Obituary

Johann Caspar Rüegg (1930–2018)

Johann Caspar Rüegg, Emeritus Professor of Physiology and former Chair of the Physiological Institute II of the University of Heidelberg, died January 18th, 2018 at the age of 88 in his home close to Heidelberg after a brief illness. The notice of his passing away was met with great sadness in the muscle scientific community. For many years until his retirement he made important contributions to muscle research, be it smooth, cardiac or skeletal muscle of vertebrates or invertebrates. With his immense breadth of knowledge of the different muscles across the animal kingdom he was an inspiration to many of us. We lost a superb mentor and friend who even after his retirement took great interest in the research of his former scholars. We remember him as a compassionate colleague for whom the advancement of science was the ultimate goal.

Caspar Rüegg was born 1930 in Zurich, Switzerland. Already in his high school years he had a keen interest in biology. So it was quite natural for him to study medicine at the University of Zurich, where he graduated in 1955. While still a medical student he began his scientific career as a doctoral student of the Nobel Laureate W. R. Hess, who was already emeritus. Rüegg, as he remembered, was allowed to set up his apparatus in one corner of Hess’ office to investigate the effect of noradrenaline and adrenaline on the isolated iris muscle, the results of which he published together with W.R. Hess (Rüegg and Hess 1953). He was fascinated by the observation of supersensitivity induced by chronic denervation, and demonstrated that the differences between the denervated and intact smooth muscles were still present in isolated dilatator muscle; the isolated, chronically denervated muscle being 100 times more sensitive to noradrenaline (Rüegg and Langmann 1955). This was the first direct evidence of the plasticity of smooth muscles, and the influence of the nervous system, and also demonstrated his independent mind in finding research questions. In fact, Caspar Rüegg, as he remembered, was much more interested in the action of hormones than on muscle function itself, but soon he realized, that the mechanisms and regulation of muscle contraction were still a “terra incognita”, which stirred his interest and redirected his research interest from hormone action to studying the “machina carnis”.

Caspar Rüegg subsequently went to Cambridge to study biochemistry (1957–1959). He remembered Cambridge as a scientifically vibrant environment where Watson and Crick had solved the structure of DNA a few years earlier. Rüegg was fascinated by the prospect of understanding nature at a molecular level. In the course of his PhD thesis on biochemistry, under the supervision of Bailey in Cambridge (1957–1959), he isolated molluscan tropomyosin (Hanson et al. 1957) and worked on the serotonin sensitive, extremely stretch-resistant prolonged contraction of molluscan catch muscles proposing that it was due to a non-actomyosin based mechanism possibly involving paramyosin (Rüegg 1961, 1971), a notion disputed for a long time. The mechanism of catch was a lifelong interest, but it was only after his retirement that the puzzle of catch was solved. He was very excited when Marion Siegman and Tom Butler showed that phosphorylation of the titin related protein, twitching regulated catch (Siegman et al., 1997, Butler et al., 2001). Their elegant kinetic investigations, and the observation that catch was not inhibited by blebbistatin (Butler et al. 2006, Andruchov et al., 2006), provided compelling evidence that catch force is not maintained by myosin crossbridges but rather by a mechanical link, likely twitchin between thick and thin filaments.

The years of postdoctoral training and traveling (1960–1967)

The next station of his scientific career was the Max Planck Institute for Medical Research in Heidelberg, where he became scientific assistant to Hans-Hermann Weber, director of the Department of Physiology founded by Otto Meyerhof, a mecca of muscle research at that time, and where Wilhelm Hasselbach worked on the Ca²⁺-ATPase of the sarcoplasmic reticulum. Rüegg became acquainted with the mentoring of doctoral students in the spirit of Otto Meyerhof, with rigorous thinking and the clear and elegant use of Hans-Hermann Weber’s German scientific language and, above all, with Wilhelm Hasselbach’s choice of the right model for the respective physiological problem (Hasselbach & Weber 1955, Pharmacological Reviews). Extensive research visits led him to the laboratories of David Bohr (Ann Arbor, Michigan), to Peter Caldwell (Plymouth) and John Pringle in Oxford and many of Caspar Rüegg’s groundbreaking discoveries were from this period of experimentation with his own hands and visits to these laboratories. Giant muscle cells of crabs, smooth muscle cells of the arteries, oscillating insect flight muscle cells, cardiomyocytes and myocytes of the skeletal muscles were examined for their physiological properties. After the respective relevant proteins of the contractile apparatus had been purified and characterized by Rüegg and his PhD students, it was possible to examine the models by biochemical methods. Hasselbach introduced Rüegg into the use of glycerinated fibers. Glycerinization of skeletal muscle had been developed by the Nobel laureate Albert Szent-Györgyi as a means to study the effect of ATP on isolated membrane free contractile structures. It was Rüegg’s great achievement of that time to realize the potential of glycerinated fibers, and to popularize the technology, which is still widely used albeit with multiple modifications, which even allowed delineating the mechanisms of pharmacomechanical coupling in smooth muscle (Kitazawa et al., 1989). He applied this technology to explore the Ca²⁺-dependence of force generation and its modulation by inorganic phosphate and ADP, small molecules such as cyclic nucleotides, and pharmaceuticals of the functionally isolated but structurally intact contractile machinery of a large variety of vertebrate and invertebrate muscles, and to determine the tension cost by simultaneously measuring ATPase activity.

