Interview with Stefan W. Hell

The 2010/11 winner of the Gothenburg Lise Meitner Award, Stefan W. Hell, talks to Gothenburg Physics Centre Update about his life in science and how STED Microscopy has affected fields of science.

What are your thoughts of both receiving the Otto Hahn Preis 2009, and the Lise Meitner Prize 2010/2011?

I feel very much honored by receiving the Lise Meitner prize. At the same time, I appreciate the fulfilling life that I am having by being a scientist. These awards also remind me of the impact scientific discoveries can have. I have great admiration and respect for Lise Meitner and Otto Hahn. At that time, only experts realized that nuclear fission was a discovery with major consequences. One can say with both good and bad ones, although I believe Otto Hahn and Lise Meitner conducted their research out of curiosity, led by the wish to explore the scientific truth. Since it is conferred here in Gothenburg, the Lise Meitner prize also reminds me about her hardship resulting from the fact that she was forced to leave her working place in Berlin. She had devoted much of her life to physics and so it must have been difficult for her to leave the unique scientific environment that she had created with Hahn in Berlin. I also started my research out of the fascination with solving a longstanding physics problem. And along the road, I realized how important the solution of this problem would be for other fields. Receiving recognition for scientific contributions also encourages one to further conduct research with the goal of expanding our knowledge and improving our well-being.

How did you get involved in the project that would result in STED Microscopy, and how would you describe the particular challenges, setbacks that you encountered along the way?
I studied physics because I was fascinated with understanding the basic laws governing nature. And like many of us physicists, I was attracted by their inherent beauty and simplicity. I also believed that in order to be profound, solutions to a problem must be clear-cut and simple. It was along this road of beauty and simplicity that I became fascinated with breaking Abbe’s diffraction resolution barrier, which later resulted in STED microscopy and its variations.

Apart from hearing about it in physics courses, I first came in contact with Abbe's barrier when I was doing my doctoral thesis. My supervisor Siegfried Hunklinger, a solid state physicist, had just set up a high-tech company developing laser scanning microscopes for optical lithography. Although we had initially agreed on a subject in solid state physics, he eventually asked me to tackle a topic which was more related to the company's efforts: the inspection of lithographically written microstructures by confocal light microscopy.

After about a year, I felt misplaced and had thoughts about giving up this rather technical subject.  As a matter of fact, I secretly shopped around for a different doctoral thesis in other labs that would involve more 'modern' physics. At the same time, I began wondering if one could still make a fundamental contribution to this 'physics subject of the 19th century' called light microscopy. Not surprisingly, this was cracking Abbe’s diffraction barrier. The resolution of light microscopy had not really improved for about a hundred years and I increasingly felt that this matter was not closed. In particular, after a while I became convinced that the massive knowledge about molecular states and transitions that has emerged in the 20th century would eventually allow us to overcome this barrier - at least for fluorescence imaging. However, since fluorescence imaging and the resolution in general were not within the scope of my thesis, I had to wait until my PhD was completed. So I decided to look into the resolution problem right after my PhD.

In any case, at this point I felt that light microscopy may not be that dull after all, and still offer some room for doing something interesting and surprising. So I happily completed my thesis in 1990 - and began to work on the resolution subject right afterwards. Initially I did it at my own risk. First I looked into improving the resolution along the microscope axis using two opposing lenses. Although that was still diffraction-limited, it gave me some lead time to find a more fundamental solution, i. e. to get an idea that really breaks the barrier. So I began screening books and papers on molecular spectroscopy and quantum optics in search for a key molecular transition or phenomenon that would improve the resolution fundamentally. After I had looked into many options, I came across stimulated emission. And that marked the beginning of STED.

Did you ever think of giving up?
Most people were skeptical and hardly anyone believed that the idea of light microscopy with diffraction-unlimited resolution would ever become reality. This disbelief can still be read from a simple fact: STED microscopy was published in 1994 as a theoretical proposal. The paper was written like a recipe. However, nobody tried to implement it, despite the fact that the concept promised a major improvement. I could not have easily done it myself, since I was in Turku/Åbo in Finland at that time with comparatively limited resources. I had left Germany because I could not find a place or a job to pursue the idea of improving the resolution. Applying for a research grant was not possible either, because I did not have a laboratory. I also did not have a mentor. In this situation, it was particularly dangerous to be perceived as a `dreamer´. I had to avoid generating the impression of promoting unrealistic ideas. Between spring 1994 and 1997, I presented the concept of STED microscopy as well as a related concept at many conferences around the world. Still most people remained skeptical. In this period, the risk of dropping out was quite high.

How did you manage to overcome the setbacks?
I managed to get another stipend, an EU Marie-Curie fellowship, and also some money from a local company in Turku, in exchange for a patent license. I could thus proceed. I was convinced that the concept is very basic and hence very strong. And that the hurdles would be merely technical - not conceptual. I was always of the opinion that if the underlying concept is sound, the chance of surmounting the technical hurdles is high. Technical issues can also be surmounted by improved technology which may improve over time, whereas conceptual problems remain. In my view it is very important to keep these two things apart. In any case, I felt that the basic physical idea underlying STED and the idea of overcoming the diffraction barrier in fluorescence microscopy was simple and compelling: Features can be discerned from their neighbors by disallowing these neighbors to fluoresce. I was convinced that this is a very powerful concept.

Would this discovery ever be made if it was not for you?
This is impossible to tell. Probably yes but then it would be difficult to say when the discovery would have been made. Perhaps 10 or 15 years later. We will never know. In my view, the insight that one can realistically overcome the diffraction barrier was not expected. It was not in the air. Otherwise it would not have taken so much time for this idea to get accepted.

What impact has STED Microscopy had in the medical field?
I think that STED Microscopy and the possibility to perform fluorescence microscopy with nanoscale resolution will transform the life sciences and the biomedical field. More than ever, I believe that noninvasively recording e.g. protein distributions and interactions at their relevant scales - which is the nanoscale- will greatly widen our knowledge about diseases at their most basic level. My optimism is based on observations in my own laboratory. I can witness how guest researchers from different fields come up with new insights simply because they get sharper data.

How would you change the world with the help of science?
I think it is very important that established scientists offer excellent working conditions to enthusiastic young researchers. I see it like a risk capital investment. Not all of them may succeed, but if one out of ten makes a major difference, that would be a fantastic outcome. I am somewhat less fond of planned grant proposals in the mainstream of science. They may restrain curiosity, spontaneity, and the element of surprise.

I also believe that scientific discoveries are the most relevant and lasting advancements made by mankind. As we know from those of Lise Meitner and Otto Hahn, discoveries can indeed be misused. On the other hand, I am convinced that our advancements in welfare, human rights, and personal freedom are ultimately based on our fundamental advancements in science and on the groundbreaking inventions that have been made as a result to meet our needs.

Interviewer: Cristophe Eléhn

Page manager Published: Sat 11 Oct 2014.