How to Run an Electron Microscopy Facility

A 20-minute read

From film to fast hybrid-pixel detectors: during Dr. Elisabeth Müller’s 34 years in electron microscopy (EM), she has seen it all. Today, she is the Head of the Electron Microscopy Facility (EMF) at the Paul Scherrer Institute (PSI), leading aspiring scientists such as Dr. Emiliya Poghosyan. On the occasion of the International Day of Women and Girls in Science (February 11, 2023), we asked Elisabeth and Emiliya to show us their realm: the world of an EM facility. 

DECTRIS: What brought you to the field of electron microscopy?

Dr. Elisabeth Müller, Head of the Electron Microscopy Facility at the PSI: I did not choose the field of electron microscopy; it chose me. After my studies, I was searching for a Ph.D. position. Back then, without the Internet, it was quite challenging. I first stumbled upon a position dedicated to researching gas exhaustion of the Etna volcano in Sicily. However, due to the physical nature of this position (I would have had to carry heavy equipment over long distances), it was not a job for me. By chance, my former diploma supervisor had an open position in his electron microscopy group, and he offered it to me. Since I had had a great experience working with him, and the topic sounded interesting, I welcomed this opportunity. Thus, I entered the field that has kept me fascinated for over 34 years. 

Dr. Emiliya Poghosyan, scientist at the PSI’s Electron Microscopy Facility: As I was coming from the field of Life Science, Transmission Electron Microscopy (TEM) was, to me, the most rewarding. Having spent my whole day purifying proteins, I could put my sample on a small grid and into the microscope and finally see what I had been working on for so long. That is how I came to appreciate the importance and strength of various methods in electron microscopy. I am thankful for this opportunity at the PSI to pursue my development in this field.

DECTRIS: Elisabeth, what does it mean for you to be an EM facility manager?

Elisabeth: I have been at the Electron Microscopy Facility for almost 10 years, and I must admit, it never gets boring. The role is so incredibly multifaceted. For starters, I am responsible for all our instruments and must ensure that everything runs smoothly to avoid any downtime. Then, both of us work closely with our 90-plus users. We provide theoretical and hands-on training to enable them to operate our instruments, and we support them in their projects. The challenge is that our users perform a variety of experiments in Materials Science and Life Science. To best assist them, we must all stay up to date with the latest research and perform our own.  Finally, as the Head of the facility, I also spend a lot of time advocating for the facility’s needs in the institute, managing finances, recruiting, and deciding how to further develop the facility and our own research. This broad scope of responsibilities is what makes this role not only interesting, but also extremely challenging. 

DECTRIS: Emiliya, what do you treasure most about working with Elisabeth?

Emiliya: Working with Elisabeth, I can gather unique insights into the highlights and challenges of her role. I am thankful for the opportunity to help out with user support and training, instrument troubleshooting, method development, and more. This experience is preparing me for the future and will help me to be successful in such a role one day.

DECTRIS: While supporting so many users with their experiments, what was the most memorable project for you?

Elisabeth: Indeed, working in a user facility like the one at the PSI, I am fortunate to be let in on many different projects and support the scientists in the implementation of their ideas. Many of these projects taught me something new. 

The one that lies close to my heart was the restoration of a 16^th-century statue of Saint Mary from a church in the Canton of Valais in Switzerland. To bring the piece to its intended look, restoration technicians needed to know the origin of the black areas on the statue. They were trying to understand whether it was simply black pigment, corroded silver, or corroded silver under a thin layer of gold that was supposed to imitate the gilding. By chipping off a tiny piece of the statue - not bigger than 1 millimeter - and analyzing it in a Scanning Electron Microscope (SEM) and an X-ray spectrometer, we were able to determine the exact composition of the material. To learn about the 3D structure of the material, we performed tomography on a larger area at the Swiss Light Source (SLS). This experiment was a great example of the complementarity of our facilities at the PSI. 

Bright and Dark Fields

DECTRIS: What are the biggest challenges of being an EM facility manager, or working in an EM facility?

Elisabeth: I would summarize it in one word: resources. It can be money, personnel, time, and even space. To stay competitive we need great equipment, the ability to cover a range of applications, personnel to provide support and assistance to the users, and time on the instruments to perform our research. In every case, we have to prioritize. 

In the team, we try to understand what instrument would generate the most value, what method would be used by the scientific community and allow us to keep our instrument busy, what research project represents the right challenge, what the additional requirements are for running an instrument, and whether or not we can fulfill them. We aim to have our instruments perform at their best, and as often as possible. The facility’s costs are very high, and if we are lucky to get financial support, we regard it as an investment and look for the maximum return. 

Emiliya: When I joined the facility, it was crucial for us to develop cryoEM capabilities further. This required not only the refinement of the instruments, but also the development of user training programs. During those first two to three years, I dedicated most of my attention to these tasks, and there was very little time left for original research. Working in a facility, or - even more so - managing one, means constantly finding an inner balance between the manager and the scientist in you. You cannot allow one to overpower the other. 

“It Is Not Always 50/50”

DECTRIS: How does one find such a balance? 

Elisabeth: Truly, one must constantly find the balance. It is important to make sure that the facility runs smoothly, but it is simply mandatory that one carries on one’s own original research. Science develops so fast; one gets outdated day by day. Both aspects of the role take a lot of time, and I guess it is not always 50/50. At the beginning, most of my focus went to the development of the facility, from the acquisition of the instruments to their setup and operation. Now the bases are here, and I can focus more on method development and research. We have started to define major topics that we want to address with our limited resources, and we launched a number of user collaborations. Thus, we have two pools of inspiration for our work: users’ projects and ideas, and emerging methods that are now gaining momentum in the community. In any case, the needs of the scientific community are at the heart of our choices. 

