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George Klein: 1925–2016

  1. Klaus Rajewskya,1
  1. aImmune Regulation and Cancer, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany

George Klein, famous cancer biologist and acclaimed writer on matters of science, human responsibility, and the human condition, decorated by innumerable awards, honorary doctorates and other honors, elected member of this Academy and many other learned societies, including the Royal Swedish Academy of Sciences and the American Philosophical Society, and Member of the Nobel Assembly of Karolinska Institute from 1957 to 1993, died on December 10, 2016 at the age of 91. He will be dearly missed by pupils, colleagues, readers, and friends throughout the world, many of whom he stayed connected with until the very end of his life. In a unique way, this included people from not only diverse fields of science, but also philosophers, historians, and artists. Klein leaves behind his wife Eva (nee Fischer), herself a distinguished biologist and scientific partner from the beginning. They had a son and two daughters.

George Klein. Image courtesy of Stefan Imreh (Karolinska Institutet, Stockholm).

Klein was born in 1925 into an assimilated Jewish family in the Hungarian-speaking part of present Eastern Slovakia, where he grew up in a well-educated and cultured environment. He moved with his mother and step-father to Budapest at the age of five. The outbreak of World War II and the German occupation of Hungary in March 1944 led to defining experiences in Klein’s life. Working as an assistant secretary at the Jewish Council in Budapest, he learned, in April 1944, of the Vrba–Wetzler Report, which was secretly communicated to the Jewish Council after Rudolf Vrba’s and Alfred Wetzler’s escape from Auschwitz and represented a firsthand account of the fate of deported Jews. Met by disbelief among his relatives and friends, the report made Klein, after having been arrested and pressed into forced labor, ultimately escape from the train station where the deportation wagons were waiting. He lived underground in Budapest until the liberation of the city by the Russian army in January 1945. Having escaped from almost certain death, Klein threw himself with all intensity into studying medicine, which had been his intention for years. He first attended the university in Szeged and then, as soon as it opened, in Budapest. Soon, however, the political developments following the country’s liberation became discomforting and Klein decided to make a second escape, this time abroad to Sweden, where he settled with his wife Eva in the summer of 1947, shortly before Hungary disappeared behind the iron curtain (1, 2). Still medical students, Klein and his wife were accepted into Torbj?rn Caspersson’s laboratory at the Karolinska Institute in Stockholm, and that’s where their scientific careers really started. Eva and George Klein would work together at Karolinska until George Klein’s death.

To work in Caspersson’s department was a stroke of luck. In an early attempt to combine cell morphology with cytochemistry, Caspersson tried to analyze the distribution of proteins and nucleic acids in various types and organelles of cells by UV microspectroscopy. Soon the Kleins would run experiments trying, unsuccessfully, to determine protein-nucleic acid distribution in living Ehrlich ascites tumor cells. Work in Caspersson’s laboratory also addressed the banding pattern of polytenic insect chromosomes, anticipating the development of banding techniques of mammalian chromosomes by Caspersson and Lore Zech many years later, and used by Klein and colleagues for their pioneering work on chromosomal translocations in cancerogenesis, as discussed below. Caspersson also arranged early on for Klein to spend 4 months at the Fox Chase Cancer Institute in Philadelphia, where he met geneticists like Jack Schultz and Theodore Hauschka and familiarized himself with genetic approaches and inbred strains of mice, unavailable at that time in Sweden. Apart from the science, Klein experienced the nonhierarchical structure and free spirit at Fox Chase as a personal revelation. When he returned to the Karolinska, the stage was set for the groundbreaking work on tumor immunology and the origin of tumorigenesis, which the Kleins and their colleagues would perform over the following decades.

From the beginning, George Klein’s main scientific interest was tumor biology: How do tumors arise from normal cells and what controls host–tumor interaction? Early work focused on the spontaneous generation of tumor cell variants and their selection in vivo, using a variety of mouse tumor models. This soon led to genetically defined experiments in which tumor variants, having lost major histocompatibility antigens, escaped control by the host immune system upon allogeneic transplantation. In 1960, Klein and colleagues provided definitive evidence that tumor cells express tumor-specific antigens through which they can be recognized and eliminated by the host, by showing resistance to chemically induced sarcomas in primary autochthonous hosts whose tumors had been surgically removed (3). However, this resistance required sensitization with killed tumor cells and did not spontaneously arise in the tumor-bearing animals; it was thus not reflecting a mechanism of tumor immune surveillance. This general problem, namely to which extent the immune system controls or can be made to control malignancy, remained a dominant theme in Klein’s thinking over the following decades, a main conclusion being that immune surveillance is restricted to virally induced—as opposed to spontaneous—tumors (4).

By the time of the work on chemically induced tumors, George Klein was already a professor at the Karolinska and head of the department of tumor biology, which had been founded for him and was about to move, in 1961, into its own new building. His work had attracted widespread attention in the scientific world, and soon the new institute became overcrowded with students and scientists streaming in from Sweden and abroad. Generously supported by the Swedish Cancer Fund, Klein ran the department in a most unconventional way, following his vision of a free scientific community and contrasting the constraints he had experienced back in Hungary. Members of the department, be they students or grown-up scientists, enjoyed a maximum of freedom and independence, scientific passion was the only common currency, and ambitions ran high. “Klein’s kids” became a brand name in the scientific community, many with bright careers ahead of them. With Klein’s broad interests in all aspects of tumor biology and beyond, a constant stream of visitors, world-famous scientists among them, came through the department, and a vast network of national and international cooperation was established. Thus, when George and Eva decided in the mid-1960s to address human cancers and chose endemic Burkitt lymphoma, a malignancy of the B-cell lineage, and the B-cell–transforming Epstein–Barr virus as the main targets, the department of tumor biology in Stockholm soon became, through Klein’s incessant activity, the central node to which Burkitt tumor samples were shipped on a weekly basis from Nairobi and from where they were in turn distributed to key collaborators in Europe and the United States. The impact of this far-sighted concept of international cooperation on the field was enormous, yielding fundamental insights into mechanisms of Burkitt lymphomagenesis and Epstein–Barr virus biology over many years.

