A life of scientific accomplishment, an untimely death
It is with deep sorrow that I compile these lines to pay tribute to Jürg Tschopp, our dear colleague at the Faculty of Biology and Medicine of the University of Lausanne. Still hard to believe, his untimely death abruptly came on March 22, 2011, while ski-touring with his son in the Swiss Alps he loved so much.
Jürg Tschopp was born in Basel in 1951. He obtained his diploma in chemistry from the University of Basel in 1974 with a thesis on spin-label probes directed by Joachim Seelig. His Ph.D. dissertation in biophysics was on the mechanism of bacteriophage T4 tail assembly in 1978 from the Biocenter of the University of Basel under the direction of Jürgen Engel. He also worked on the complement cascade, and this interest led him to perform postdoctoral work with Hans Müller Eberhard at the La Jolla Research Institute on the late components of the complement common pathway, C5–C9. These studies led to the momentous discovery of the complement pore formed by C9 multimers 1.
He became Assistant Professor at the department of Biochemistry of the University of Lausanne in 1982, was promoted to Associate Professor in 1987 and to Full Professor in 1990. In 2003 he took on the co-directorship of the Department of Biochemistry and founded in 2009 the Institute of Arthritis Research in Lausanne.
During his early stages at the department of Biochemistry of the University of Lausanne, Jürg Tschopp turned his attention to the deciphering of the biochemical nature of the so-called cytolytic granules. These were, at the time, a prominent morphological feature of the cytolytic T lymphocytes (CTLs), a subset of T cells that had been discovered in Lausanne in the 1970s by scientists at the Department of Immunology of the Swiss Institute for Experimental Cancer Research and at the recently created Lausanne branch of the Ludwig Institute for Cancer Research, two scientific institutions located on the same campus as the Department of Biochemistry. Major discoveries were hidden in these granules. Equipped with a formidable fresh practical knowledge of protein biochemistry, Jürg Tschopp readily identified perforin, the major lytic protein in the granules, and a whole family of proteases, the so-called granzymes 2. It is now well established that granzymes, together with perforin, are required for the efficient lysis of the cells targeted by CTLs, such as virally infected cells or transformed tumor cells. He spearheaded the efforts to generate perforin-deficient mice in the early 1990s, a time when knockout technology was still a major endeavor. These mice revealed that CTLs could resort to a second lytic pathway initiated by Fas ligand (FasL), a now well-established apoptosis-inducing ligand 3.
These observations set Jürg Tschopp's sights on the biochemical underpinnings of apoptosis. In taking apart this process, he identified a number of proteins that control apoptosis, among which was FLIP, a most powerful inhibitor of death receptor signaling 4. He was also first to discover that, similar to apoptosis, caspase-independent cell death (necroptosis) was a tightly controlled cell biological process that was dependent on the kinase RIP1. Making early use of bioinformatic approaches, Jürg Tschopp fueled the discovery of several additional Fas and FasL-related proteins, including APRIL and BAFF 5. The latter two ligands inhibit B-cell death and are essential for B-cell maturation and survival. Today, the use of BAFF antagonists is being developed by the pharmaceutical industry for the treatment of autoimmune diseases and have shown particular promise in the treatment of severe systemic lupus erythematosus.
Jürg Tschopp was behind the major discovery in 2002 of the multiprotein complex that activates caspase-1 and pro-IL-1β processing, which he baptized the “inflammasome” 6. The clinical implications of this seminal discovery have become apparent in recent years. Together with other groups, Jürg Tschopp found that mutations in one of the proteins forming the inflammasome cause several autoimmune disorders (the CAPS). Patients suffering from these genetic disorders are now successfully treated with IL-1 antagonists such as anakinra or blocking antibodies. Recently, Jürg Tschopp's group identified the molecular bases of gout, as uric acid crystals efficiently activate the inflammasome 7. This key insight was immediately exploited to successfully treat acute episodes of gout with IL-1 antagonists, providing fast relief of symptoms.
Jürg Tschopp described a novel cytoplasmic protein complex that detects RNA and which is essential for sensing most intracellular viruses. This complex consists of RIG-I and CARDIF and triggers a robust type I interferon response. His group demonstrated that CARDIF is proteolytically cleaved and inactivated by HCV, thereby explaining the persistence of this viral infection 8.
Jürg Tschopp's most recent insights dwelled on the role of inflammasomes in sensing the metabolic states of the intracellular milieu. In this regard he proposed a role for mitochondria in NLRP3 inflammasome activation 9. He could very clearly visualize the inflammasome platforms as conveyors of signals for the triggering of innate immune responses to a very diverse array of signals born out of cellular stress. He was vigorously pursuing complex circuits of molecular interactions. To cite just one very recent example, his group demonstrated that some type I interferons can efficiently block two of the inflammasomes, notably the NLRP3, and that this property was the likely mechanistic explanation for the therapeutic effect of IFN-β in patients with relapsing-remitting multiple sclerosis 10.
Not surprisingly, Jürg Tschopp gained wide recognition by his peers around the world. He received many early prizes: the Friedrich-Miescher Award in 1986, the Max Cloëtta award in 1992, and the San Salvatore Cancer Award in 2004. As his many achievements attracted increasing attention and won unanimous acclaim, he was bestowed the European Cell Death Organisation Award in 2006, the Louis Jeantet prize in 2008 and the Novartis Prize in Clinical Immunology in 2010. His extremely busy schedule notwithstanding, Jürg remained a very down-to-earth and always accessible person. I cannot remember a day when we crossed in the hallways of the Epalinges research center when he would not spontaneously stop to tell me his recent findings and brand new ideas. I was always amazed at his encyclopedic knowledge and his bold insights. I am certain that I am not alone in this experience. He was a scientist that knew how to communicate ideas and enthusiasm for research at the cutting edge of science to whomever would lend him an ear. The scientific community has lost a giant who was at the pinnacle of his many talents. Jürg Tschopp's passing away is a tragic untimely death. We shall all pay tribute to his invaluable contributions in a lifetime of unrelenting focus on scientific discovery. He was driven by both a boundless curiosity and an almost obsessive desire to change people's lives for the better via the advancement of our knowledge of the immune system directly at the molecular level. His legacy shall inspire current and future generations of scientists.
Pedro Romero, MD
Translational Tumor Immunology Group,
Ludwig Center for Cancer Research of the University of Lausanne,