J. Caspar Rüegg, Sir Andrew Huxley, Wilhelm Hasselbach, and Richard J. Paul at the occasion of the international congress on calcium sensitivity modulation of myofilaments in cardiac and smooth muscle in 1995

In the early 1960 understanding the mechanism of Ca²⁺-regulation of contraction was center stage in a number of laboratories around the world. Using the novel Ca-chelators, Annemarie Weber had demonstrated in an elegant series of experiments that Ca²⁺ activated ATPase activity and superprecipitation of crude actomyosin preparations occurred in the micromolar range (Weber 1959). S. Ebashi in Japan discovered troponin and its role in conferring Ca²⁺  sensitivity, and several laboratories made important contributions to identifying the relaxing factor, which was finally identified independently by Hasselbach and Makinose (1961), and Ebashi and Lipman (1962) to be the Ca²⁺-pump of the sarcoplasmic reticulum. During a research visit in Peter Caldwell’s laboratory in Plymoth, Rüegg, who had learnt from Annemarie Weber how to use Ca-EGTA buffers, microinjected EGTA with varying pCa into surviving giant crab muscle fibers, and demonstrated that just as with isolated actomyosin (Weber 1959), contractile activity in the intact muscle was initiated by micromolar concentrations of Ca²⁺ (Portzehl et al., 1964). Importantly, it was concluded from these experiments that the free Ca²⁺ concentration of the resting muscle fiber must be below ~ 0.1 µM. Experiments performed together with Ron Filo in David Bohr’s laboratory using glycerinated mammalian vascular smooth and skeletal muscle, which were published in Science (Filo et al., 1965) and cited more than 1000 times, showed that the threshold Ca²⁺ concentration necessary to elicit a contraction was quite similar in skeletal and smooth muscle, but smooth muscle contraction additionally required Mg²⁺.

From 1964 to 1965 he was senior research officer at the department of Zoology in Oxford on the invitation of John Pringle. Pringle had discovered the myogenic oscillations in intact insect flight muscle, and had found that they were not initiated by action potentials. Together with Brian Jewell and John Pringle, Rüegg discovered that oscillatory contractions triggered by stretching glycerinated, membrane free insect flight muscle fibers from the tropical water bug occurred at low Ca-concentrations, and were thus a property of the contractile machinery, and not due to rapid release and reuptake of Ca²⁺. Rüegg recalled that the discovery was rather fortuitous because they used the slow flight muscles from the tropical water bug which oscillate at 20 Hz, which corresponded to the slow resonance frequency of his myograph. Had they used faster oscillating flight muscles they would have missed it. Furthermore, in switching from relaxing to contracting solutions and back led to contamination of the relaxing solutions with traces of Ca²⁺ necessary to activate the oscillatory behavior. Later they recognized that oscillations at high Ca²⁺ could only be observed if an ATP regenerating system was added. In the next step Rüegg together with Richard Tregear modified his setup so that it was possible to measure the contractile ATPase at different mechanical loads and oscillation frequencies and to determine the efficiency of the machina carnis. (Rüegg and Tregear 1966).

The Bochum years (1967–1973)

In 1967 he was appointed Professor of Cell Physiology in the department of Biology at the newly founded Ruhr University Bochum. In a series of papers he explored the chemo-mechanical energy transformation in insect flight muscle, which was still at the center of his research interests. The force–pCa relationship, and its modification by pH and phosphate were explored in skinned fibers from mammalian heart, smooth muscle but also insect flight muscles. Together with his colleagues Schädler, Steiger and Müller, he demonstrated that phosphate, through a direct effect on the contractile mechanism, inhibited force development. Several publications followed, in which the phosphate effect on the force development in smooth and heart muscle was also documented. As early as 1971, in experiments that were at that time technically extremely sophisticated, he showed that radioactive phosphate is rebound in the working insect flight muscle generating radioactive ATP (Ulbrich and Rüegg 1971). These experiments indicated that the chemo-mechanical energy transformation is reversible, and that there must be the formation of an energy-rich intermediate (actomyosin-ADP) during the contraction process induced by stretching and that this intermediate was assumed to accumulate transiently after stretching. These incorporation experiments predicted the re-binding of phosphate and thus the reversibility of the so-called “cleavage-steps” (Myosin. ATP < - > Myosin. ADP. Pi < - > Myosin.ADP), were groundbreaking. They showed that the myosin cross bridge can leave the force-generating state not only in the “forwards” but also “backwards” direction into the weak binding states. This interpretation can be found in current kinetic schemes and is interpreted in the same way as Rüegg and his colleagues showed in the 1970s.

