A tribute to Sjur: Sjur Olsnes, 1939–2014

In the summer of 2014, the community of scientists studying bacterial protein toxins lost one of its pioneers and most prolific members, Sjur Olsnes. Sjur was a valued friend and colleague to those of us who knew and worked with him, and his passing was a deep loss.

Sjur was born in Bergen, Norway, in 1939 and grew up on a farm nearby. He studied medicine in Bonn and after a short period at the University of Bergen moved to Oslo, where he did doctoral research in the Institute for Cancer Research at the Norwegian Radium Hospital. Except for brief periods as visiting scientist at institutions abroad, Sjur spent his entire career performing fundamental biochemical and cell biological research at the Radium Hospital. He progressed there from Senior Scientist (1972) to Head of Biochemistry (1990) and also held professorial appointments at the University of Oslo in Biochemistry and Tumor Biology. The research group he headed at the Radium Hospital was internationally recognized for their work on the actions of toxins at the molecular and cellular levels and became a mecca in the field.

Sjur's scientific contributions, documented in more than 280 papers, include major discoveries that form the foundation of our current understanding of how protein toxins act at a biochemical and cellular level. While much of his research focused on protein toxins of plant or bacterial origin, his studies also extended to animal viruses and growth factors. The questions he addressed were primarily of a fundamental nature, but he always had an eye on relevance to cancer therapy. Below I briefly describe a few of Sjur's major contributions.

Sjur's doctoral research on protein synthesis, mRNA and polyribosomes formed the context for his first major discovery in the toxin field. He reported in 1972, in a paper coauthored by his mentor and collaborator, Alexander Pihl, that the toxic plant lectin, ricin, was a potent inhibitor of protein synthesis (Olsnes and Pihl 1972). Subsequently, he showed that ricin and the related lectin, abrin, each consisted of two complementary polypeptides, connected by a disulfide bridge. The A chain blocked protein synthesis by inactivating the 60S ribosomal subunit, while the B chain bound to galactose-containing cellular receptors. This pioneering research served to launch studies that extended over decades, in which Sjur and his students and collaborators revealed mechanisms and pathways of entry of these and other toxins into cells.

Elucidation of the physiological entry pathway of ricin was difficult, as the toxin binds to many cell-surface glycoproteins and glycolypids containing galactose, and only a small fraction ever undergoes translocation to the cytosol (Olsnes and Kozlov 2001). However, Sjur and his coworkers devised elegant approaches that led them ultimately to conclude that physiologically relevant toxin follows a retrograde pathway, in which it is first endocytosed, then enters the trans-Golgi network and finally is transported into the endoplasmic reticulum (ER), where translocation to the cytosol occurs. Passage through the trans-Golgi and ER compartments was conclusively demonstrated in a remarkable study in which recombinant DNA technology was used to add peptide signals for tyrosine sulfation (trans-Golgi) and glycosylation (ER) to the C terminus of the ricin A chain (Rapak, Falnes and Olsnes 1997).

Another major discovery was the finding, made together with Kirsten Sandvig, that low pH within the endosomal compartment triggered translocation of the catalytic A chain of diphtheria toxin to the cytosolic compartment, where the toxin's molecular target resides (Sandvig and Olsnes 1980). This conclusion was based in part on a beautiful experiment in which cell-associated toxin was induced to undergo transmembrane translocation to the cytosol by acidification of the extracellular medium. The low pH dependence of translocation explained, among other things, the curious earlier finding that the action of diphtheria toxin, like infection by certain animal viruses, was blocked by ammonium chloride and other agents that raise the pH of acidic membrane-bound intracellular compartments. The low pH-dependent pathway of entry is now known to be used by a wide variety of protein toxins, such as botulinum, tetanus and anthrax toxins, as well as a broad array of animal viruses. Discovery of the involvement of low pH in diphtheria toxin entry set the stage for investigations in many laboratories, including Sjur's, to understand how protein toxins insert into, and cross, lipid bilayers—still a topic of major interest.

