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Hans Thoenen: A Tribute

2012; Cell Press; Volume: 75; Issue: 4 Linguagem: Inglês

10.1016/j.neuron.2012.08.007

1097-4199

Yves‐Alain Barde,

Neurology and Historical Studies

Hans Thoenen passed away on June 23, 2012, a few months after being diagnosed with lung cancer. He left us grateful for what he had been able to accomplish in his life as scientist, but he was neither exuberant nor proud. Hans remained extraordinarily modest about his achievements—he felt far more comfortable by understating his contributions and never liked receiving compliments from colleagues he did not know well. Given the choice, he preferred to have critics than adulators around him. “At least the former are honest,” he would say. Loyalty was probably the quality Hans valued most in his interactions with others. He also was a realist, and when we both talked about his approaching death, his only regret was to leave his dear wife Sonja alone as he felt she may still need him. Hans knew well that without Sonja’s support, life as a scientist and group leader would have been much more difficult for him. Hans was born in Zweisimmen, a beautiful village located in the so-called Berner Oberland, just north of the French linguistic border. This was one of very few borders that Hans seemed to have had some respect for, and even this was surprising with Hans, as Swiss Germans are typically remarkable polyglots. The Swiss Alps made a great and lasting impression on him: strong feelings for freedom and independence characterize alpine dwellers, which may explain Hans’s lack of readiness to compromise on anything, including in his interactions with colleagues or journal editors. During the early part of his life, he was a passionate mountain climber. His expeditions were not limited to the Alps; his tours also took him to far off places, such as the Peruvian Andes. This attraction for adventurous undertakings explains his later passion for research and the riskier a project was, the more Hans liked it. One of his most striking traits was that he was fearless, especially with regard to the use new technologies, a key to his scientific endeavors, which he summarized in a recent autobiography (http://www.sfn.org/skins/main/pdf/history_of_neuroscience/hon_vol_6/c14.pdf). Incidentally, I found it surprising—but very fortunate—that Hans accepted to write this piece after an invitation from Larry Squire. He was apparently given unrestricted space to detail the many steps of his scientific trajectory and, remarkably, this piece seems not to have been edited much at all, so that posterity will still be able to enjoy Hans’s voice “à l’authentique.” While the scientific community is presumably most familiar with Hans’s achievements in the field of neurotrophic factors, fewer may know that his first scientific big bang came in the late 1960s, with the accidental discovery of 6-hydroxydopamine as a drug that could selectively kill noradrenergic terminals. In close collaboration with a dear colleague of his, Jean-Pierre Tranzer at Roche in Basel, they discovered through the use of electron microscopy that this drug selectively destroys sympathetic nerve endings. They suggested that 6-hydroxydopamine is taken up by these terminals where it readily oxidizes, with its killing specificity ultimately explained by the high local concentrations created by the dopamine transporter. Hans’s desire to further explore the mechanisms of action of 6-hydroxydopamine using biochemical markers led him to join the laboratory of Julius Axelrod at the NIH. While of short duration, this stay had a profound impact on Hans. First, because of the discovery of transsynaptic induction (see below) and second because of the way science was done in the Axelrod laboratory. The lack of hierarchy, the openness for unexpected discoveries that others would perhaps reject as a nuisance slowing the confirmation of preconceived ideas, the unusual career path of Axelrod, including his PhD late in life, all this was interpreted by Hans as indications that, after all, there might be room in Academia not only for adventure, but also for scientists with unconventional trajectories. Long after leaving the Axelrod laboratory, Hans would often talk fondly about “Julie,” as he would invariably say. As Hans describes in his autobiography, the discovery of transsynaptic induction was an entirely unexpected consequence of the use of 6-hydroxydopamine. Together with Axelrod and Müller, Hans showed in a series of short but remarkable publications in 1969 that increased presynaptic activity leads to elevated levels of enzyme activity, which they illustrated with tyrosine hydroxylase. While neither antibodies nor RNA probes were available at the time to directly quantify the levels of tyrosine hydroxylase, this work showed that increased enzyme activity necessitates ongoing transcription and translation, a conclusion that was at the time quite innovative with respect to how electric signals impact gene expression. Upon his return to Europe, Hans found it initially more difficult to publish in highly regarded journals and for years, when he would run out of patience with journal editors—and this would typically happen quite rapidly—he would often use the argument that, after all, he was just a boy from the Swiss Alps, unfamiliar with the sophisticated formulations that people learn by default (he thought) when brought up in large U.S. cities. Upon his return from the NIH, Hans spent a few years again in Basel, where he was appointed University Professor. Here, in close collaboration with Martin Schwab, who joined his laboratory at the Biozentrum, a then newly created institute that was, and still is, part of the University of Basel, Hans reported on the extraordinary (and, again, entirely unexpected) observation that tetanus toxin not only is transported retrogradely from peripheral nerve terminals, like nerve growth factor, but also enters the central nervous system by transsynaptic transport. This early work again involved electron microscopy and, in this case, it was coupled with autoradiography. The results and their interpretation were spectacular, given the lack of knowledge in the field of ligand-mediated internalization, even outside the nervous system. In