The Heidelberg years

In 1974 he was appointed Chair of Physiology, and was Director of the Institute of Physiology II of the University in Heidelberg until his retirement in 1998. Under his leadership, the Heidelberg Institute became internationally renowned and many Humboldt-Fellows from the United States and Japan came to work with Caspar Rüegg. He continued to investigate the chemo-mechanical energy transformation in insect flight muscle but also in mammalian striated muscle with his co-workers Konrad Güth, Hans J Kuhn, and Peter Griffiths. Richard Paul from the University of Cincinnati joined the institute as Humboldt fellow and studied the crossbridge ATP utilization in smooth muscle (Paul et al., 1976). Ca²⁺-regulation of cardiac and smooth muscle and modulation of sensitivity to Ca²⁺ by inorganic phosphate, cyclic nucleotides, protein phosphorylation, and small molecules became more and more the focus of his research interests. He was first to show together with U. Mrwa that cAMP directly inhibits the contractile mechanism of smooth muscle (Mrwa et al., 1979), and together with J. Sparrow, who visited from Australia and F. Hofmann (then at the Department of Pharmacology at the University of Heidelberg) that calmodulin is essential for the activation of smooth muscle contraction (Sparrow et al., 1981). The notion of PKA-mediated desensitization to Ca²⁺ of smooth and cardiac muscle was pursued very intensively in the following years, and in a seminal report he showed that cGMP/protein kinase G likewise decreased sensitivity to Ca²⁺ (Pfitzer et al., 1982), at a time, when the physiological role of cGMP was still poorly understood. It was only after ~ 1984 that cGMP became center stage when it was recognized that a rise in cGMP in vascular smooth muscle mediates endothelial NO-induced vasodilation (Murad et al., 1985). Rüegg with his co-workers reported that PKG unlike PKA did not desensitize all smooth muscles to Ca²⁺ (Pfitzer et al., 1986). We know now, that the PKG sensitivity is related to expression of the leucine zipper positive+splice variant of the myosin phosphatase regulatory subunit, MYPT1 (Dippold and Fisher 2014). Based on biochemical evidence that PKG unlike PKA does not lower the Ca-CaM affinity of MLCK, they proposed that PKG probably acts through increasing the activity of myosin phosphatase, a notion that was proven ~ 10 years later by the Somlyo laboratory (Wu et al., 1996). But, one of the most far reaching discoveries he made together with the Humboldt fellow Akira Takai from Japan and Corinna Bialojan, a postdoctoral fellow in the institute, was that the black sponge toxin, okadaic acid inhibits myosin phosphatase (Takai et al. 1987). This was the first available myosin phosphatase inhibitor and provided proof of concept that inhibition of myosin phosphatase sensitized smooth muscle to the activator Ca²⁺ (Somlyo and Somlyo 2003). His book “Calcium in Muscle Activation” (Rüegg 1986) which covers invertebrate and vertebrate striated, cardiac, and smooth muscle became a classic.

Caspar early recognized that increasing the responsiveness of the contractile machinery to Ca²⁺ in cardiomyocytes could be exploited therapeutically to treat myocardial insufficiency. Together with Achim Herzig he found that a compound from Boehringer Ingelheim, AR-L115 BS, an imidazole derivative, increased sensitivity to Ca²⁺ of skinned cardiac fibers (Herzig et al., 1981). As visiting professor in R.J. Paul’s laboratory at the Department of Physiology of the University of Cincinnati, where he was appointed Adjunct Professor of Physiology in 1985, he collaborated with John Solaro to show that this compound increased Ca-binding to myofibrils (Solaro and Rüegg, 1982). His idea of using pharmaceuticals to increase the sensitivity to Ca²⁺ of the contractile apparatus of the myocardium to achieve an increase in force, independent of an increase in Ca²⁺, i.e. without increasing the energetic demand, had a major impact and was taken up by a number of pharmaceutical companies (Rüegg 2003). One compound, levosimendan, reached market maturity to treat acute cardiac insufficiency. He also was quick to recognize the high potential of molecular biology at a time when molecular biological approaches were rarely used in physiology. This was reflected in several studies on myosin isoforms in in cardiac and smooth muscle in the 1990s, an area of research driven by his group leaders Ingo Morano and Rudolf J. Wiesner. Another question that puzzled him was how do sarcomeres lengthen when an isotonically shortened muscle relaxes. So when the third filament titin, an elastic spring, was discovered, he offered Wolfgang Linke who was at that time a post-doctoral fellow in Seattle, a position to study titin in his laboratory. This resulted in several important papers. Indeed, much of the work done between 1985 and his retirement were carried out by his post-doctoral fellows and group leaders, but, he still stood at the “bench” himself testing out new ideas. One of his last fortuitous discoveries at the bench was that troponin-I could be selectively extracted from skinned cardiac fibers with vanadate which resulted in a Ca²⁺-independent contraction. Reconstitution with exogenous troponin-I restored Ca²⁺-regulation of contraction (Strauss et al., 1992). This method was invaluable for structure function relationships of troponin I within the structurally intact sarcomere (van Eyk et al., 1993). It has been adopted by many laboratories worldwide, refined, and modified in such a way that not only cTnI but the whole troponin complex could be exchanged, which helped to explore the functional consequences of mutations of the troponin complex that cause familial hypertrophic cardiomyopathies in humans.

