1931 Nobel Prize in Physiology or Medicine β Otto Warburg
What You Will Learn in This Article
You will understand exactly what machinery inside our cells transforms the oxygen we inhale with each breath into energy, and how the discovery that revealed this machinery continues to influence cancer research 90 years later.
Where Does Oxygen Actually Go?
"We breathe oxygen to make energy." This is a fact found even in elementary school textbooks. However, until the early 1900s, no one knew the precise mechanism behind this process.
It was known that oxygen enters the body, passes from the lungs into the bloodstream, and from the bloodstream into tissues. However, exactly what does the oxygen combine with inside the cell, and how does it participate in energy conversion? This question remained one of the last major mysteries in biochemistry.
If we were to liken a cell to a program, oxygen is the essential input resource that allows the program to run. The problem was that no one knew the identity of the function that processed this input. The input and output (energy) could be observed, but the intermediate processor was a black box.
Otto Warburg was the one who opened this black box and revealed the precise machinery inside. His discovery remains valid today in two ways: elucidating the nature of cellular respiration, and unexpectedly opening the door to cancer metabolism research as an unforeseen byproduct.
The Landscape of the Time β The Depths of the Great Depression
In 1931, the world was in the midst of the Great Depression, reaching its deepest point. The unemployment rate in the United States was over 16% and continued to rise. Bank failures occurred, and in May, the Austrian bank Creditanstalt collapsed, spreading the Great Depression to Europe. The unemployment rate in Germany reached 24% by the end of the year.
This economic collapse was giving rise to political radicalization. The Weimar Republic was virtually dysfunctional, and President Hindenburg was ruling by emergency decree. The Nazis were rapidly growing in this chaos. Hitler becoming Chancellor was only 15 months away, in January 1933.
The Kaiser Wilhelm Institute (the predecessor of today's Max Planck Institute) in Berlin, where Warburg worked, was one of the centers of world science at that time. Einstein, Haber, Planck, SchrΓΆdinger β the largest concentration of the greatest scientists in human history was gathered here. However, a significant number of them were Jewish, and a few years later, under the Nazi regime, this cluster of knowledge would be explosively dispersed, migrating to the United States and the United Kingdom. This was the decisive reason for the shift of the 20th-century scientific axis from Europe to North America.
Warburg is the only one among them who remains. We will revisit this story later.
If we compare it to Korean history, in July 1931, the Manbo Mountain Incident occurred. A dispute between Korean and Chinese farmers in Manchuria over irrigation water escalated into anti-Chinese riots across Korea. The Japanese Kwantung Army used this as an excuse to launch the Mukden Incident in September and establish Manchukuo. While the world was collapsing due to the Great Depression, in the Far East, the prelude to a new war was unfolding. While the bond between oxygen and cells was being revealed in Europe, the bond between countries in Asia was being forcibly broken.
Character Narrative β The Tool Maker
Otto Warburg was born in 1883 in Freiburg, Germany. His father, Emil Warburg, was a renowned physicist, and this family was one of the leading Jewish families in Germany. From an early age, he grew up in an environment where Einstein and Max Planck visited his home.
His educational background was crucial. He received training in all three fields: chemistry, medicine, and physics. This multidisciplinary training shaped his research style β he becomes a person who deals with both principles and tools.
The Invention of the Manometer
What made Warburg's research possible was the special instrument he improved: the manometer. This device could measure the amount of oxygen consumed per unit of tissue with great precision.
The fundamental problem in cell respiration research at the time was measurement sensitivity. The amount of oxygen used by a piece of tissue was so small that it was difficult to quantify with existing equipment. Warburg's manometer overcame this limitation. This single tool transformed cell respiration research from qualitative observation to quantitative experimentation.
This attitude led to his Nobel Prize. To delve into principles, you must first create tools that allow you to see those principles. Today, this principle remains valid in biomedical research. Without a PCR machine, there is no gene testing; without a fluorescence microscope, there is no cell imaging.
The Hint from Cyanide
The method by which Warburg made his key discovery was as follows: He added various chemicals to tissues and precisely measured how the oxygen consumption rate changed using a manometer.
Among them, potassium cyanide (KCN) was decisive. When a small amount of cyanide was added to the tissue, oxygen consumption completely stopped. Cyanide is known to bind strongly to certain metal ions. Therefore, the oxygen consumption machinery must be something that contains metal ions.
From this hint, he began to look for the iron-containing pigment in the tissue. This was the "respiratory enzyme," which was later identified as cytochrome c oxidase. This protein complex, embedded in the mitochondrial membrane inside the cell, is the machinery that finally converts the oxygen we consume every second into water.
Key Achievements β Cellular Respiration as a Native Library
Oxygen Meets at the Last Moment
What Warburg revealed was the final stage of cellular respiration. In the process by which cells break down glucose in several stages to create energy currency in the form of ATP, oxygen precisely meets the machine called cytochrome c oxidase in this final stage. When oxygen binds to this machine to form water, the reaction energy drives the production of ATP.
The CS analogy is naturally relevant here. This is like a native library binding.
When a program reads a file or sends data over a network, it ultimately calls the operating system's system calls (e.g., read(), send()). These system calls eventually interact with hardware. The interface at the very end of the software world that interacts with hardware, that is the system call.
