Otto Warburg: the journey towards the seminal discovery of tumor cell bioenergetic reprogramming

Ana M Urbano
Biochimica et Biophysica Acta. Molecular Basis of Disease 2020 September 16, : 165965
Metabolic reprogramming is now regarded as a hallmark of cancer. This phenomenon was first observed at the level of cellular energetics, in the form of very high rates of lactic acid fermentation, not only in anoxia, but also in the presence of oxygen levels that do not compromise respiration. This intriguing tumor phenotype, characterized by a very low energy yield, was unveiled, in the early 1920s, by Otto Warburg, one of the greatest biochemists of all time. This manuscript outlines aspects of Warburg's personal and research life that, in retrospect, might be viewed as a preparation for his successful approach to the cancer problem. It also discusses the experiments that led to the discovery and briefly presents Warburg's theory for the origin of tumors. Finally, it concludes with considerations regarding the novel avenues that this monumental and still intriguing discovery opened in terms of diagnosis and treatment of cancer. Note on sources Biographical notes were mostly taken from a biography of Otto Warburg written by Hans Krebs (1). This biography is an expansion of the obituary memoir of Warburg that Krebs prepared for the Royal Society of London (2). Krebs worked in Warburg's laboratory as a research assistant from January 1926 until March 1930 and the two maintained a friendship and were in regular contact until Warburg's death, on 1 August 1970. Krebs had an immense admiration for Warburg's "penetrating intelligence, and original and imaginative approach to any situation", as well as for Warburg's "independence from common-held beliefs, judgements, and prejudices" (1), acknowledging that he learned from him more than from any other teacher (3). From his first encounters with Warburg, Krebs immediately perceived that he was dealing with a unique personality, which prompted him to keep notes about "his way of life and some of his sayings" (1). These Warburgiana, as Krebs designated them, would prove invaluable while writing Warburg's biography. Another important source of biographical information, as well as of information regarding Warburg's research career, was a biography of Krebs written by Frederick Holmes (4). This biography had a significant input by Krebs himself, who made available a large number of his laboratory note books and with whom Holmes had extended conversations. A firsthand account of Warburg's outlook on scientific research can be found in an autobiographical chapter that he wrote for the Annual Review of Biochemistry, in 1963 (5). Nobel Prize acceptance speeches (Nobel Lectures) were invaluable for a better appreciation of the awardees' theoretical thinking and of the contemporary state of knowledge in their fields of research. There were two main types of sources for the section on Warburg's initial work on the metabolism of tumors. On one hand, the original research papers, written in German and published in 1923 and 1924. Most of these papers can also be found in a compilation that Warburg edited in 1926, entitled Über den Stoffwechsel der Tumoren: Arbeiten aus dem Kaiser Wilhelm Institut für Biologie (6). This compilation has been translated into, at least, English and French (7, 8). The second source is a paper written in English and published in 1925, which is a transcript of an address delivered by Warburg before the Rockefeller Institute, in 1924 (9). In this address, Warburg not only summarized his early findings on the metabolism of tumors, he also presented, with an outstanding clarity, the rationale for both his experiments and the conclusions that he drew.

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