The Heidelberg institute was truly cosmopolitan, and was visited by many researchers from all over the world, be it on short term visits or for longer periods, and Caspar Rüegg encouraged his young postdoctoral fellows to go abroad and collaborate with other laboratories. He was a great and generous mentor, who granted his postdoctoral fellows and group leaders independency for pursuing their ideas, and developing their projects, but he always took great interest in the progress of projects sharing his broad knowledge of muscle physiology. Several of his scholars became professors and chairs at German universities. He used to proof read papers at the coffee table, which was located in the central hallway of the institute, so that everybody had to pass by, and thus, perhaps not at the bench himself, he was always in close contact to the research activities in the laboratory. By offering advanced seminars and laboratory tutorials in physiology to students of medicine and physics he introduced undergraduate students to science. He also played an important role in the scientific development of young scientists, such as B. Brenner and M. Gautel from other institutions. Remarkably, at a time when gender equality was not yet center stage, and female scholars were still rare in physiology departments, several female PhD students and postdoctoral fellows were always part of the group. One of us, G.P. benefited greatly from his unbiased support for career advancement in academia. But he had not diversity in mind, his genuine motivation was to support young scientists, whatever their background was, as long as he considered them scientifically excellent.

Caspar Rüegg sitting at the coffee table, his favorite place in the institute for proof reading manuscripts and staying abreast of activities in the laboratory

His research was continuously funded by the German Research foundation (DFG) and also by other funding agencies. From 1973 to 1976 he was Dean of the Faculty of Preclinical Medicine (Fakultät für Naturwissenschaftliche Medizin) of the University. He also served for many years on the reviewing board of the German Research Foundation (DFG). In 1990, he was President of the German Physiological Society and chair of the Annual Meeting of the German Physiological Society, which took place in March 1990, just a few months after the Berlin Wall opened and East Germans were allowed to travel. About 50 East German physiologists applied to attend. It was no question for him that everything had to be done to make participation possible. However, because the former GDR and the BRD were still two states with different currencies, it was very difficult for the East German colleagues to pay their travel expenses, and the abstract book was already in print. Of course the registration fee was wavered, but how to find cheap accommodation and deal with the abstracts? His solution was to print an extra abstract book and a call was made in the local newspaper asking Heidelberg citizens for free private accommodations. Thus, it worked, hosts were found for all 50 “east” German scientists and some lasting friendships were established.

Emeritus Period

As Professor Emeritus he still took great interest in the progress of muscle research even though he was no longer directly involved. Rather he started a very successful second career. As a muscle physiologist, he very much took a reductionist approach using physical and chemical principles to study the machine “muscle”. In this Emeritus period, he was very much interested in the question how the assembly or interaction of single molecules or nerves in neuronal networks give rise to emergent novel properties and functions that cannot be deduced from the reductionist approach. Physiology to him, was the study of the logic of life needing both reductionism and integration. He was fascinated by the idea of Eric Kandel that words and, thus, psychotherapy might change the architecture of the synapses of the brain, neuronal networks for that matter, and he published successfully several books on the mind/body interaction, i.e. a neurobiological foundation of psychosomatics (Rüegg 2004, 2011).

Caspar Rüegg was a highly creative, visionary scientist with a marvelous intuition but also a sharp analytical mind. He obtained several prestigious awards for his research: in 1974 he was awarded the Adolf-Fick-Preis, the most important award of the German Physiological Society, for his contributions to physiology. He was elected in 1988 as corresponding member of the Swiss Academy of Medical Sciences, and in 2011 as honorary member of the German Physiological society. He was of great importance for the field of physiology as a scientist, a university lecturer, and as a mentor. But as much as he loved science, he loved his family more, his wife and two children, and later his three grandchildren. His family gave him the support and the freedom to pursue his passion, science. In his spare time, he enjoyed oil painting. The love he had for nature as a school boy never left him, and he spent as much time as he could in the Swiss Alps. He was an excellent skier, and for several years, he went with members of the department for a skiing weekend to the Swiss Alps. He will be missed deeply by those who had the privilege to know him as mentor, scientist, and friend, but most dearly he will be missed by his family.

Acknowledgements. Gabriele Pfitzer gratefully acknowledges the access to the recording of a 3 h interview on Professor Rüegg’s career as a muscle physiologist and his personal thoughts on physiology, which he gave as an emeritus to J. Hescheler, Institute of Neurophysiology, University of Cologne. In writing this personal memory, it became more and more apparent that there were many more students and scientists that interacted with Caspar Rüegg over the years and contributed to his science. We regret that due to space limitations we could not mention everyone and for this we apologize.

