Otto Warburg

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Otto Warburg

Biochemist Otto Warburg (1883-1970) discovered cell oxidation and identified the iron-enzyme complex, which catalyzes cell oxidation. For this work, he was awarded the Nobel Prize in physiology or medicine in 1931.

Otto Warburg is considered one of the world's foremost biochemists. His achievements include discovering the mechanism of cell oxidation and identifying the iron-enzyme complex, which catalyzes this process. He also made great strides in developing new experimental techniques, such as a method for studying the respiration of intact cells using a device he invented. His work was recognized with a Nobel Prize for medicine and physiology in 1931.

Otto Heinrich Warburg was born on October 8, 1883, in Freiburg, Germany, to Emil Gabriel Warburg and Elizabeth Gaertner. Warburg was one of four children and the only boy. His father was a physicist of note and held the prestigious Chair in Physics at University of Berlin. The Warburg household often hosted prominent guests from the German scientific community, such as physicists Albert Einstein, Max Planck, Emil Fischer—the leading organic chemist of the late-nineteenth century, and Walther Nernst —the period's leading physical chemist.

Warburg studied chemistry at the University of Freiburg beginning in 1901. After two years, he left for the University of Berlin to study under Emil Fischer, and in 1906 received a doctorate in chemistry. His interest turned to medicine, particularly to cancer, so he continued his studies at the University of Heidelberg where he earned an M.D. degree in 1911. He remained at Heidelberg, conducting research for several more years and also making several research trips to the Naples Zoological Station.

Warburg's career goal was to make great scientific discoveries, particularly in the field of cancer research, according to the biography written by Hans Adolf Krebs, one of Warburg's students and winner of the 1953 Nobel Prize in medicine and physiology. Although he did not take up problems specifically related to cancer until the 1920s, his early projects provided a foundation for future cancer studies. For example, his first major research project, published in 1908, examined oxygen consumption during growth. In a study using sea urchin eggs, Warburg showed that after fertilization, oxygen consumption in the specimens increased 600 percent. This finding helped clarify earlier work that had been inconclusive on associating growth with increased consumption of oxygen and energy. A number of years later, Warburg did some similar tests of oxygen consumption by cancer cells.

Warburg was elected in 1913 to the Kaiser Wilhelm Gesellschaft, a prestigious scientific institute whose members had the freedom to pursue whatever studies they wished. He had just begun his work at the institute when World War I started. He volunteered for the army and joined the Prussian Horse Guards, a cavalry unit that fought on the Russian front. Warburg survived the war and returned to the Kaiser Wilhelm Institute for Biology in Berlin in 1918. Now 35 years old, he would devote the rest of his life to biological research, concentrating on studies of energy transfer in cells (cancerous or otherwise) and photosynthesis.

One of Warburg's significant contributions to biology was the development of a manometer for monitoring cell respiration. He adapted a device originally designed to measure gases dissolved in blood so it would make measurements of the rate of oxygen production in living cells. In related work, Warburg devised a technique for preparing thin slices of intact, living tissue and keeping the samples alive in a nutrient medium. As the tissue slices consumed oxygen for respiration, Warburg's manometer monitored the changes.

During Warburg's youth, he had become familiar with Einstein's work on photochemical reactions as well as the experimental work done by his own father, Emil Warburg, to verify parts of Einstein's theory. With this background, Warburg was especially interested in the method by which plants converted light energy to chemical energy. Warburg used his manometric techniques for the studies of photosynthesis he conducted on algae. His measurements showed that photosynthetic plants used light energy at a highly efficient sixty-five percent. Some of Warburg's other theories about photosynthesis were not upheld by later research, but he was nevertheless considered a pioneer for the many experimental methods he developed in this field. In the late 1920s, Warburg began to develop techniques that used light to measure reaction rates and detect the presence of chemical compounds in cells. His "spectrophotometric" techniques formed the basis for some of the first commercial spectrophotometers built in the 1940s.

His work on cell respiration was another example of his interest in how living things generated and used energy. Prior to World War I, Warburg discovered that small amounts of cyanide can inhibit cell oxidation. Since cyanide forms stable complexes with heavy metals such as iron, he inferred from his experiment that one or more catalysts important to oxidation must contain a heavy metal. He conducted other experiments with carbon monoxide, showing that this compound inhibits respiration in a fashion similar to cyanide. Next he found that light of specific frequencies could counteract the inhibitory effects of carbon monoxide, at the same time demonstrating that the "oxygen transferring enzyme," as Warburg called it, was different from other enzymes containing iron. He went on to discover the mechanism by which iron was involved in the cell's use of oxygen. It was Warburg's work in characterizing the cellular catalysts and their role in respiration that earned him a Nobel Prize in 1931.

