adapt. These methods also lack the spatial and temporal precision required to investigate highly dynamic cellular processes.

To overcome these limitations, chemo-optogenetic systems have emerged as powerful tools. These systems combine chemical molecules, optics, and genetically engineered proteins to control protein activity at specific locations in cells using light-sensitive small molecules.

Professor Yaowen Wu’s lab is at the forefront of developing these chemo-optogenetic systems.

Previously, the Wu lab introduced molecular glue-based systems, which bring two proteins into proximity to alter localization or activity. These molecular glues are activated or deactivated by light through the removal or cleavage of a light-sensitive group.

While these tools represented significant progress, they had limitations in usability, photo-stability, and chemical stability.

Next-Generation Light-Controlled Molecular Glues

In two recent publications—highlighted as hot papers in Angewandte Chemie International Edition and Chemistry – A European Journal—Wu’s team has developed next-generation chemo-optogenetic tools using photoswitchable molecular glues that overcome these challenges.

By refining the molecular design, the new molecular glues can be switched "on" or "off" using light of specific wavelengths. This enables multiple activation cycles, where each state either enhances or inhibits protein function.

"The new modular design offers enormous versatility, adaptable properties, and greater stability."

— Jun Zhang, Staff Scientist, Department of Chemistry, Umeå University

"In our experiments, we demonstrated precise control over several cellular processes, including protein function and localization, organelle positioning, and protein levels."

— Laura Herzog