Gabriele Pfitzer

Institute of Vegetative Physiology

University of Cologne

Avril V. Somlyo

Molecular Physiology and Biological Physics

University of Virgina

References

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Recollections from some of Caspar Ruegg’s colleagues and friends

It was unusual in 1957 for scientists from continental Europe to come to England to study for a PhD. In this Caspar was a forerunner. He was fortunate to work with Kenneth Bailey, who discovered tropomyosin B and the molluscan tropomyosin A (paramyosin). Bailey had his own style of biochemistry and I think Caspar was influenced by this, particularly in his work on different muscles from both vertebrates and invertebrates. During his stay in John Pringle’s group in Oxford in 1964, the use of glycerinated flight muscle from the giant waterbug, Lethocerus, enabled Caspar and Brian Jewell to show that oscillatory contraction of the flight muscle is an intrinsic property of the fibres. This transformed the study of the mechanism of contraction in flight muscle. Glycerinated fibres were then used in X-ray diffraction, electron microscopy and mechanical experiments on Lethocerus muscle. Lethocerus became the model system for studying flight muscle.

When Caspar returned to Heidelberg, there was frequent exchange of workers between Heidelberg and Oxford. An attraction in Oxford was the PDP-8 computer that Roger Abbott used to run his mechanical experiments. I remember Caspar and visitors from his group gathered in awe round the PDP-8. Shortly before Pringle retired in 1979, we had a meeting in Oxford on insect flight muscle. The book of the proceedings was known as the “Bug Schrift” because of the major contribution from Caspar’s group in Heidelberg. Caspar contributed to a lively debate on stretch activation. At a party in my house, we were trying to persuade some waterbugs to fly. Pringle had one walking up his chest. These bugs can inject you with a painful nerve toxin. Caspar suddenly stood on a chair and made a lengthy speech extolling the advantages of insect flight muscle for all aspects of muscle research. He was enthusiastically trying to convert the already converted.

We met again when I was at EMBL in Heidelberg. Caspar showed that troponin I could be extracted from cardiac fibres with Na-vanadate and we used a modification of the method to extract troponin C from Lethocerus fibres. After Caspar retired, we met at European Muscle Conferences. He had a thirst to hear recent results and the questions came thick and fast. On a bus ride in Berlin, we sat upstairs at the front and he was keen to discuss the difference between length dependent activation in cardiac muscle and stretch activation in flight muscle. As always, he had plenty of ideas.

Belinda Bullard, PhD

Honorary Visiting Professor

Department of Biology

University of York

Obituary Johann Caspar Rüegg

Thinking back on Caspar Rüegg, I would like to think he lived his academic life to the full. Probably only having been loosely connected to his research and to him as a mentor, I however, remember this professor I experienced very early in my medical studies at Heidelberg in second year physiology. I was about 21 that time, and I had no idea that professors actually have heaps of other schedules besides teaching. Little did I know about research, and there was this one professor who told us about smooth muscle and heart contractility, regulatory motor protein regulation in conjunction with names of colleagues he worked with who did not actually ring any bell to me. After all, we were more worried about getting through the textbooks. But Professor Rüegg was memorable in his lectures for presenting in a very calm and reflective way. He always appeared very knowledgeable to all of us, and the lectures were usually well attended, probably also because of that funny Swiss accent, we thought was something for a change. It was later then, when I joined his institute for my medical doctorate that I witnessed him as a very balanced and reflective leader. Although he was not my direct supervisor, I remember him from various functions and conversations he got engaged in while spending much time at the coffee area table to read through manuscripts and literature. He always was interested in what people from other groups in the institute were doing and frankly always wanted to know how experiments were going. I remember his retirement, in particular his machina carnis farewell lecture and the farewell function where I surprisingly, for the first time, learned that Caspar Rüegg was also a passionate painter of landscapes. I think he got some canvas as a gift from all with the notion finally have the time to combine his passion for Swiss Alps and painting. But Caspar Rüegg did not stop being involved with academia. In fact, I think my contact with him grew particular after his retirement. He was a regular visitor in the institute, and we also regularly met at the Annual Physiological Society Meetings where he was very interested in my growing muscle work. We spent several occasions talking about the future of physiology in Germany, teaching (I was writing a textbook at that time), and he told me about his new passion for muscle-brain-consciousness, more from a philosophical perspective. I consulted him a few times on professional decisions of mine and his wealth of knowledge and life experience certainly have marked some of my decisions to be where I am today. Thank you, Caspar.

