ERC Synergy Grant for trailblazing project 4D-BioStem

Professors Henning Stahlberg, Knut Müller-Caspary, and Carsten Sachse. Credit: EPFL/ Ludwig-Maximilians University/ Forschungszentrum Jülich.

Professors Henning Stahlberg, Knut Müller-Caspary, and Carsten Sachse. Credit: EPFL/ Ludwig-Maximilians University/ Forschungszentrum Jülich.

Professor Henning Stahlberg (EPFL/UNIL), with two colleagues in Germany have been awarded a prestigious ERC Synergy Grant for their innovative project, 4D-BioSTEM that aims to advance cryo-electron microscopy for enhanced molecular understanding in neurodegenerative disease research.

The ERC Synergy Grants are given each year “to provide support for a small group of two to four Principal Investigators to jointly address ambitious research problems that could not be addressed by the individual Principal Investigators and their teams working alone.” The Grants are among the best endowed awards for researchers in Europe, celebrating the collaborative spirit in pushing the boundaries of scientific exploration.

Among the awardees of the ERC Synergy 2023 Grants, are Professors Henning Stahlberg (EPFL School of Basic Sciences, School of Life Sciences, and UNIL's Faculty of Biology and Medicine), Carsten Sachse (Forschungszentrum Jülich), and Knut Müller-Caspary (Ludwig-Maximilians University of Munich).

The three researchers, who one Grant reviewer has dubbed “a high-power team”, have been awarded with a total of 7.5 million euros, for their pioneering project, 4D-BioSTEM, which aims to take cryo-electron microscopy to new heights, enabling higher resolution imaging of smaller proteins in cellular tissue.

Cryo-electron microscopy (cryo-EM) has revolutionized the life sciences, making it possible to directly determine the 3D structure of proteins in their natural state. But for many molecules, especially those that play a role in neurodegenerative diseases such as Alzheimer's and Parkinson's, established imaging methods can only achieve inadequate resolution and contrast.

“4D-BioSTEM aims to expand cryo-EM to become able to image smaller proteins in cellular tissue at highest resolution,” says Stahlberg. “This revolutionary goal can be addressed much faster in an interdisciplinary manner within the framework of the ERC Synergy Grant than would be possible separately in individual labs.”

About 4D-BioSTEM

In conventional cryo-electron microscopy, many thousands of snapshots of identical protein particles are taken from a wide variety of viewing directions using transmission electron microscopy and then computed into a detailed three-dimensional image.

4D scanning transmission electron microscopy (4D-STEM), in contrast, scans the sample line by line in tiny steps. For each individual scan position, a so-called electron diffraction pattern is thereby recorded. As a result, thousands to millions of overlapping diffraction patterns are created, which are converted back into an interpretable image using so-called ptychographic algorithms.

Among other things, the 4D-BioSTEM project aims to develop appropriate techniques for the structure determination of biomolecules that so far were too small for cryo-EM to be visualized. In addition, the 4D-BioSTEM project will expand cryo-electron ptychography to tomography to image 3D tissue slices at improved contrast. The process is very data- and computationally intensive.

The goal is to extract the maximum signal from very noisy data. This is because biological samples are typically extremely sensitive to the electron beams, so that only a limited dose is available for examination. While the developed technology will be universally applicable to a wide range of specimens, the primary application in the 4D-BioSTEM project is to study neurodegeneration in the human brain.