Cytochrome c oxidase plays the same role in cells. The glucose breakdown, which is a purely chemical process, goes through several steps, but the final payment of energy is the chemical bond between oxygen, a physical element. Cytochrome c oxidase is that interface point. The last touchpoint between software (biochemical circuit) and hardware (oxygen atom).
If cyanide blocks this interface, the program (cell) stops completely. If you remove the system call, the rest of the program will not work, just as if it cannot read a single file, no matter how normal it is. This is why cyanide can kill a person in a few minutes.
However, this analogy breaks down here. Native bindings in software are explicitly designed by us. However, cytochrome oxidase is created by evolution, and why this specific metal arrangement and specific reaction pathway were chosen remains, in part, an open question. Some bacteria have systems that use other elements (nitrate, sulfate) as the last payment target instead of oxygen. Our system is one of the possibilities.
An Unexpected Byproduct β The Strangeness of Cancer Metabolism
During his cell respiration research, Warburg observed an abnormal metabolic pattern in cancer cells. Normal cells, when there is sufficient oxygen, prefer to use oxygen-based complete oxidation (respiration). However, the cancer cells he observed preferred the fermentation pathway even under sufficient oxygen conditions.
Fermentation is much less efficient than oxidation. 2 ATP per glucose molecule vs. more than 30 ATP in oxidation. Why do cancer cells choose this inefficient pathway? This observation is the first description of what is now called the "Warburg effect."
Warburg made a bold hypothesis based on this observation: Cancer cells rely on fermentation because their respiratory system is damaged. This metabolic change is the root cause of cancer. It is difficult to say that this hypothesis is completely correct today. However, his observation that the metabolism of cancer cells is fundamentally different from normal cells was correct, and research targeting this difference with anticancer drugs is active today. Metformin, 2-DG, and other metabolic target anticancer drugs have their roots in Warburg's research.
This is why his research has survived to this day. Even if the hypothesis he provisionally set up was not completely correct, the questions he opened up are still unresolved and active today.
The Jew Who Survived the Nazi Era β An Ironic Legacy
The most controversial part of Warburg's life is how he survived the Nazi era (1933-1945).
After the Nazis came to power in 1933, the purge of Jews from the German academic community began. Many Jewish scientists, including Einstein and Haber, were dismissed and forced into exile. Warburg was also of Jewish descent. However, he remained in his position as director of the institute and continued his research.
There are several theories about the reason for this exceptional status. The most plausible is that it was due to Hitler's personal fear of cancer. Hitler, having lost his mother to breast cancer, was extremely afraid of cancer and it is said that Warburg was designated as a scientist who could "conquer cancer" and was given special protection. The Nazis reclassified his Jewish grade as "1/4 Jewish" (nur teilweise jΓΌdisch), nominally giving him Aryan status.
This fact cast a negative shadow on his reputation after the collapse of the Nazi regime. While other Jewish scientists were forced into exile or killed, he remained in Berlin and continued his research. His attitude was neither clear Nazi collaboration nor clear resistance.
Let's organize this irony with a CS analogy: This is similar to the license issue of an open-source project. The moral judgment of the person who created a useful tool is separate from the usefulness of that tool. When we decide whether to continue using the tool, we must consider both the usefulness of the code and the social impact of the creator. Warburg's discoveries are undeniably useful, but his attitude during that era has a separate moral weight.
Why Is It Important?
Warburg's Nobel Prize remains valid today on three levels.
Biochemical level: After the final stage of cellular respiration and cytochrome c oxidase were identified, the entire map of cellular energy metabolism, including the Krebs cycle, oxidative phosphorylation, and mitochondrial membrane potential, was completed over the next 20 to 30 years. The last arrow in the cellular respiration diagram in today's high school biology textbooks is Warburg's discovery.
Cancer research level: The Warburg effect was re-examined in the 1990s. With the introduction of PET scans (imaging using the increased uptake of glucose by cancer cells) into clinical practice, Warburg's observation 90 years ago suddenly became clinically usable knowledge. Research on metabolic target anticancer drugs is generating thousands of papers every year.
Research tool level: His principle of "If you can't measure it, you can't understand it" remains relevant. Just as the manometer made his discovery possible, all the advances in biomedical research today come with the invention of new measurement techniques. NMR, cryo-EM, single-cell sequencing β all of these have opened up new knowledge with new tools.
He left us with this lesson: "To understand an interface, you must first be able to measure that interface precisely." Without a profiler, it is difficult to tune program performance. In order to find the bottlenecks in a system, you must be able to extract accurate metrics at each point. If Warburg had not created the manometer 100 years ago, his discovery would not have been possible.
Even now, while you are reading this sentence, cytochrome c oxidase in your cells is converting oxygen molecules into water. The nature of this machinery was revealed 90 years ago with a precise manometer in Berlin.
Summary of the Final Stage of Cellular Respiration: Warburg demonstrated that cyanide precisely blocks oxygen consumption, suggesting that the oxygen-using machinery is a metal ion-containing enzyme (cytochrome c oxidase). This discovery was the last piece of the puzzle in the entire map of cellular energy metabolism and later became the basis for research on cancer metabolism (the Warburg effect).
β Experience it with coding: DevBench β Program Performance Profiling and Bottleneck Identification β Learn CS concepts: DryBench β System Calls and Kernel Interface