Oliver Friedrich, MD PhD

Professor and Chair

Institute of Medical Biotechnology, FAU Erlangen, Germany

UNSW Sydney Australia

Caspar Rüegg

I was attending a Gordon Conference on Muscle in the summer of 1979, and got on a bus at Logan airport. As it departed, I started to talk with a middle-aged gentleman in a suit and a tie who sat next to me. He turned out to be Professor Caspar Rüegg from Heidelberg. I was delighted to see this person, who I knew from literature—in particular I liked Rüegg and Tregear (1966) paper on correlation of oscillatory work and the ATP hydrolysis rate in insect flight muscles. I was thrilled to talk with the person who did the actual experiments. I was still early in my career, not known to the field, but amazingly, he recognized my name and knew my work on sinusoidal analysis of skinned skeletal muscle fibers. He asked me about my research funding, and I said that I was lucky to get an NSF grant. He smiled and hesitatingly said that he was one of the reviewers of my application—I was very much excited and thanked him for the good review he did for me.

Later, I wanted to learn the ATP hydrolysis rate measurement technique on skinned fibers, and visited his Physiological Institute II in University of Heidelberg for the summer of 1985. I took my family with me (my wife and two young daughters in early teens). He kindly invited us to his home in Hirschberg, introduced us to his wife Elvi, son Christian, and daughter Barbara. Their and our children were in the same age group, played together, chased each other, and laughed with each other a lot. We started to talk our works, in particular, how messy my desk was, and Caspar asked me if I wanted to see his desk. He looked to be competitive in our desk’s “messiness”, in spite of Elvi’s opposition for the same reason. At that time Caspar was writing a book on Calcium in Muscle Activation, and many papers were scattered around his desk. Indeed his desk was as messy as mine or perhaps “messier”. We came back to Heidelberg next summer, and I brought a manuscript which described the phosphate effect on the ATP hydrolysis rate we did at Caspar’s lab, and its correlation with sinusoidal analysis results I did in my lab. He was impressed and complimented my speedy writing. I submitted this manuscript to Professor Wilhelm Hasselbach in person, who was in Heidelberg and an editor of Pflügers Archiv, European Journal of Physiology.

At Caspar’s lab, a round table discussion was a daily routine and an essential element of his communal research. We surrounded this table for coffee breaks and for lunch hours. On the wall there was a poster, which said “Everything is finished with the paper work” with a cartoon of a baby sitting on a portable toilet and a toilet roll alongside. That was a motivation of my writing a manuscript quickly. I learned a few German conversations with Caspar. Wie geht es? Gut, und Ihnen? Auch gut, and so on… I asked Caspar why he had not carried out sinusoidal analysis recently, to which he replied “Because you do it in a much better way”. I was very much honored to hear this, but in retrospect, he must have had many more things to carry out. Caspar was a good mentor and an enthusiastic supporter for me. He wrote many letters for my promotion and a new job search. I was proud that he treated me in the same way he treated his laboratory members. I owe him very much, and I miss him very much. He was a great scientist, but at the same time, a great teacher and a good friend.

One thing I regret was that I was about to send out Caspar my song CDs. But just prior to mailing them, I heard the sad news of his passing. I never had a chance to talk with him about music, because I started much of it after his retirement. It would have been interesting to know whether he liked music, and how he would have responded to my primitive voice and keyboard technique. It turned out that I was too late to send these side works to Caspar.

Masataka Kawai, Ph.D.

Professor

Department of Anatomy and Cell Biology

College of Medicine, University of Iowa

I don’t quite remember when I first met Caspar. I am pretty sure it was at a Muscle Gordon Conference or at a Biophysical Society Meeting while I was a post-doc in Bob Adelstein’s lab at NIH. Although I don’t remember the occasion, I remember his warm and engaging smile. He seemed to be so happy to meet me.

A few years later after I had become an Assistant Professor, I asked Caspar if I could come to his lab to do a mini-sabbatical. He gladly said yes and my wife and I spent 2 months in Heidelberg. He arranged for us to rent a small but very nice apartment in the old part of town that was around the corner from a great bakery. The apartment was also within walking distance of the lab, making it extremely convenient. One of the high points of our stay was having Elvi and Caspar over for dinner. I had cooked some curry that may have been more spicy than Caspar and Elvi were comfortable with, but they ate on gamely. I also remember Sandy and I having dinner at their house and being introduced to “Heisse Himbeer mit Rahm”. Wow! Still one of our favorite desserts.

The two months I spent in Caspar’s lab was truly a high point in my scientific career. My scientific objective was to master skinned fiber preparations. I did this and brought the technology back to my lab. Caspar had everything well organized in the lab and the work went smoothly. What I remember most is Caspar encouraging all of us to develop a good nose for science, that is, an intuition of what is going to be important and tractable.

Caspar was also a devoted friend and father. Caspar came to Chicago a couple of times to give seminars. When he did, he stayed with Sandy and me. On one occasion, his daughter wanted a very specific pair of gym shoes, ones made by Chuck Taylor. All he could talk about when he got off the plane was finding these shoes and Sandy spent almost an entire day driving Caspar around to various stores until he found just the right shoes.

