- Email: [email protected]
An Interview with Harald H. Sitte
TrendsTalk
An Interview with Harald H. Sitte
Harald H. Sitte is Professor of Psychopharmacology at the Medical University in Vienna, Austria, Center of Physiology and Pharmacology. Early in his career as a medical student, Dr Sitte learned about the enigmatic mechanistic understanding of the action of psychostimulants such as amphetamine. Soon after, he got interested in basic neurochemistry and neurodegenerative disease. However, the mechanism of amphetamine action – and various congeners – never really left his scientific focus. Furthermore, he assessed the importance of regulatory kinases for amphetamine’s effects in vitro and in behavioral pharmacological experiments. Apart from the work on psychostimulants, Dr Sitte examined the behavior and functional role of oligomerization of various neurotransmitter transporters. A scientific visit to the Panum Institute (Professor U. Gether) in Copenhagen, Denmark initiated his interest in protein biochemistry and fluorescence spectroscopy. Based on this work, he and his team started to explore bacterial homologs of neurotransmitter transporters on an atomistic level. More recently, his lab became interested in the interplay between membrane lipids and their impact on transporter function as well as on their oligomeric properties; again, amphetamines were part of this research work.
How did you become interested in studying neuropsychopharmacology? I was always fascinated by the brain and how it works. However, my interest in pharmacology was piqued during my medical studies. One example I recall vividly was during a clinical traineeship in the Department of Surgery at the Charité in Berlin, Germany. Here I attended an abdominal operation and witnessed the pharmacological stimulation, and subsequent initiation, of bowel movements at the end of the surgical procedure. I was truly fascinated to see the immense power of pharmacology, live and alive! But my immediate interest always focused on the brain and its neurotransmitters. This interest was strongly augmented during my medical thesis studies, which focused on the dopamine-releasing activity of neuropeptides in the striatum of freely moving rats. As a control compound, we used amphetamine. This was my first experimental encounter with sympathomimetic psychostimulants. At that time I was preparing for my pharmacology exam. I simply could not find an acceptable explanation for the mechanism underlying amphetamine-induced substrate efflux in my textbooks. This knowledge gap captured my intense interest. To this day, understanding the mechanisms of action of psychostimulants continues to be a central theme of my research.
Why did you focus in particular on monoamines? During the end of my doctoral studies and medical thesis, I was approached by Professor Oleh Hornykiewicz, one of the eminent researchers in the field of dopamine research. He asked whether I wanted to join him at the Institute of Biochemical Pharmacology in Vienna. Honored by such an invitation, and eager to join his lab because of its strong focus on neurodegenerative disease and monoaminergic neurotransmitters, I was quick to complete my doctoral studies. In Professor Hornykiewicz’s lab, I was fascinated
learning about Parkinson’s disease, amyotrophic lateral sclerosis, and other diseases – but also about NMDA receptors and monoamine transporters. It was a very stimulating environment for me, where I was a sponge, absorbing as much information as possible. The close contact with Professor Hornykiewicz certainly supported my lasting interest in monoamines. I was truly intrigued by the logical sequence of his observation of dopamine loss in Parkinson’s towards the development of treatment with LDOPA. The medical relevance of his research played an important role in shaping my thinking. Put simply, for me, medical relevance justifies the entire reason for doing research!
Part of your work has concentrated on psychostimulants, which can be used therapeutically and also be abused. How do you view this tension between help and harm when it comes to these drugs? First it is worth highlighting that this yin– yang between therapeutically beneficial and harmful effects of drugs is not limited to psychostimulants. In fact, this is not an uncommon phenomenon in medically relevant drugs. However, the case with sympathomimetic psychostimulants and similar drugs is especially problematic, in part because of the ease with which these drug can be obtained illicitly and in part because of the advent of the socalled ‘new psychoactive substances’ (NPS), or ‘research chemicals’. These psychostimulants pose new challenges to research, clinics, and legislation. NPS are synthesized by rogue chemists who circumvent legal boundaries by making subtle changes in the structure of illegal drugs. However, unlike drugs used clinically, NPS are completely untested and therefore pose considerable health threats. For instance, 4,4-dimethylaminorex (DMAR), also known as ‘Serotoni’, has already led to the deaths of more than 30 users in the UK and Poland. With more and more NPSs flooding the market in an
Trends in Pharmacological Sciences, December 2017, Vol. 38, No. 12
1039
unpredictable and erroneous manner, along with their unknown toxicity, it is of utmost importance for neuropharmacology research to keep pace with understanding their mechanisms of action and toxicity profiles. The ‘tension between help and harm’ of psychostimulants is indeed a fine balance and one that has always fascinated me. How can drugs with such therapeutic benefits on the one hand be so harmful on the other? Clearly the answer to this question is complex. However, it is crucial that we fully understand the mechanisms of actions of psychostimulants, and the subtle differences among them, if we are to realize drugs that are therapeutically beneficial (‘help’) but lack abuse potential (‘harm’).
this advice and encouraged me to be open to new avenues, especially in the case of novel techniques. However, perhaps the most useful practical advice came from my early mentor Oleh Hornykiewicz. I had just obtained my first dataset in his lab and enthusiastically approached Professor Hornykiewicz to discuss the result. He briskly rejected talking with me about my experimental data and told me to come back once I had a sample size greater than 1! His comment was most impactful, making me take a step back and learn to think twice before running.