many ways, the subsequent move of Hans’s laboratory to Martinsried was very fortunate. The Max Planck Society, of which he became a member in 1977, treated him extraordinarily well, to the extent that a few years after his move to Martinsried near Munich, a new institute was built next to the existing Max Planck Institute of Biochemistry. As Max Planck Director, he was largely shielded from the worries of grant writing, an exercise that Hans was not good at. Hans’s impatience toward anyone unable to immediately understand what he had in mind, combined with his use of undiplomatic language when responding to comments about his intentions, would have made it exceedingly difficult for him to successfully compete for grants large enough to implement his vision of science. In Martinsried, the support of the Max Planck Society allowed him to comfortably accommodate his growing group and, importantly, to also recruit several excellent junior scientists as independent group leaders. These included Wieland Huttner, Heinrich Betz, Reinhard Jahn, the late Werner Risau, and many others. These energetic and talented colleagues contributed further to creating a vibrant as well as challenging atmosphere. The framework provided by the Max Planck Society also immensely facilitated the pursuit of long-term projects including the purification and eventual cloning of molecules of interest such as brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF). In this latter project, Michael Sendtner played a critical role as the exercise went far beyond the mere purification and cloning of CNTF, a molecule that remains most intriguing with regard to its secretion and relevance in paradigms involving lesion and neuronal dysfunction. As almost everything is unexpected about CNTF, this was a perfect project to be successfully tackled by these two creative individuals. The skills deployed by Michael and Hans in deciphering out some of the main aspects of the pathophysiology of CNTF remain, to this day, most impressive. While Hans’s behavior may have suggested otherwise to those who did not know him well, he actually loved the chaotic and unpredictable nature of research and relished the thrill of unexpected observations. The discovery of what became known as BDNF followed a similar trajectory. Contrary to post hoc rationale reconstructions of the kind “it was clear from the outset that there must be other factors out there,” the very start of the project was the result of an accidental observation linked with failed attempts to detect nerve growth factor (NGF) in sources other than the adult male mouse submandibular gland. When I joined the laboratory at the Biozentrum in Basel, Hans had developed a strong and deep interest in NGF and he warned me that essentially all published results related to its distribution and quantification in tissues or conditioned media were artifactual, resulting from misinterpreted radioimmunoassay and bioassay determinations. In his autobiography, Hans gives me credit for something he actually figured out himself, presumably a reflection of his exceptional generosity. In any event, because I often questioned Hans’s sweeping statements, I wanted to check for myself in the glioma cell-conditioned media whether NGF would account for the biological activities reported by others. By that time, I had learned from Hans’s wonderful colleague Kitaru Suda, a Japanese chemical engineer, how to reliably detect NGF. I received a sample from my friend Ron Lindsay, then working with C6 glioma cells in the group of Denis Monard at the Friedrich Miescher Institute across the Rhine River. Hans turned out to be right in this case and, using the techniques available at the time, there was no detectable NGF activity in this conditioned medium. Quite unexpectedly, there was something else that could readily be distinguished from NGF by simple criteria. Retrospectively, I doubt whether this activity had anything to do with BDNF but, much inspired by discussions with David Edgar in Hans’s laboratory, I thought it would be safer to use a real tissue as a source to characterize this potentially novel neurotrophic activity and went ahead using brain extracts. The unfailing, very active, and patient support of Hans during the cloning of BDNF was remarkable, especially in the face of his proverbial impatience. This support was all the more important considering that in the 1980s, there was a lot of skepticism concerning the existence of “factors” other than NGF and later fibroblast growth factor(s) or, conversely, there was uncritical faith in the relevance of candidate trophic molecules such as neuroleukin, sciatin, purpurin, or pyruvate, as well as many others. In short, Hans has been a wonderful mentor who later also became a close friend. He was everything but the stereotype of the solitary mountaineer. He loved having guests and many recall countless festive occasions to which Hans and his wonderful wife Sonja invited visitors from abroad and colleagues from the laboratory. We were spoiled with spectacular dinners while Hans kept filling our glasses with what seemed to correspond to much of the yearly production of Swiss wine. His lack of inhibition in crossing borders was inspiring, as was his total lack of understanding for the concept of political correctness, and I will miss him for this as well. I feel very privileged to have met him early, as it was truly enjoyable to work in an environment in which everything seemed possible thanks to Hans and the extraordinarily generous support provided by the Max Planck Society over a period of almost 20 years. Hans was permanently conscious of the privileges he enjoyed and up until age-related retirement in 1996, he felt the constant tension of fearing that perhaps he did not fully deserve these privileges. In the rare moments when he would look back at his achievements and comment about them, it was impossible to extract from him more than statements like, “By and large I think I have done more or less OK.” As close colleagues and friends, we will do our best to ensure that Sonja knows how grateful we all are for what Hans has given us. He died peacefully and was very grateful for having been in a position to lead an independent, adventurous scientific life, essentially as he wanted it to be.