Sjur Olsnes, 1939–2014 (photo by Chema Bassols).

Finally, let me highlight Sjur's long-term studies on the dual signal transduction modes by certain growth factors and cytokines. The discovery that many toxins penetrate to the cytosolic compartment of mammalian cells prompted his interest in the notion that the actions of some growth factors might not be fully explained simply by a classical signal transduction pathway, that is, by binding of the factor to a cell surface receptor that in turn transmits a signal to the interior of the cell. Sjur and his coworkers approached this question in a critical, scholarly manner (characteristic of all of his research) and managed to accumulate compelling evidence that at least one growth factor, aFGF, not only acts by the well-documented signal transduction pathway, but also penetrates to the cytosol, enters the nucleus and stimulates DNA synthesis. Sjur and his associates have summarized evidence that a number of growth factors, cytokines and hormones have dual modes of action (Olsnes, Klingenberg and Wiedłocha 2003).

Sjur received many accolades for his accomplishments, including scientific prizes and election to many prestigious organizations, including EMBO, the Norwegian Academy of Sciences, the Russian Academy of Sciences and the American Academy of Microbiology. His legacy also includes a large cadre of superbly trained students, fellows and associates, who carry forward his incisive, scholarly style of investigation. The respect and affection for Sjur by his students and associates were always evident in my visits to his lab.

Another aspect of Sjur's career as a scientist deserves mention. Early in his studies (1968) he obtained a fellowship to work for several months at the Institute of Molecular Biology in Moscow. Besides what he gained there from his research experience, he became fluent in the Russian language and was influenced by the warmth and friendliness of the Russian people. Many years later, in 1993, Sjur played a key role in founding at the University of Oslo, The Centre for Medical Studies, Moscow. He served as scientific director and board member of the Centre through 2008. The aim of the Centre was to counteract the brain drain of medical scientists from Russia and to exchange of information and personnel between the medical communities of Russia and Norway. The Centre represents a remarkably successful example of academic collaboration between two countries, having funded hundreds of financed researcher working years, articles in international journals, and joint symposia and workshops.

Sjur's effectiveness in leading the Center and fostering international cooperation is a reflection of his integrity, his competence as a scientist, his generosity, his lack of pretense, and his humble and sympathetic nature. Sjur enjoyed high respect, confidence and trust in Russia, as he did among his colleagues and students in the west.

I first met Sjur at a Gordon Conference in the 1970s, and recall feeling instant respect and liking for him. We became friends, visited each other's labs and had an opportunity to collaborate on a couple of occasions. My wife, Joan, and I visited Sjur and his wife, Barbara, many times over the years, including several days in 2006, when we were taken on a cruise of Norwegian fjords and had an opportunity to meet Sjur's sister and her family.

In this time period, Sjur began to show symptoms of what was to be diagnosed as Parkinson's, and he became hesitant to attend scientific meetings. By the time of the ETOX 16 meeting in Freiburg, his symptoms had worsened, and my wife and I decided to make a special trip to Oslo to see him. We were warmly received, as always, had an enjoyable meal with Sjur and Barbara, and exchanged gifts. Sjur's condition had stabilized, we were told, and he and Barbara were making plans to sell their home near the Radium Hospital and move to Bergen, to be near their daughter and her family. Sadly, however, Sjur's condition continued to deteriorate, and we learned in July 2014 that he had passed away in Oslo peacefully with Barbara at his side.

Sjur Olsnes was a leading, internationally recognized researcher in an era in which the fundamentals of how important protein toxins act were elucidated, and he deserves credit for major discoveries in this realm. Future generations will build upon the foundation Sjur and his coworkers built to deepen our understanding of these proteins and relevant biochemical and cellular processes. Further, they will use these molecular weapons from nature to create new drugs to treat human ailments, including cancer. Sjur sparked excitement about scientific discovery among those around him, and his kind and gentle nature fostered an atmosphere of cooperation and collaboration in the field. He will be remembered with respect, admiration and affection by all who knew him.

Conflict of interest. None declared.