What’s the best scientific advice you’ve ever been given?
The best part of a life in scientific research is the freedom to choose and follow whatever is interesting and challenging to you – and then to transmit that ‘fire’ in scientific discovery to the new generation of scientists. Nothing is more gratifying than watching a trainee pick up the ‘torch’ and move dauntlessly into the unexplored. There are also other, more cumbersome roles that ‘decorate’ the life of a scientist; for instance, the everlasting need to obtain funds to support one’s
‘Move forward and try it!’ said my fatherin-law. This was one of the greatest pieces of advice I have ever received – even if it was given by a non-scientist! It motivated me to find out for myself whether a clinical–medical career or a career as a researcher was best for me: deciding on the latter, I also applied this advice to launching my scientific career. My mentor, Misha Freissmuth, extended
1040
What do you think is the best part about choosing a life in scientific research? The most challenging part?
Trends in Pharmacological Sciences, December 2017, Vol. 38, No. 12
research program, a process that is becoming increasingly challenging for all of us these days.
Tell us something about your work that is exciting for you right now. Right now, I am extremely excited about the atomistic detail in which we can study monoamine receptors and transporters. This is very rewarding in terms of how rapidly this level of detail can advance our field to understand more about the intricate molecular mechanisms of drug binding and action at these clinically relevant proteins. Also of great excitement is the enormous increase in translational research, which is close to my heart for its direct medical relevance. Translational research is the only way to explore and establish novel treatment options for nonresponding patients and the provision of treatment for the untreated. The quest right now to understand basic mechanisms and translate these into the clinic is of utmost importance. Directing our vision to advance findings from bench directly to bedside is the most exciting aspect of my research right now. https://doi.org/10.1016/j.tips.2017.10.001
An Interview with Harald H. Sitte
Harald H. Sitte is Professor of Psychopharmacology at the Medical University in Vienna, Austria, Center of Physiology and Pharmacology. Early in his career as a medical student, Dr Sitte learned about the enigmatic mechanistic understanding of the action of psychostimulants such as amphetamine. Soon after, he got interested in basic neurochemistry and neurodegenerative disease. However, the mechanism of amphetamine action – and various congeners – never really left his scientific focus. Furthermore, he assessed the importance of regulatory kinases for amphetamine’s effects in vitro and in behavioral pharmacological experiments. Apart from the work on psychostimulants, Dr Sitte examined the behavior and functional role of oligomerization of various neurotransmitter transporters. A scientific visit to the Panum Institute (Professor U. Gether) in Copenhagen, Denmark initiated his interest in protein biochemistry and fluorescence spectroscopy. Based on this work, he and his team started to explore bacterial homologs of neurotransmitter transporters on an atomistic level. More recently, his lab became interested in the interplay between membrane lipids and their impact on transporter function as well as on their oligomeric properties; again, amphetamines were part of this research work.
How did you become interested in studying neuropsychopharmacology? I was always fascinated by the brain and how it works. However, my interest in pharmacology was piqued during my medical studies. One example I recall vividly was during a clinical traineeship in the Department of Surgery at the Charité in Berlin, Germany. Here I attended an abdominal operation and witnessed the pharmacological stimulation, and subsequent initiation, of bowel movements at the end of the surgical procedure. I was truly fascinated to see the immense power of pharmacology, live and alive! But my immediate interest always focused on the brain and its neurotransmitters. This interest was strongly augmented during my medical thesis studies, which focused on the dopamine-releasing activity of neuropeptides in the striatum of freely moving rats. As a control compound, we used amphetamine. This was my first experimental encounter with sympathomimetic psychostimulants. At that time I was preparing for my pharmacology exam. I simply could not find an acceptable explanation for the mechanism underlying amphetamine-induced substrate efflux in my textbooks. This knowledge gap captured my intense interest. To this day, understanding the mechanisms of action of psychostimulants continues to be a central theme of my research.
