The SwissFEL, the PSI's latest largescale research facility, boasts sophisticated X-ray laser technology, as well as refined sensor systems. In addition to materials science, environmental and energy research, life sciences in particular will benefit from the new possibilities offered by the 750 metre-long facility.

Professor Gebhard Schertler and his Team. Photo: Basil Stücheli

One of the most exclusive attractions in Switzerland lies tucked away in woodland in Würenlingen. “If there's one thing they're jealous of us for in Japan or the USA, it's this,” says Professor Gebhard Schertler pointing at the “Jungfrau”, which stands gleaming with shimmering surfaces, cables and flashing LEDs in the middle of the room. It is an innovative, two-dimensional pixel detector for high-performance research with X-ray light, which was developed for the SwissFEL. The detector conceals the extremely high-precision measurement sensor systems for the X-ray light pulses that are produced in the facility, which is almost 750 m long and which lies hidden beneath the ground in the wood. The SwissFEL is the Paul Scherrer Institute's (PSI) most recent large-scale research facility. It can be used to generate extremely short and intense pulses of Xray light. The process opens up completely new possibilities for researchers; for example, they will be able to record structural changes in biomolecules “in real time” for the first time ever.

The area of woodland where the facility is located borders the PSI site, just a short walk away. Schertler takes real pride in showing it off. He is Head of the Biology and Chemistry research division at the PSI and is responsible for using sophisticated biological experiments to get the maximum potential out of the PSI's measuring instruments. The researchers are particularly interested in the new ways to decipher the structure of protein molecules. The spatial structure of proteins has been successfully studied for some time now using the protein crystallography
technique on the PSI's Swiss Light Source (SLS). However, proteins are not rigid objects, but perform movements that last between femtoseconds and a few seconds. Schertler and his colleagues' aim is to capture images of the proteins in motion. After all, if we know how changes in the structure of a protein affect its function, we can also find out how a drug works or why a disease develops.

“Life is dynamic. Structural changes in proteins are the basis for every living system and are the drivers of all life processes", Professor Schertler points out.

In order to “film” structural changes, the first thing to do is to integrate many proteins into many crystals in which they are arranged in a regular lattice structure. Now you have to get the proteins to start moving at the same time. The best way to do this is with light-activated proteins that occur naturally. First of all, the proteins are excited by short laser pulses of visible light in order to make them move synchronously. They are then measured with the X-ray pulse from the SwissFEL. If the time span between activation and measurement is changed, it is possible to “record“ a protein structure at any point during its movement and thus turn molecular snapshots into a “molecular film”.

The time resolution that researchers achieve with their experiments at the SwissFEL is currently several hundred femtoseconds. One femtosecond is a quadrillionth of a second. The time resolution indicates the time interval between two consecutive images in the virtual “film” that visualises the movement of the proteins. A higher time resolution means that even faster processes can be observed in the proteins. Schertler considers up to 50 femtoseconds to be a challenging goal.

Jungfrau am PSI

The PSI's “Jungfrau“ is rated among the “top of the world“: an innovative, twodimensional pixel detector for highperformance research with X-ray light for the SwissFEL. Photo: Basil Stücheli

In this sense, the facility buried away in the forest is the focus of a potentially revolutionary breakthrough in life sciences. As Schertler puts it, “life is dynamic. Structural changes in proteins are the basis for every living system and are the drivers of all life processes.” There has been little access to these dynamic processes up to now. It is like reaching a new continent.

One of the most important tasks in Schertler's remit is not only to map this continent, but also to explore it further. Schertler and his colleague Gregor Cicchetti firmly agree that the findings are of immense relevance for life sciences. These processes are difficult to observe with classical biological techniques. But the SwissFEL will only be able to demonstrate its strengths in combination with other analytical techniques, such as modern spectroscopy or electron microscopy. Schertler calls it “integrative structural biology“.

Schertler feels certain that the latest successes are only the beginning. At some stage, it will be possible to observe biological structures in situ, i.e. in their natural cellular environment rather than in a crystal or in a pure protein solution at atomic resolution. Only a research institute such as the PSI would be able to achieve a goal as ambitious as this. The PSI traditionally also carries out long-term research projects.