In May 2021, Dr. David Haselbach took up a tenure track professorship at the Faculty of Chemistry and Pharmacy, Institute of Physical Chemistry, of the University of Freiburg. In the Cluster of Excellence CIBSS, he continues his previous research on protein complexes, so-called molecular machines, which fulfil important tasks in cells. His expertise in cryoelectron microscopy enables CIBSS to newly establish this complex technology at the University of Freiburg. In an interview with Mathilde Bessert-Nettelbeck, he talks about his enthusiasm for the nanoworld, the challenges of electron microscopy and what "integrative" means to him.  

What subject title would you use to describe yourself? Are you a biologist, physicist, biochemist?

David Haselbach: I am not a fan of pigeonholing: the categorisation into different disciplines makes cooperation between scientists difficult. The integrative approach across disciplines is very important to me for understanding molecular processes. I would describe myself as a natural scientist, perhaps a structural biologist. I studied biochemistry, but I have always been very enthusiastic about physics. Now I am assigned to the department of physical chemistry.

You are appointed CIBSS Tenure Track Professor for Physical Chemistry with a focus on cryo-electron microscopy (cryo-EM) - what fascinates you about this tool?

In the words of physicist Richard Feynman, "It is very easy to answer many of these fundamental biological questions; you just look at the thing!" For my research, this means looking directly at individual molecules. Structural analyses of proteins are very important for signalling research. Cryo-EM provides a true image of the individual molecule, as opposed to the indirect scattering and spin data of crystallography and NMR (nuclear magnetic resonance). I use the transmission electron microscope (TEM) for frozen samples of purified proteins (single particle EM) or for extremely thin snap-frozen tissue sections (tomographic EM). I've been using the technology since 2008, even before many research groups started working with it around 2012 - before it became cool, so to speak. Ideally, today you not only see individual molecules like receptors or antibodies in the highest resolution, but even how they react to signals and change. And with your own eyes! I find that fascinating.

Why is Freiburg and the CIBSS the right place for your research?

I am very pleased to be able to establish exciting collaborations in the Cluster of Excellence for my own research, and to contribute my expertise to the CIBSS projects. The many different disciplines represented at CIBSS can also help in the evaluation of the images. Expertise in machine learning and artificial intelligence algorithms are becoming increasingly important for electron microscopy. I am looking forward to making new connections in this area. My research focus is on the ubiquitin-proteasome system, which is a central component of many signalling protein networks - this is a great fit with the research approach at CIBSS.

What is a molecular machine?

Some proteins form complexes in the cell or in the cell membrane that can convert chemical energy and thermal noise into mechanical energy. They are often compared to technical machines like engines, but I find the image misleading. Because these molecular machines do not function like diesel engines with a fuel that then drives the vehicle. A well-known example of a molecular machine is the ribosome or the proteasome. These complexes assemble the proteins of the cell based on the information of the RNA or degrade them again when they are no longer needed. However, we know very little about the principles of action of many such machines! Many signals in the cell proceed via a mechanical change in one or more proteins: a chemical reaction or thermal noise alone causes a rearrangement of the atoms in the protein. On the other hand, only a movement enables the chemical interaction with a signalling substance, for example because the movement creates new binding surfaces. This is different from the macromolecular realm. Mechanics and chemistry are actually inseparable on this scale.

What are you looking forward to in Freiburg?

Freiburg is in the exceptional position of being ideally connected locally and internationally in the “Dreiländereck” – the border triangle. There are also very exciting cooperation opportunities and groups in the universities and research centres in the region with whom I am already looking forward to establishing contacts. Basel or Strasbourg are just as close to Freiburg as my laboratory in the centre of Vienna is to my current high-performance EM in Lower Austria. A stone's throw away.

For more information:

https://www.imp.ac.at/groups/david-haselbach/