Klein’s group played its own significant role in these scientific developments. Their most fundamental discoveries, based on the chromosome banding technique developed by their neighbors Caspersson and Zech, and initiated in the Klein laboratory by George Manolov and Yanka Manolova, were recurrent reciprocal chromosomal translocations first in Burkitt lymphoma, then also (through a collaboration with Mike Potter’s group at the NIH) in a mouse model of plasmacytoma. Strikingly, these translocations involved homologous chromosomal sites in the two species. As a common denominator, the translocation breakpoints were at a site on chromosome 8 in the human and 15 in the mouse, which became adjacent to chromosomal regions harboring Ig heavy- or light-chain genes. Considering that (human) Burkitt lymphoma and (mouse) plasmacytomas are tumors of the B-cell lineage and share expression of antibody genes, Klein proposed the hypothesis that, along the lines of the promoter insertion model of avian leukosis virus-induced lymphomas in chickens (5), the same critical proto-oncogene was activated in the two tumor entities by coming under the control of the transcriptionally active Ig gene loci (6). Although considered by a friend the “most hair-raising extrapolation from the centimorgans to the kilobases” (2), Klein’s hypothesis was proven right by a flood of papers from leading molecular biology laboratories in the United States and Australia just a year later. As in the avian model, the culprit was the c-myc gene, which was activated in Burkitt lymphoma and the murine plasmacytomas through translocation into Ig loci. I remember long discussions with Klein about the puzzling observation that the c-myc translocations in Burkitt always involve the inactive Ig alleles of the cells, thus preserving antibody expression; and his satisfaction when we found the latter to be essential for the survival of B lymphocytes, the progenitors of the Burkitt lymphoma cells. These discussions, which began decades ago, have continued and stimulated work that is still ongoing.

Apart from his work on oncogenes and the Epstein–Barr virus, Klein also had played a pioneering role in the development of the concept of tumor-suppressor genes. In classic experiments carried out in collaboration with Henry Harris in Oxford in the early 1970s, Wiener, Klein, and Harris had shown that cell hybrids between malignant and normal cells reacquired malignancy only after chromosome loss, “malignancy thus [behaving] as if it were a recessive character” (7). Most notably, however, in the mid-1980s Klein began a second, parallel career as a popular writer. Although he wrote his books in Swedish, including memoirs of his life in Hungary, three books are available in English translation (8?10). These are collections of essays dealing initially with matters of science and scientists connected to them, and personal experiences in the same context. However, eventually the essays go beyond this into the realm of philosophy, art, and the human condition in general. They also testify to his, an atheist’s, attachment to institutions, historical sites, and personalities in Israel. Without attempting an appraisal of this astounding and fascinating work, I will mention only one aspect to which I have a personal connection. Benno Müller-Hill, a friend and distinguished colleague of mine at the Institute for Genetics in Cologne, Germany, had like George entered a second career, researching the role of German scientists and doctors in the elimination of Jews, Gypsies, and the mentally ill during the Third Reich. In 1984, Müller-Hill published a shocking book in which he described the participation of normal scientists and doctors in the Nazi atrocities (11). When Müller-Hill and Klein met at a meeting I had helped to organize at the Institute for Genetics, a close friendship developed immediately, with an extensive correspondence and mutual visits over the following two decades. Discussions with Müller-Hill, including those at a meeting Klein arranged in Paris between himself, Müller-Hill, Rudolf Vrba, and Fran?ois Jacob, appear repeatedly in Klein’s books, in their attempt to understand how scientists could be drawn into state-promoted criminal behavior, and in which contexts similar dangers might loom in present times.

With the ghosts of the past present throughout his life, Klein built his own universe like a true renaissance man: by accumulating and interconnecting encyclopedic knowledge in vast areas of human activity, speaking several languages (and reciting by heart poems of Dante and Rilke, among other poets), engaging in scientific work, practicing and listening to music, and entertaining a continuous discourse with scientists, artists, musicians, and philosophers all over the world. This was his true homeland, where he lived, obsessively curious and searching for meaning, and much of his time in a state he called “flow,” after the psychologist Mihály Csíkszentmihályi (12): an experience of timelessness and euphoria while concentrating on a task. All of us who feel close to him, a huge community of people from many angles of society, remember Klein from his work and personal encounters with immense gratefulness, for a wealth of inspiration, new insights, and encouragement. George Klein lives on in our memory.

Acknowledgments

I thank Georg Bornkamm, Thomas Blankenstein, and Hans Wigzell for advice and helpful discussions, and Riikka Lauhkonen-Seitz for editorial help.

Footnotes

  • ?1Email: klaus.rajewsky{at}mdc-berlin.de.
  • Author contributions: K.R. wrote the paper.

  • The author declares no conflict of interest.

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