DECTRIS: Elisabeth, among all the available technologies, how do you choose which one is the best for your facility?

Elisabeth: Choosing the right technology is not an easy task. It is not always about the latest developments. Sometimes, one has to choose between new technology and a familiar workhorse. We orient ourselves towards the needs of our users. If we can make sure that the instrument will be used, we consider purchasing or upgrading it. Then, we must keep in mind our own resources. Even if we have a budget for new equipment, we need to make sure we have enough qualified personnel to integrate it into our ecosystem and maintain it. Last but not least, we are looking around us. What do other facilities offer? What can be done with other methods? Is there a gap, and will this technology help us to bridge it? For example, the PSI’s large research facilities allow for a high throughput and are used in high-volume research, whereas our facility focuses on resolution. Thus, we complement each other.

Exploring the Potential of Hybrid-Pixel Detectors

DECTRIS: How would you describe the evolution of detection technologies and its impact on electron microscopy?

Elisabeth: When I started working with electron microscopes, we were convinced that the method had reached its ceiling. Then, in the 1990s, several developments - most importantly the aberration correctors, but also field emission guns, vacuum quality, and more - gave the method a second life. More and more new possibilities started to emerge. One aspect that had not yet changed was the detector. We managed to achieve so much with our microscopes, but could not reach the method’s full potential without better detection technology. Working with photographic film allowed for a high resolution, but digital quantification was difficult. The first CCD cameras were a step forward, but they were slow. Next came CMOS detectors, enabling faster readout speeds and more sensitivity. That paved the way for in-situ and time-resolved experiments. 

Today’s cameras open a lot of new possibilities - in particular, direct electron detectors and hybrid-pixel detectors, as they bring the sensitivity, dynamic range, and speed to a whole new level. These advancements in detector technology enabled scientists to develop new methods in electron microscopy.

Emiliya: The development of direct electron detectors had a tremendous impact on Life Science. All of a sudden, with these precise electron-counting devices, we could solve the structures that we had thought were impossible to figure out. So many projects that were stuck started to deliver structures, enabling further research and finding industrial application in structure-based drug discovery and other areas. My colleagues in Materials Science seem to have had a similar experience with hybrid-pixel detectors. Perhaps there will be a hybrid-pixel detector that could also serve Life Science applications well. I would be very excited to try it. 

DECTRIS: Can you share some of your latest or most exciting research projects, and the role that the latest (detector) technologies play in them?

Elisabeth: Currently, we are focusing on two methods that are possible only thanks to the development of detector technologies. These are micro-electron diffraction, or microED, and Four-Dimensional Scanning Transmission Electron Microscopy (4D STEM). The former was thought to be impossible due to the stronger nature of the interaction between the electrons and specimen, compared to X-rays. We used to believe that it would be unfeasible to quantify the resulting diffraction patterns. However, thanks to the speed and sensitivity of new detectors, and the courage of the scientists who dared to try, the method is now taking shape and offers the possibility of determining the structure of crystals that are too small for X-ray-based techniques.

The latter - 4D STEM - is, in reality, a combination of methods from virtual detectors to ptychography. It opens a lot of doors and, in a way, removes many complications. Prior to the development of 4D STEM and the instruments that could adequately perform it, each acquisition mode would require a dedicated detector. One could not acquire data simultaneously; this was a no-go for beam-sensitive materials. 4D STEM and fast detectors remove this hurdle: one data set covers a large angular range, allowing for better evaluation of your data. This is a new method that is not yet largely available in Switzerland. Having an opportunity to develop our facility for it, in collaboration with the PSI’s in-house detector development team and using commercial detectors by DECTRIS, is exhilarating. We cannot wait to share our results.

Emiliya: In addition to microED and 4D STEM, I am personally very excited about our work on STEM tomography for Life Science applications. This method is also not widely available in Switzerland, but it has a lot of potential to bridge the gap between electron microscopy methods that focus on high resolution and well-established X-ray methods that cover large volumes. STEM tomography could offer nanometer-range resolution at a higher throughput.

About Dr. Elisabeth Müller

Dr. Elisabeth Müller has been working in the field of electron microscopy for over 34 years. After obtaining her degree in Physics, she joined the Swiss Federal Institute of Technology (ETH Zurich) for a postdoctoral fellowship in Solid-State Physics, where she used a Transmission Electron Microscope (TEM) to investigate the structure of semiconductors. Later, she joined the Paul Scherrer Institute (PSI) as a Senior Scientist for materials characterization, quality control, and development of materials. 

Never leaving electron microscopy, Elisabeth has worked as a TEM Specialist, a Staff Scientist, and a Facility Manager. Today, she is the Head of the Electron Microscopy Facility at the PSI and the Group Leader of the Electron Microscopy and Diffraction group.

About Dr. Emiliya Poghosyan

Dr. Emiliya Poghosyan obtained her Bachelor of Science degree from Yerevan State University and her Master’s degree in Nano-biophysics from the Technical University of Dresden. Right after that, she joined the Swiss Federal Institute of Technology (ETH Zurich) for her Ph.D. in cryo-electron microscopy and completed a postdoc at the University of Basel. 

Since 2018, Emiliya has been working at the PSI’s Electron Microscopy Facility. She is in charge of user support and education in basic TEM and cryo-electron microscopy, as well as method development and implementation for biological electron microscopy.