#187 - The Warburg Effect: Otto Warburg’s Cancer Metabolism Theory with Sam Apple

KEYPOINTS

• 01

  A journalist found his story in a single sentence

  Sam Apple, a writer who teaches science writing at Johns Hopkins, was researching the clustering of metabolic diseases since the 19th century when he read that in 1923 a German scientist had made an important discovery about cancer metabolism. Googling Otto Warburg was a 'light-bulb moment'. He says he only writes about science when he has a central character, and Warburg became the subject of his New York Times Magazine piece in 2016 and then his book Ravenous.

• 02

  Warburg grew up among the titans of German science

  Born in 1883 to Emil Warburg, a prominent physicist from a famous Jewish family who rose to the top of German physics at the University of Berlin, Otto grew up with Einstein, Max Planck and Emil Fischer visiting the house. Einstein called Emil his favourite physicist. Otto served in World War I in his early 30s, although Einstein had urged him not to go and wrote to him again in 1918. A friend described his devotion to science as a prophet's fervour, and Warburg said a scientist must be prepared to die for the truth.

• 03

  The Warburg effect: cancer cells ferment glucose even with oxygen available

  Warburg had found that fertilized sea urchin eggs use more oxygen as they grow. In 1923 he expected cancer cells to do the same. Instead, they took up huge amounts of glucose and fermented it to lactate even when oxygen was present. Peter notes that fermentation yields about 2 ATP per glucose versus about 32–34 from full respiration, a roughly 17-fold difference, which is why the behaviour seemed so strange.

• 04

  Warburg insisted damaged respiration was the prime cause of cancer

  He argued that fermentation compensated for defective mitochondria and occurred in 100% of cancers. Apple says today's estimate is perhaps 70% or more. Warburg distinguished a 'prime cause' (damaged respiration) from many 'secondary causes', such as carcinogens. He never had a good way to test the idea, and his own first experiments in the early 1920s showed respiration continuing.

• 05

  He won the 1931 Nobel Prize for respiration, not cancer

  Warburg was nominated in 1926 for his cancer work, in what was apparently a tie that went to someone else. In 1931 he won for identifying the respiratory enzyme now called cytochrome oxidase, the last step of respiration. Apple and Peter discuss whether his later work on hydrogen transfer and coenzymes was his best science, research that ended up having a vast, mostly unseen influence on American life.

• 06

  A Jewish-descended scientist survived inside Nazi Germany

  Of about 2,500 Jewish scientists at German institutions, Warburg was the only one who stayed to the end. He was useful for propaganda around the 1936 Berlin Olympics, but by 1941 that value was gone. On June 21, 1941, he was summoned to meet Viktor Brack, architect of the Nazi euthanasia killing programme, and was told he could live on one condition: that he work on cancer. Apple argues that Hitler, who lost his beloved mother to breast cancer when he was a teenager, was likely involved in that decision.

• 07

  Oncogenes eclipsed Warburg, until a 2009 rethink

  After the war, Warburg feuded with critics such as Sidney Weinhouse in Science in 1956 and died in 1970. The discovery of oncogenes in the 1970s, recognized with the 1989 Nobel to Harold Varmus and Michael Bishop, pushed metabolism aside. Weinberg and Hanahan's 2000 'Hallmarks of Cancer' paper left Warburg out. The renaissance came with a 2009 Science paper by Matthew Vander Heiden, Lewis Cantley and Craig Thompson. They accepted the Warburg effect but argued the mitochondria are largely intact, and that the cells take up glucose to get building blocks for nucleotides and lipids rather than to make up for an energy shortfall.

• 08

  Apple's thesis: hyperinsulinemia may link obesity and cancer

  In the late 1990s, just as labs such as Craig Thompson's and Chi Van Dang's returned to Warburg metabolism, epidemiology showed that elevated insulin and obesity both correlate with cancer. Apple thinks prevention should focus on hyperinsulinemia. Peter notes that insulin could only be measured in blood from the late 1960s. Even tumours with PI3K pathway mutations may remain responsive to insulin, he notes. Obesity's link is harder to untangle than tobacco's because its hazard ratios are far smaller.