Since its invention in the 1930s, electron microscopy has revolutionized biological research, making microscopic structures visible that would otherwise remain unseen. However, to obtain sufficient resolution to identify specific proteins in the electron density, electron microscopy relies on the averaging of identical structures, thus limiting, thus limiting their applicability for dynamic processes occurring within living cells. This is where Jonas and his team come in: “I think that optical super-resolution microscopy is the ideal, complementary technology because it allows us to investigate individual structures without any averaging, with very high contrast in the living cell”, Jonas says.
Jonas explains further: “At the moment, we can achieve a resolution of around ten nanometers in 3D and in multiple colors.” However, the time required to obtain that resolution is relatively slow, which limits its application in living cells. Consequently, the Ries lab is pursuing three approaches to improve dynamic super-resolution microscopy: first, they are enhancing the image acquisition speed to facilitate dynamic measurements with sufficient temporal resolution. Secondly, following the acquisition of thousands of snapshots in fixed cells, they are constructing a machine learning model to compile these snapshots into a molecular movie. Finally, the Ries lab is developing MINFLUX microscopy, due to its superior spatial and temporal resolution compared to conventional techniques. Ultimately, the Ries group aims to permit the direct recording of movies within living cells using their technologies.
Once established, these technologies will be applicable to many biological research questions. Jonas explains: “As a group that focuses on technology and development, we enable other research groups to make breakthroughs in their research. Therefore, it is very important for us to have many collaborations with biologists and to make all our developments easily accessible.” In the next 10 years, Jonas and his team hope to deliver on one of the holy grails of structural biology: to directly observe conformational changes in proteins in a living cell.