We scientists focus on judging the success of our careers based on scientific contributions, the papers we published, the discoveries we made and the scientists we mentored. Rarely can we check all three boxes. Caspar Rüegg had the luxury of doing so. He was a towering scientist by any measure. What made Caspar special was his warm heart and the way he was open to new ideas and people. His lab was special because he attracted interesting people, nurtured them and encouraged them to pursue new and creative ideas.

Primal de Lanerolle, PhD

Professor

Department of Physiology and Biophysics

University of Illinois at Chicago

I met Caspar when he came to Harvard for a lecture in 1973. I was well aware of his work, as Smooth Muscle Tone was published in 1971 (Physiol. Review, Band 51, 1971, S. 201–248), which guided much of my thoughts. I was headed for my “grand science tour” to University College London, where I was to start in July, 1974. My Instructor appointment at Harvard was to officially end in March, and Caspar invited me to spend several months in Heidelberg. Caspar just took over as chair of the II. Physiologisches Institut, at the new Universität campus. It was an eye-opener, brand new spacious laboratories and, for a very parochial American, quite a different culture. More importantly, was the cast of bright (present company excluded) young, eager scientists. I stayed for 16 months, as it was too exciting to leave, until Doug Wilkie firmly suggested that my British-American Fellowship in London couldn’t be extended indefinitely. Thus began my career- and life-long interactions with Caspar and the Rüegg family. During this period my colleagues included Joachim Herzig, Elvira Glück, Konrad Guth, Hans Kuhn, Ulrike Mrwa, Hans Reiermann, and later Gabriele Pfitzer. Of course there were many more and visiting scientists, too numerous to remember and to whom I apologize. These interactions were a large part of my continuing education.

For better or worse, I was used to making my own research decisions while in the Biophysics Program, so was not necessarily apprehensive, but more like optimistically curious about what style of management might hold in this German Department. Caspar was remarkably open to whatever direction I wanted to pursue in smooth muscle energetics. He provided not only encouragement, but practical advice, and anything and everything that I needed in scientific equipment, as well as technical and student assistants.

Following up on a suggestion from Andrew Somlyo on VSM aerobic glycolysis, Elvira Glück and I discovered that while oxygen consumption was correlated with isometric force, aerobic glycolysis was rather correlated with Na–K ATPase activity. The investigation of metabolic compartmentation with specific ATP requiring functions began in Heidelberg and was a major part of my career. Caspar’s leadership and gentle suggestions, I’m sure formed a similar part of everyone’s career in his Department.

Richard J Paul, PhD

Professor emeritus

Dept. of Pharmacology and Systems Physiology

University of Cincinnati,

College of Medicine

In 1979, I had the honor and pleasure of working in Heidelberg in the Physiology Department headed by Caspar Rüegg. I had contacted Caspar about working there to learn the technique pioneered in his department of simultaneous determination of force and ATP hydrolysis in skinned fiber preparations as well as stretch activation. I had known Caspar from the literature and met him through Rick Paul, a colleague at the University of Cincinnati, where I was at the time. Caspar and Elvi were very kind to us, inviting us into their home. Caspar even managed to arrange housing for my family and to obtain remuneration to offset the costs. Together with Joachim Herzig, who worked closely with me, we investigated the effects of phosphate on cross-bridge kinetics of cardiac skinned fibers (PMID: 6908844). This was my first exposure to stretch activation, a phenomenon now recognized as significant in cardiac dynamics, but not recognized at the time by many cardiac researchers. As with many of Caspar’s contributions, his experience with stretch activation in insect flight muscle illuminated the interpretation of the results in the heart. The laboratories in Heidelberg had a wonderful atmosphere; Caspar, Herzig, and Gaby Pfitzer, among others, became lifelong friends. A special feature of the atmosphere was the “Kaffeetisch”, the place for meeting with colleagues, analyzing data, and drinking coffee. At the Kaffeetisch, conversations began with Caspar and Herzig regarding the possibility that cardiac sarcomeric proteins may be targets for inotropic agents. A brief publication on such effects of a phospho-diesterase inhibitor had been published. We had developed a technique for determination of Ca-binding to TnC in cardiac myofibrils in our laboratory, and soon Caspar appeared in Cincinnati with vials of the agent ARL-115 BS from Karl Thomae GmbH. The outcome was a paper in Circulation Research in in 1982 (PMID: 6214330) widely recognized as the seminal study indicating that indeed sarcomeric proteins could be and should be considered as targets for therapy. The rest is history. Thirty-six years later, ongoing development of this concept by biotech and big pharma continue as do clinical trials. Caspar Rüegg was the consummate scientist. The contributions evolving from his insights and insatiable curiosity will continue to have high impact.

R. John Solaro, PhD

Distinguished University Professor

Director, Center for Cardiovascular Research

Dept. Physiology and Biophysics, M/C 901College of Medicine

University of Illinois at Chicago

In Memory of Professor Rüegg

From 1986 to 1988 I was fortunate to spend 2 years in the laboratory of Professor Caspar Rüegg in Heidelberg University as a research fellow of the Alexander-von-Humboldt Foundation. I always remember Prof Rüegg as a kind and generous mentor.

