³Ô¹ÏÍøÕ¾

Mathias Grote, science historian and Heisenberg Fellow at Humboldt University, talks with Dieter Oesterhelt about his research

For the series “Lives in Chemistry”, Mathias Grote, science historian and Heisenberg Fellow at Humboldt University, spoke with Dieter Oesterhelt about his research. With the consent of the publisher, we are publishing an excerpt from the interview in advance. The book will be published in the spring of 2022 in German.

Mathias Grote: Bacteriorhodopsin, the molecule that essentially defined your career, was discovered in San Francisco. In 1970, you brought this completely new research topic to Munich. You were the only one in Germany working on this topic. How did you deal with the uncertainty of whether this venture into the unknown would lead to anything?

Dieter Oesterhelt: I was met with everything from disinterest to complete disbelief from colleagues. But it was clear to me that there must be something important behind the colour change of this molecule from purple to yellow that I had observed in the test tube. And I stood by this conviction. Feodor Lynen, my doctoral supervisor at the Department of Biochemistry of the University of Munich and Nobel Prize winner, wasn’t particularly enthusiastic about this new topic either. But he let me do it because he had the attitude that habilitation candidates should seek out their own topics and work on them independently. After I had sketched my theory of the biological function of the new molecule on the blackboard, he told me: “Mr Oesterhelt, I don’t believe that. But I wish you were right”. The situation changed rapidly after 1972, when I collected the first data on the function of this molecule and showed that it was a pump that converts light energy into chemical energy for the cell – essentially a new form of photosynthesis. From this point on, this discovery generated considerable interest.

What plans and projects were proposed to develop technologies based on this “molecular pump”? And what became of them?

Essentially, four experiments can be distinguished: As early as the 1970s, in the wake of the oil crises, people were thinking of using this molecular pump to harness light energy through a sort of artificial photosynthesis. But these ideas never went beyond the planning stage. In the mid-seventies, we looked into the possibility of using the pump to desalinate seawater. But nothing came of that either. In the 1980s and 1990s, attempts were made to use the substance as an optical data storage medium, which would be written to and read from with a laser – something like a compact disc. There were several such projects worldwide – interestingly also in the Soviet Union. We pursued this intensively together with the physicist Norbert Hampp from the Universities of Munich and Marburg. The potential of these applications was fascinating. Hampp showed me for the first time how a remote-controlled car could be directed with bacteriorhodopsin! There were tremendous effects. For example, in the field of material testing. Using interferometry, it was possible to detect cracks in a weld seam with this molecule. The technology worked. But after a certain point, the interest dwindled. After 2000, the bacteriorhodopsin-related light-sensitive pump halorhodopsin and the channelrhodopsin discovered by Peter Hegemann was introduced into tissue using genetic engineering. Karl Deisseroth and his colleagues successfully applied this to neurons and thus initiated the birth of a new field of research: optogenetics. This entails activating nerve cells with light and switching them off again with light of a different wavelength. This time span of almost 40 years illustrates the staying power it takes to develop technologies from scientific findings and that even functioning technologies cannot always find a market.

Describe the path from your research on halorhodopsin to the first optogenetic experiments. What steps were important for this?

This development began in our department with the doctoral thesis of Peter Hegemann. In the early 1980s, he set himself the goal of isolating halorhodopsin – extracting it from the cells and purifying it so that it could be characterized using chemical and physical methods. Halorhodopsin is a molecular pump similar to bacteriorhodopsin. However, not for hydrogen ions but for chloride ions. Peter Hegemann was incredibly tenacious and made some important discoveries. For his efforts, he received the Otto Hahn Medal of the Max Planck Society. He then went to the US as a post-doctoral fellow. I had promised him that he would then get a five-year position as head of his own group in my Department at the MPI of Biochemistry. In Ken Foster’s group, he looked for comparable proteins in algae and found that they functioned more like molecular channels than a pump. However, they can also be targeted with light. He then relentlessly pursued this topic with us for five years and at the University of Regensburg in the nineties. This led to the discovery of channelrhodopsins. The first optogenetic experiments took place in 2005. This is where the neuroscientist Karl Deisseroth, the third winner of this year’s Lasker Award, comes into play. He was primarily concerned with how these molecular tools could be applied in nerve tissues. Here too, it becomes clear how much staying power scientists need in order to push forward a new development from a self-imposed goal of basic research!

At what point were you able to imagine that the light-sensitive molecular pumps you discovered could be used as molecular tools in neuroscience and medicine?

Frankly, never. The research in our department simply took a different direction. We did not do the necessary electrophysiology and instead focused more on understanding the molecular mechanism of these pumps, which functioned as light energy converters and sensors in the cell. We later used techniques from genomics and systems biology. In this respect, the application in optogenetics was not my interest, even though some of the necessary basics were researched by us – but with a different objective. I later saw a spectacular experiment by a Frankfurt group. The video showed the model organism Caenorhabditis elegans contracted when illuminated after the light-sensitive channels from algae had been genetically introduced into its muscle cells. This study was a vivid reminder to me of the potential of optogenetics – what would become possible if these pumps and channels were built into nerve tissue or sensory cells. And then it really took off – but you would have to ask Peter Hegemann and Karl Deisseroth about the details of this research because that happened after my active time.

The discovery of bacteriorhodopsin in San Francisco was also essentially based on a chance observation of a specially coloured substance and was not on the path of your actual research project. Why should one pursue such observations? If you think in terms of careers or applications, such digressions can also prevent you from achieving pre-set goals.

For me, the answer is always simply: out of pure curiosity. When I find a question I can’t answer, I want to know. Not with every question. Because my curiosity relates to phenomena that can most likely not be explained. Curiosity paired with novelty – that has always fascinated me. I started observing nature carefully as a child and then later in experiments in the laboratory. Whether this succeeded or failed was certainly satisfying or disappointing. But it didn’t really matter. What was important were observations – above all the unexpected – apart from mistakes such as false assumptions or approaches. In moments like these, something like a “feeding frenzy of curiosity” set in: “Why is that? What’s behind it? Why did I observe that?”

An experimental strategy involving chance has a different temporal structure than systematic experimentation because it does not center on predetermined projects but rather consists of unforeseen observations that may become meaningful or be investigated only much later or in a different context.

Exactly – I never shied away from revisiting some observations. I always kept everything in mind. I looked to see whether a problem, a find, or something similar fitted a student who wanted to pursue a doctoral thesis. Of course, systematic work remained just as important and was complementary to random observations. All our research on halorhodopsin, a central “light switch” in optogenetics, was systematic. I knew we had to get the structure of the molecule because I wanted to compare this chloride pump with the proton pump bacteriorhodopsin. Seeing the minute differences between the two was fascinating as were the transformations of one molecule of certain functionality into the other: from a proton pump into a chloride pump and vice versa. All of this was systematic experimentation. Also in terms of quantity, systematics outweighed chance. I cannot emphasize enough how important it is always to be open to chance, and to keep pursuing even that which at first may appear to be insignificant.”