Prize recipient 2024 | Jesper Qualmann Svejstrup

What is your research about?

For many years, my laboratory has studied the molecular 'machine' that reads (transcribes) our genes, namely RNA polymerase II (RNAPII), and all the processes that surround its function.

All the cells of the body carry the same genetic material, so it is the specific genes that are transcribed by RNAPII that define the individual cell type and its characteristics. If the cell-specific regulation of transcription goes wrong, it may result in serious pathology. The research we do is thus highly disease-relevant, not least for cancer and neurological diseases.

Transcription takes place in several tempi, regulated by cofactors and protein modifications, depending on where in the process RNAPII is active. We study these complex time and place sensitive modifications and interactions, and also what happens when cells are exposed to stress, such as cancer-causing UV radiation. Even when cells are not exposed to stress, transcription is actually a risky process for the cell, as it can generate genome instability and mutations. We are thus also studying the interplay, or counterplay, between transcription and the maintenance of genome the stability.

What are the challenges and prospects for your research?

I am driven by a curiosity of how life works at the molecular level. Indeed, I started out using biochemistry to understand the molecular machines and their basic functions. Over time, it has become possible to combine this with studies inside living cells. Techniques in genome sequencing have also evolved and opened up new possibilities, and we now use these to understand transcription as part of cellular feedback loops with other processes, such as protein production. Our aim is always to answer big fundamental questions.

When studying fundamental mechanisms, you never know where the results will lead you. My laboratory has thus often 'stumbled upon' answers to why certain diseases develop. It wasn't necessarily what we were looking for, but we made a very important discovery. Likewise, in the broad, historical perspective, it is primarily in fundamental research that the really big discoveries happen, sometimes by chance.

How did you become interested in your research field?

I had no idea what I wanted to study until was in my 2nd year in high school. Then we learned about cells and DNA, and my path was immediately clearly laid out. I studied Biology at Aarhus University, which involved the whole palette from animals and plants to genetics and biochemistry, but I knew that I wanted to specialize in the molecular part.

I did my PhD with Docent Ole Westergaard at the Institute of Molecular Biology. Ole created a fantastic research environment and it was a very formative time, where I used biochemistry to study Topoisomerases; enzymes that change DNA topology. During these studies, I became interested in more biological questions around DNA, and so it was natural to become attracted to studying transcription.

As a postdoc, I worked with Professor Roger Kornberg at Stanford and the years I spent there were truly transformative. I have continued to study transcription ever since, and there is still much to learn, especially because the process is so complex and disease-relevant.

What are the greatest insights or discoveries you have made?

Some of my earlier discoveries may have been quite groundbreaking, but I am always proudest of the latest ones. I am not young, but I rarely look back as I feel there is still much to learn. If I had to describe what my laboratory is best known for, it is probably the discovery of the lengths to which cells will go to ensure genome stability.

RNAPII is, in a way, the origin of all proteins. It can be argued that RNAPII itself is the cell's 'most important' protein, as it enables the formation of all other proteins. It has thus always been thought that cells contain plenty of RNAPII and that it is very stable. Our research shows that this is not the case. In fact, cells have only just enough RNAPII to function, and RNAPII is often rapidly degraded, in a tightly regulated manner, when there are problems with transcription. We have thus made fundamental contributions to understanding how and why cells constantly 'sacrifice' their important RNAPII so that genome stability can be maintained.

What does it mean to you to win the Carlsberg Foundation Research Prize?

I left Denmark in 1996 to do a postdoc at Stanford University. I thought it would just be a few years before I was back, but I have actually spent most of my research career in England.  I have received much support and recognition there over the years, but I have always been closely connected to Denmark, and it is a very great honour to be recognised in this way in my own country, now that I am finally back. I am extremely proud to receive the Carlsberg Foundation's research award.

The award not only means a lot to me personally, but also to my laboratory, as it gives us the opportunity to do things we probably wouldn't be able to do otherwise. Funding such as this, which has much less restrictions in its use, means that we can initiate projects that are even more ambitious and imaginative than those for which we already have grants.