Let me tell you a personal story from my early days in Heidelberg. On 30 July 1986, the next day of my arrival in Germany, I met with Prof Rüegg in his office. It was on the occasion of this very first meeting that he spoke of okadaic acid, “an interesting compound isolated from a Japanese black sponge, which had an enhancing effect on smooth muscle contraction”, which he had learned about from reading a recently published paper and a manuscript under review. At his suggestion, I wrote to Dr Tsukitani at Fujisawa Pharmaceutical Company in Tokyo and then Yasumasa Tsukitani very kindly sent 2.8 mg okadaic acid. With this precious compound in hand, Prof Rüegg suggested to me that I should firstly examine its effect on contractility to Triton X-100-skinned fibre of guinea-pig taenia caeci. It was soon found that okadaic acid not only enhanced Ca²⁺ induced contractions of the skinned fibre but also strongly inhibited the relaxation caused by Ca²⁺ removal. This latter finding indicated the possibility that okadaic acid might exert the tension enhancing effect by inhibition of the myosin phosphatase activity. I was lucky to collaborate with Corinna Bialojan, a postdoctoral fellow in the lab, who had developed a sensitive system for assaying myosin phosphatase activity. Jointly, we found that indeed okadaic acid inhibited the phosphatase activity within skinned fibres but it did not affect the myosin light chain kinase activity. Corinna and I tested the effect of the toxin on various phosphatases, some of which were provided by other groups through Prof Rüegg’s international personal network, and we could thereby establish that the effect of okadaic acid is very specific to protein (Ser/Thr) phosphatases, particularly type 2A (K_i = 32 pM) and type 1(K_i = 150 nM).

I think that my story above concretely exemplifies the great ability of Prof Rüegg to guide and support (then) young researchers like me as well as his deep and quick insight on new materials to be used for muscle research. He was truly a great scientist and we will all miss him. I myself will always cherish the memories that I am privileged to have of him.

Akira Takai, MD, PhD

Professor and Chair

Department of Physiology,

Asahikawa Medical College,

Hokaido, Japan

I met Professor Caspar Rüegg in the summer of 1980, when he allowed me as a pregraduate student to join his lab for one summer term to learn the technique of using isolated papillary muscles to study heart metabolism and function in an organ bath. I guess I was one of the first at that time to use new substances which sensitize the heart to calcium, which really astoundingly increased the isometric force of these contracting preparations.

In the next 8 years, I completely devoted my work to find out how mitochondrial metabolism is rearranged during hypoxia and ischemia in the heart (Wiesner et al., 1989). Mitochondria became my favorites, and so I was quite surprised—and happy—when in 1989 I met Caspar again at his visit at the University of Chicago Medical School, where I did my post-doc in Radovan Zak’s lab. There, he invited me to become a postdoctoral fellow at his institute in Heidelberg. I kept working on the molecular biology of these organelles, which produce most of the ATP for muscle contraction and relaxation, but it wouldn’t have been Caspar if he wouldn’t have managed to convince me to work on muscle as well, e.g. myosin isoforms, which resulted in at least one nice paper (Wiesner et al., 1997).

I guess the most important reason for appointing me was to introduce all the—at that time—novel molecular biology techniques like Western Blot, Northern Blot, PCR (Wiesner et al., 1993) and cloning, e.g. of recombinant troponin mutants (Strauss et al., 1996), into his physiology department, which I had just learned fresh from the bench. One of the most memorable scenes in those 8 years in Heidelberg was when the molecular mechanism of ATP production by ATP synthase elucidated by Boyer and Walker was given the Nobel Prize in 1987. He rushed into my office and said: “Look, finally even the main function of your favorite research object is explained by movement!!!”

Caspar Rüegg was instrumental for my scientific life, since even more than Zak he insisted to ask when I told him about new projects: Is this an important question? And if we find out something, there was always the question: And, what is new about it?

References

• Strauss JD, Eyk JE, Barth Z, Wiesner RJ, Rüegg JC. Kluwe L. (1996). Recombinant troponin I substitution and calcium responsiveness in skinned cardiac muscle. Pflugers Arch 431:853–862.

• Wiesner RJ, Beinbrech B, Rüegg JC (1993). Quantitative PCR [letter]. Nature 366: 416.

• Wiesner RJ, Deussen A, Borst M, Schrader J. Grieshaber MK (1989). Glutamate degradation in the ischemic dog heart: contribution to anaerobic energy production. J Mol Cell Cardiol 21:49–59.

• Wiesner,R.J., Ehmke,H., Faulhaber,J., Zak,R., and Rüegg,J.C. (1997). Dissociation of left ventricular hypertrophy, beta-myosin heavy chain gene expression, and myosin isoform switch in rats after ascending aortic stenosis. Circulation 95:1253–1259.

Rudolf J. Wiesner, PhD

Professor

Institute of Vegetative Physiology,

University of Cologne, Germany