INTERVIEW

Ursula Egner

Interviewed by Laura Spinney

Posted September 14, 2001 · Issue 110

Background

Biography
In 1977 Ursula Egner went to the University of Heidelberg to study physics and in particular spectroscopy, moving to the Max Planck Institute for Medical Research, also in Heidelberg, to carry out her thesis on X-ray structure analysis of proteins. After gaining her PhD at the University of Freiburg she moved to the lab of the well-known X-ray crystallographer Wolfram Saenger, at the Free University of Berlin, where she also studied molecular modeling and bioinformatics in a position funded by Schering AG. The Berlin-based pharmaceutical company had decided to support the post because in the early 1980s there was nobody at Schering with any knowledge of protein structures. Egner remained in Saenger's lab for five years, until 1991, then moved full-time to Schering where she has since developed macromolecular modeling for use in structure-based drug design. After a recent reorganization at the company she is now in the process of building a new structural biology group.

What event led you into research?

That was very funny. At the University of Heidelberg the X-ray structure analysis of proteins belonged to biophysics, which was part of the biology department. So being attached to the physics department I didn't come across it. Then I moved to the Max Planck Institute for Medical Research, where things were organized differently. I found that to get to spectroscopy I had to go through the X-ray structure analysis group. They had posters on the wall, and I had a look at the posters and found the research very interesting. I got side-tracked on the way to spectroscopy! After that, I got the permission of the professors in the X-ray structure analysis group to get involved in some practical work, and that's how it started.

Who has most inspired and/or influenced your work?

Some of the ancient Greeks, for example the philosopher Heraclitus. He said, if you don't expect the unexpected, you will never find the unexpected. I am inspired by people who fought for their ideas, and that has been my guiding philosophy, because the unexpected is not easy to find. When I started to work in crystallography, everybody told me, if you study crystallography you won't find a job. Nobody works on crystallography, they said, it has no future. Now you see its uses in structural biology, but you would never have expected that. My work has also been influenced by a number of papers, including one on the first crystal structure of a nuclear receptor ligand-binding domain, the RXR-alpha ligand-binding domain. This paper marked the beginning of a long and outstanding collaboration with Dino Moras from the University of Strasbourg, and it was also when I joined the research field of nuclear receptor ligand-binding domains.

What was your best experiment?

That is a difficult question for someone who works in industry, because you can't reveal everything you'd like to. But I would say the structure I was most excited about was the androgen receptor ligand-binding domain. We solved that two years ago with our collaborators at the University of Lisbon. We were allowed to publish it last year, in the Journal of Biological Chemistry. It was the first structure of the androgen receptor ligand-binding domain, and the androgen receptor is very important for cancer research, for example. Until then only the structures of two other steroidal ligand-binding domains were known, that of the estrogen receptor and that of the progesterone receptor. At the same time that we published the androgen receptor with a ligand we also published the progesterone receptor with the same ligand. That's important because if you want to develop a drug that targets only the androgen receptor and not the progesterone receptor, you have to know what drives the specificity of a given ligand for a given binding site.

What is the biggest obstacle to your work?

Crystallization. You have to attempt many, many crystallizations of a protein until you get crystals that diffract well, which is the key to X-ray structure analysis. You also have to experiment with many different crystal forms until you get ones that allow you to add ligands without the crystals cracking. So I am disappointed about all the crystallizations that haven't worked out. It's an ongoing depressing experience!

Which scientific idea (yours or others') do you regret the most?

It has nothing to do with my field, but I regret the development of the hydrogen bomb. I remember when I was quite young seeing pictures on the TV of children running in the streets, severely injured.

What are your scientific plans for the next 5 years?

I would like to build up a successful structural biology group at Schering. That involves X-ray structure analysis and modeling, but it also involves target assessment. That means that you provide your colleagues in drug design with all the information that structural biology can yield about a given protein target - for example, is it similar to other proteins in the field? Is there a structure? Has it a binding site? Can I develop a small molecule to fit that site? Is it, ultimately, "druggable"? We will be focusing on a wide range of proteins: nuclear receptor ligand-binding domains and kinases, to name but a few.

What are the qualities of a successful researcher?

Curiosity, patience. I am a convinced teamworker. You have to share ideas and persuade others to participate in your project, to see the benefits it will have for them and for the company. At Schering, work on proteins is organized in project groups, and I have sometimes been the head of such project groups. That involves convincing people in other groups to provide the protein to crystallize, to synthesize compounds - and generally getting them on your side.

If you could work with any scientist (historical or current), who would it be?

Andrew Wiles, the mathematician who solved Fermat's Last Theorem. Again, he was somebody who fought for his ideas, against all the odds, and who was convinced a solution could be found. It would be interesting to see how he tackled some of the questions confronting us in structural biology.