A nanoscopic look at gene regulation

Johannes Stein joined the MPIMG in 2025. His lab will use state-of-the-art microscopy techniques to examine the organization of the genome at a molecular level. We talked to him about how, despite being a trained physicist, he ended up in biology, the importance of his research and the power of interdisciplinary teams. 

Johannes, what will your lab work on?

We want to understand how gene activity is physically controlled inside living cells. Even though nearly every cell in our body contains the same DNA, different cell types behave differently because different sets of genes are turned on or off inside the nucleus. Our lab studies how DNA, RNA, and proteins come together in space to control gene activity - especially during processes such as transcription and RNA processing. We are particularly interested in how these processes relate to the three-dimensional arrangement of DNA in the nucleus: does genome folding help guide gene activity, and can gene activity reshape genome folding? To study this, we develop super-resolution microscopy methods that allow us to directly observe these molecular interactions inside cells with a level of detail that was previously inaccessible.

Why is that important? What will people ultimately gain from this research?

Many diseases arise when gene regulation fails. In cancer, for example, genes that should remain silent become active, while protective programs shut down. In neurological disorders, cells can no longer maintain their identity or function properly. We often still do not know why this happens because the relevant processes occur at the molecular scale and are largely invisible with conventional methods. 
By directly observing how genome regulation works inside healthy cells, we can understand how it breaks down in disease. In the long term, this knowledge can contribute to more precise diagnostics and targeted therapies. At the same time, the technologies we develop provide new tools for biomedical research and biotechnology.

You are trained as a physicist. Why did you decide to move into biology?

If you really look at a cell at the molecular level, biology becomes an interplay of many disciplines. Structural biology, chemistry and biochemistry describe how biomolecules are organized and interact – and these are ultimately governed by physical principles.
Physicists often try to precisely measure and perturb systems in order to understand the rules that regulate their behavior. Applying this way of thinking to living cells, and building new instruments that allow us to actually see molecular organization, fascinated me and drew me into biology.

Are physicists the better biologists?

I don't think so because biology is so vastly complex and physicists are usually bad at remembering things. [laughs] But on a serious note, I think to tackle the big open questions of modern biology, interdisciplinary teams are needed with a mix of biologists, physicists and computer scientists. I greatly enjoy working with biologists in my team and across the institute to complement our expertise and think we can learn a lot from each other.

You recently transitioned to an independent group leader and now need to recruit a team. What kind of lab do you want to build?

I want to build a collaborative and supportive environment with passionate and kind team members. You don’t need extensive microscopy experience to contribute
No specific technical background is required to learn our imaging approaches – we warmly welcome biologists, biochemists and bioengineers who are excited about diving into genome biology. At the same time, we will also pursue nanotechnological projects that develop the next generation of nanoscale imaging tools. My goal is that trainees leave the lab not only with strong scientific skills, but as excellent candidates for careers in both academia and industry.

Assuming everything works out perfectly, what would you like to have discovered in ten years?

I would like to have contributed to understanding how spatial organization inside the nucleus controls gene activity and to uncovering the rules by which the genome operates in living cells.
At the same time, I hope the technologies we develop can become widely used tools in biomedical research. The ability for both researchers and clinicians to routinely observe disease-relevant processes at the molecular level could mean a shift toward earlier and more precise diagnosis, and ultimately support the development of more targeted therapies.