Photo: The inside of the super microscope. The cryo-TEM is four metres high and extremely sensitive. Charité | Wiebke Peitz
ERC Advanced Grant for Charité biophysicist Christian Spahn
Berlin, 17 June 2025
Ribosomes are the miniature factories of life. Understanding their mechanical masterpiece in detail provides the knowledge base for a wide range of applications – from vaccine production to the development of new antibiotics. Prof Christian Spahn, biophysicist at Charité – Universitätsmedizin Berlin, therefore wants to see the nano factories in action. And he spares no effort: using ultra-cold temperatures and a four metre high microscope, which has to be stored like a raw egg, he wants to image ribosomes in unprecedented temporal resolution. He has now been awarded an ERC Advanced Grant, one of the most prestigious European funding programmes, for his work.
Every living cell needs ribosomes. The factories, which are only 25 nanometres in size, decipher the genetic code and produce proteins according to its instructions, which are required as structural elements, messenger substances or other molecular tools in the cell. Ribosomes assemble hundreds of components into protein products around the clock at breakneck speed, as if on an assembly line.
‘So far, we have only been able to capture snapshots of this extremely complex process,’ explains Christian Spahn, Director of the Institute of Medical Physics and Biophysics at Charité. ‘Now we want to take a closer look and visualise the ultra-fast intermediate steps.’ His project has convinced the European Research Council (ERC), which is funding the ‘DeepRibosome’ project with around 2.5 million euros over the next five years as part of an Advanced Grant.
The finer the view, the greater the effort
Together with his team, Christian Spahn wants to decipher how exactly the ribosomes change their shape during their work and how temperature, ions or antibiotics influence the processes. This is easier said than done – and requires state-of-the-art technology. A whole series of scientific institutions in Berlin have been working for years to establish the necessary technical infrastructure in the capital – funded by the state and federal government.
In order to take up actively producing ribosomes, Christian Spahn’s team must first release the ribosomes from the cell and stimulate them to work outside their native environment. The researchers have developed a new method specifically for this purpose. Then comes the freezing cold: the samples are shock-frozen in liquid ethane at minus 150 degrees Celsius so that no ice crystals form, but crystal-clear ice encloses the molecules in their natural form. Wafer-thin slices of the sample – just 300 nanometres thick – are then placed under a high-performance microscope that has it all: the cryo-transmission electron microscope (cryo-TEM).
The super microscope: as big as a colossus, more sensitive than a raw egg
The special feature of the five million euro device is that it is able to visualise the tiniest cell structures in their natural aqueous environment in three dimensions – at almost atomic resolution, i.e. in the range of less than a millionth of a millimetre. Previous electron microscopes required chemical preparation of the samples and therefore did not necessarily reflect the original structure of the molecules. In 2017, the Nobel Prize in Chemistry was awarded for the development of cryo-electron microscopy, in which the samples are not chemically altered. One of the prize-winners was Joachim Frank, from whom Christian Spahn learnt the intricacies of the imaging method.
The technology built into the cryo-TEM not only takes up a lot of space – the microscope measures a full four metres – but is also highly sensitive: it cannot tolerate temperature fluctuations, excessive humidity or vibrations. This is the reason why the cryo-TEM has been given its own building. Built with double walls like a ‘house within a house’, with a 1.25 metre thick concrete floor that compensates for vibrations and an efficient ventilation system.
Complex analysis of hundreds of thousands of images
However, the microscope itself only provides individual images that appear rather noisy. To create a 3D model of the ribosome, the final step requires modern digital image processing – and computing power. ‘We analyse hundreds of thousands of images using modern computer processes to automatically sort and classify them,’ explains Christian Spahn. “The calculations take weeks to months. In this way, we can also visualise very rare, short-lived intermediate states of the ribosomes in the millisecond range, which previously remained hidden.”
The scientist compares the process to analysing a horse’s gallop. “Let’s assume we photograph a herd of identical horses galloping across a field countless times from different angles. Then we will have captured each animal at a slightly different point in the movement sequence. We sort all these individual shots and then put them together to create a three-dimensional film that shows the gallop in every detail.”
The effort is worth it: a better mechanical understanding of protein factories not only clarifies a fundamental principle of life, but also has potential relevance for biotechnology or medicine. ‘The findings could be used to optimise artificial protein production – for example for the production of drugs, vaccines or artificial cells,’ says Christian Spahn. ‘Because ribosomes are the main target for antibiotics, a better understanding of how they work can also help to develop more effective drugs against resistant bacteria.’
About the cryo-TEM
The cryo-transmission electron microscope is operated by the Core Facility for Cryo-Electron Microscopy (CFcryo-EM), which is maintained by Charité in collaboration with the Max Delbrück Centre and the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP). The acquisition of the device was funded by the German Research Foundation (DFG), the State of Berlin, the Charité and the Free University of Berlin. The construction of the building on the Buch campus was financed by the Max Delbrück Centre. The building and the microscopy infrastructure were officially opened in 2023. Charité’s CFcryo-EM is part of the Alliance Center Electron Microscopy (ACEM) of the Berlin University Alliance (BUA), a jointly funded virtual and interdisciplinary electron microscopy equipment centre of Freie Universität Berlin, Humboldt-Universität zu Berlin, Technische Universität Berlin and Charité.
ERC Advanced Grants
The Advanced Grants funding line is one of currently five research funding programmes of the European Research Council (ERC). It supports established top researchers with an outstanding scientific track record who wish to develop new areas of research. The funding programme provides up to 2.5 million euros over a period of five years.