Nobel Foundation records indicate that Warburg was considered for Nobel Prizes on two additional occasions: in 1927 for his work on metabolism of cancer cells, then in 1944 for his identification of the role of flavins and nicotin-amide in biological oxidation. Warburg did not receive the 1944 award, however, because a decree from Hitler forbade German citizens from accepting Nobel Prizes. Two of Warburg's students also won Nobel Prizes in medicine and physiology: Hans Krebs (1953) and Axel Theorell (1955).

In 1931 Warburg established the Kaiser Wilhelm Institute for Cell Physiology with funding from the Rockefeller Foundation in the United States. During the 1930s, Warburg spent much of his time studying dehydrogenases, enzymes that remove hydrogen from substrates. He also identified some of the cofactors, such as nicotinamide derived from vitamin B3 (niacin), that play a role in a number of cell biochemical reactions.

Warburg conducted research at the Kaiser Wilhelm Institute for Cell Physiology until 1943 when the Second World War interrupted his investigations. Air attacks targeted at Berlin forced him to move his laboratory about 30 miles away to an estate in the countryside. For the next two years, he and his staff continued their work outside the city and out of the reach of the war. Then in 1945, Russian soldiers advancing to Berlin occupied the estate and confiscated Warburg's equipment. Although the Russian commander admitted that the soldiers acted in error, Warburg never recovered his equipment. Without a laboratory, he spent the next several years writing, publishing two books that provided an overview of much of his research. He also traveled to the United States during 1948 and 1949 to visit fellow scientists.

Even though Warburg was of Jewish ancestry, he was able to remain in Germany and pursue his studies unhampered by the Nazis. One explanation is that Warburg's mother was not Jewish and high German officials "reviewed" Warburg's ancestry, declaring him only one-quarter Jewish. As such he was forbidden from holding a university post, but allowed to continue his research. There is speculation that the Nazis believed Warburg might find a cure for cancer and so did not disturb his laboratory. Scientists in other countries were unhappy that Warburg was willing to remain in Nazi Germany. His biographer Hans Krebs noted, however, that Warburg was not afraid to criticize the Nazis. At one point during the war when Warburg was planning to travel to Zurich for a scientific meeting, the Nazis told him to cancel the trip and to not say why. "With some measure of courage," wrote Krebs, "he sent a telegram [to a conference participant from England]: 'Instructed to cancel participation without giving reasons."' Although the message was not made public officially, the text was leaked and spread through the scientific community. Krebs believed Warburg did not leave Germany because he did not want to have to rebuild the research team he had assembled. The scientist feared that starting over would destroy his research potential, Krebs speculated.

In 1950 Warburg moved into a remodeled building in Berlin which had been occupied by U.S. armed forces following World War II. This new site was given the name of Warburg's previous scientific home—the Kaiser Wilhelm Institute for Cell Physiology—and three years later renamed the Max Planck Institute for Cell Physiology. Warburg continued to conduct research and write there, publishing 178 scientific papers from 1950 until his death in 1970.

For all of his interest in cancer, Warburg's studies did not reveal any deep insights into the disease. When he wrote about the "primary" causes of cancer later in his life, Warburg's proposals failed to address the mechanisms by which cancer cells undergo unchecked growth. Instead, he focused on metabolism, suggesting that in cancer cells "fermentation" replaces normal oxygen respiration. Warburg's cancer studies led him to fear that exposure to food additives increased one's chances of contracting the disease. In 1966 he delivered a lecture in which he stated that cancer prevention and treatment should focus on the administration of respiratory enzymes and cofactors, such as iron and the B vitamins. The recommendation elicited much controversy in Germany and elsewhere in the Western world.

Warburg's devotion to science led him to forego marriage, since he thought it was incompatible with his work. According to Karlfried Gawehn, Warburg's colleague from 1950 to 1964, "For him [Warburg] there were no reasonable grounds, apart from death, for not working." Warburg's productivity and stature as a researcher earned him an exemption from the Institute's mandatory retirement rules, allowing him to continue working until very near to the end of his life. He died at the Berlin home he shared with Jakob Heiss on August 1, 1970.

Further Reading

Krebs, Hans, Otto Warburg: Cell Physiologist, Biochemist and Eccentric, Clarendon Press, 1981. □