July 13, 2024
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My friend Barry Shain recently asked me about the Warburg effect (I have no idea why!), and so the hero of today’s article is Otto Warburg. But before we get to him, we should muse about his family, which was one of the great German-Jewish families of the 19th and early 20th centuries—Strauss, Furstenberg, Rathenau, Schiff, Loeb, Kuhn, Warburg. The Warburg family name came from its town of origin in Germany and was prominent because of the M.M. Warburg Bank, founded in 1798, which rivaled that of Rothschild in France, and from which the family derived its social standing and wealth.

Many of its descendants also became bankers, financiers, or economists—Paul Warburg emigrated to the U.S. at the age of 34 and is credited with originating the Federal Reserve system. While the roots of the family were Orthodox, assimilation and conversion were common among its descendants in order to try to gain acceptance in German society.

This brings us to Emil Warburg, whose parents were Orthodox but who assimilated and then converted. He was professor of physics at the University of Berlin in the early 20th century at the time that Albert Einstein was there, and the two were close friends. As a result, Emil’s son, Otto, came under the influence and mentorship of Einstein, who recognized his brilliance and potential. Because of this connection, Otto resolved that he, too, would obtain a Nobel Prize.

As a proud German, Otto served a distinguished stint as a cavalry officer in World War I before university. He decided that physics was too crowded and difficult a field in which to get a Nobel and that biology/medicine would be easier (same reason I went into it). He then reasoned that the most straightforward way to win a Nobel Prize would be to cure cancer, which at the time, in the early 1920s, was on a dramatic rise, and striking great fear in Germany. He was unusually brilliant and innovative and does not seem to have had a problem with self-esteem and self-confidence. He studied with Emil Fischer, himself a Nobel Prize winner in chemistry, and then went off on his own research.

The hallmark of malignancy is uncontrolled proliferation. On a cellular level, this requires much enhanced energy sources and respiration in order to maintain this ongoing process. In normal aerobic respiration, a cell combines glucose and oxygen to form adenosine triphosphate (ATP) for energy, generating carbon dioxide and water as waste products. This would be inadequate to maintain the rate of proliferation observed in malignant cells, as the oxygen supply would not be adequate. Warburg discovered an alternative metabolic pathway, fermentation or aerobic glycolysis, by which cells convert glucose to lactic acid and thereby release energy. This is a less efficient mechanism for overall energy production but requires dramatically less oxygen and utilizes much more glucose and thus can support much more rapid rates of cellular proliferation.

This mechanism leads to dramatically enhanced glucose uptake by cancer cells. Warburg believed this cellular change to be the root cause of cancer. He was awarded the 1931 Nobel Prize in Medicine for this discovery: The clever and innovative lab techniques he devised to describe and define it certainly merited the award. It led over the years to the belief by many that sugar restriction in cancer patients would cure or improve cancer outcomes, but this has generally been unavailing.

As became apparent after 1950, cancer arises primarily from molecular genetic causes, and thus the Warburg effect is just a secondary consequence or manifestation of the malignant phenotype. Interest in it, therefore, has waned for decades, though recently it has raised its head anew and some investigators have explored which enzymes may regulate the expression of the Warburg effect, with the idea that by identifying and inhibiting them, they can find new pathways to cancer treatment. Chief among them has been Lewis Cantley, current director of the Weill-Cornell Cancer Center.

After his prize, Warburg became director of the Kaiser Wilhelm Institute for Cell Physiology in Berlin. When the Nazis came to power, he was considered half-Jewish (his mother was Protestant) though this was not adequate protection, of course. In addition, he was homosexual; his partner served as his administrator in the lab as well as his assistant at home. Their relationship seems to have been fairly open. Warburg had the opportunity to leave Germany, as did most other prominent scientists, but did not want to abandon his carefully created precision scientific instruments and well trained staff. So he ignored the Nazis and just continued to work.

His brazenness, arrogance and, one may say, chutzpah apparently worked because he basically persisted throughout the war, not without some hiccups, but pretty well, all things considered. It is likely that Hitler, the Gestapo and the Nazi leadership all felt paranoid about cancer—Hitler’s mother died of breast cancer when he was a teenager—and hoped Warburg would achieve his ultimate goal. After the war, he was ostracized by prior colleagues for remaining, essentially seen as a collaborator, though it would seem incredibly unlikely he had any sympathy for Nazism and was simply oblivious to anything but his science.


Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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