2nd October 2020

Dr. Stefan Pfeffer

It is very rewarding to eventually see all the pieces falling into place after months or sometimes years of working on one particular structure.

Why did you choose to focus your research on the structure of macromolecular complexes?

Macromolecular complexes are pivotal for all cellular processes and their function is often closely linked to their shape and structural plasticity. So from a rational point of view, our research is motivated by our desire to better understand these structural aspects.
From a more personal perspective, it is very fascinating for me to actually see these complexes ‘with my own eyes’, through the lens of a cryo-electron microscope, and to understand their three-dimensional structure and working mechanisms. In fact, many of these complexes have such intricate building plans that to unravel their architecture often feels like solving a molecular puzzle. It is very rewarding to eventually see all the pieces falling into place after months or sometimes years of working on one particular structure. Very much like tiny machines, macromolecular complexes frequently undergo large-scale structural changes during their reaction cycle. We often capture individual steps of the underlying motion, which helps us better understand the workings of one particular ‘molecular machine’. More than once, I have been amazed by the elegant solutions of ‘engineering’ that we observed in the process.

Is there a certain goal that you have set yourself in your research?

We are mostly interested in molecular processes that are linked to ribosomes, large “molecular machines” required for cellular protein biosynthesis. In studying these molecular machines, one of our biggest aims is to understand how molecular chaperones and enzymes can promote the correct folding and maturation of proteins during their synthesis, and how these processes can be coordinated on the surface of the ribosome.
We ultimately hope that these studies will produce structural and mechanistic data that can contribute to a better understanding of pathological cellular conditions, like the de-regulation of protein synthesis observed in cancer, or the protein aggregation and imbalance of protein homeostasis found in neurodegenerative diseases.

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What will the future of your research look like?

Most approaches in structural biology focus on deciphering the shape of macromolecular complexes after biochemical isolation. However, biochemically purified or reconstituted complexes do not always faithfully reproduce the situation in vivo. Therefore, one of our central goals for the future is to routinely image and analyze macromolecular complexes directly in their physiological cellular environment, and, in doing so, reach a level of detail similar to the one we already achieved for isolated samples.
I am confident that this approach holds high potential for a better understanding of the molecular details of the inner workings of a cell, and that it will allow us to shed light on many outstanding questions in structural and cell biology.

What do you do to unwind from work? How do you relax?

Two energetic children and a wonderful wife make it easy for me to get distracted from science. Whenever I have some spare time, I like to read ‘hard science fiction’.

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What do you like about your research environment?

Located at the Center for Molecular Biology of Heidelberg University (ZMBH), we are surrounded by world class experts in many areas of biology that are very attractive from a structural biologist’s perspective. Even though I only started to establish my group in Heidelberg two years ago, many wonderful and productive collaborations have already emerged across campus, which shows that we are enjoying a very inclusive research environment here in Heidelberg.

How could the research conditions be improved for young scientists?

As for many young scientists with a family, the biggest challenge for me is the insecurity that comes with fixed-term employment contracts now ubiquitously present in academia. Tenure-track positions may be a step in the right direction, but it remains to be seen whether they can really help create a more reliable and family-friendly academic environment.

© Tobias Schwerdt