Why did you focus in particular on monoamines? During the end of my doctoral studies and medical thesis, I was approached by Professor Oleh Hornykiewicz, one of the eminent researchers in the field of dopamine research. He asked whether I wanted to join him at the Institute of Biochemical Pharmacology in Vienna. Honored by such an invitation, and eager to join his lab because of its strong focus on neurodegenerative disease and monoaminergic neurotransmitters, I was quick to complete my doctoral studies. In Professor Hornykiewicz’s lab, I was fascinated
learning about Parkinson’s disease, amyotrophic lateral sclerosis, and other diseases – but also about NMDA receptors and monoamine transporters. It was a very stimulating environment for me, where I was a sponge, absorbing as much information as possible. The close contact with Professor Hornykiewicz certainly supported my lasting interest in monoamines. I was truly intrigued by the logical sequence of his observation of dopamine loss in Parkinson’s towards the development of treatment with LDOPA. The medical relevance of his research played an important role in shaping my thinking. Put simply, for me, medical relevance justifies the entire reason for doing research!
Part of your work has concentrated on psychostimulants, which can be used therapeutically and also be abused. How do you view this tension between help and harm when it comes to these drugs? First it is worth highlighting that this yin– yang between therapeutically beneficial and harmful effects of drugs is not limited to psychostimulants. In fact, this is not an uncommon phenomenon in medically relevant drugs. However, the case with sympathomimetic psychostimulants and similar drugs is especially problematic, in part because of the ease with which these drug can be obtained illicitly and in part because of the advent of the socalled ‘new psychoactive substances’ (NPS), or ‘research chemicals’. These psychostimulants pose new challenges to research, clinics, and legislation. NPS are synthesized by rogue chemists who circumvent legal boundaries by making subtle changes in the structure of illegal drugs. However, unlike drugs used clinically, NPS are completely untested and therefore pose considerable health threats. For instance, 4,4-dimethylaminorex (DMAR), also known as ‘Serotoni’, has already led to the deaths of more than 30 users in the UK and Poland. With more and more NPSs flooding the market in an
Trends in Pharmacological Sciences, December 2017, Vol. 38, No. 12
1039
unpredictable and erroneous manner, along with their unknown toxicity, it is of utmost importance for neuropharmacology research to keep pace with understanding their mechanisms of action and toxicity profiles. The ‘tension between help and harm’ of psychostimulants is indeed a fine balance and one that has always fascinated me. How can drugs with such therapeutic benefits on the one hand be so harmful on the other? Clearly the answer to this question is complex. However, it is crucial that we fully understand the mechanisms of actions of psychostimulants, and the subtle differences among them, if we are to realize drugs that are therapeutically beneficial (‘help’) but lack abuse potential (‘harm’).
this advice and encouraged me to be open to new avenues, especially in the case of novel techniques. However, perhaps the most useful practical advice came from my early mentor Oleh Hornykiewicz. I had just obtained my first dataset in his lab and enthusiastically approached Professor Hornykiewicz to discuss the result. He briskly rejected talking with me about my experimental data and told me to come back once I had a sample size greater than 1! His comment was most impactful, making me take a step back and learn to think twice before running.
What’s the best scientific advice you’ve ever been given?
The best part of a life in scientific research is the freedom to choose and follow whatever is interesting and challenging to you – and then to transmit that ‘fire’ in scientific discovery to the new generation of scientists. Nothing is more gratifying than watching a trainee pick up the ‘torch’ and move dauntlessly into the unexplored. There are also other, more cumbersome roles that ‘decorate’ the life of a scientist; for instance, the everlasting need to obtain funds to support one’s
‘Move forward and try it!’ said my fatherin-law. This was one of the greatest pieces of advice I have ever received – even if it was given by a non-scientist! It motivated me to find out for myself whether a clinical–medical career or a career as a researcher was best for me: deciding on the latter, I also applied this advice to launching my scientific career. My mentor, Misha Freissmuth, extended
1040
What do you think is the best part about choosing a life in scientific research? The most challenging part?
Trends in Pharmacological Sciences, December 2017, Vol. 38, No. 12
research program, a process that is becoming increasingly challenging for all of us these days.
Tell us something about your work that is exciting for you right now. Right now, I am extremely excited about the atomistic detail in which we can study monoamine receptors and transporters. This is very rewarding in terms of how rapidly this level of detail can advance our field to understand more about the intricate molecular mechanisms of drug binding and action at these clinically relevant proteins. Also of great excitement is the enormous increase in translational research, which is close to my heart for its direct medical relevance. Translational research is the only way to explore and establish novel treatment options for nonresponding patients and the provision of treatment for the untreated. The quest right now to understand basic mechanisms and translate these into the clinic is of utmost importance. Directing our vision to advance findings from bench directly to bedside is the most exciting aspect of my research right now. https://doi.org/10.1016/j.tips.2017.10.001