1955 Nobel Prize in Physiology or Medicine: Theorell and Oxidoreductase Chemistry

What You Will Learn

Understand how Axel Theorell, at the Karolinska Institute, was the first to obtain several oxidoreductase enzymes in crystalline form, meticulously elucidating their structure and mechanism, and how this discovery has remained the cornerstone of today’s alcohol metabolism, metabolic diagnostics, and clinical enzymology.

Beyond Common Knowledge: Oxidation is Not Just Burning

We often associate the term “oxidation” with combustion or rusting. While chemically related, oxidation within cells is much more sophisticated. Oxidation within cells is the movement of electrons, and this movement is facilitated by a specific class of enzymes called oxidoreductases.

These enzymes are the primary executors of cellular respiration. Reduced equivalents (NADH, FADH2) from the Krebs cycle (see the 1953 Nobel Prize) carry electrons, which are then transferred through a series of enzymes to the final electron acceptor, oxygen. At each transfer step, a small amount of energy is released, and this energy is used to synthesize ATP.

Unraveling the precise chemistry of this electron transfer chain was a major challenge in biochemistry during the 1930s and 1950s, and Theorell provided crucial pieces of the puzzle. His methodology was key: by obtaining and purifying enzymes in crystalline form, he enabled other laboratories to study these enzymes in a reproducible manner.

Expressed in the language of computer science, oxidoreductases are the individual stages of an electron transfer middleware pipeline. An input (a substrate carrying electrons) passes through a series of stages, each performing its specific processing, ultimately producing the final output (ATP). Theorell's work was to isolate each stage of this pipeline and understand it as a discrete, manageable component.

The Zeitgeist: From Reconstruction to Growth

1955 was a year when Europe was transitioning from a period of reconstruction to one of growth. The effects of the Marshall Plan were becoming tangible throughout Western Europe, and West Germany's economic miracle was gaining momentum. In April, the Bandung Conference saw 29 Asian and African nations declare their non-aligned stance. This was a clear declaration of a third political space outside the Cold War's bipolar framework.

Also in April of that year, Einstein passed away. The atomic age, born from his famous equation E=mc², was already showing its two faces. In September, President Eisenhower suffered a myocardial infarction, and this event highlighted the clinical implications of the 1950 Nobel Prize in Cortisone, as it played out in the real world of politics.

The Nobel Committee's choice of Theorell in this year also carried the significance of recognition of a Swedish scientist. The Nobel Committee itself is based at the Karolinska Institute, and Theorell spent the majority of his life working there. The issue of balancing awards given to domestic scientists likely played a role in this decision, as noted by scholars of Nobel Prize history.

When viewed in conjunction with Korean history, 1955 was the year that Lee Ki-bung, Syngman Rhee's wife, consolidated her power within the ruling Liberal Party. Amidst the deepening corruption and authoritarianism of the Liberal Party, the seeds of the April Revolution began to sprout in various places.

Theorell: Chemistry Seen Through Crystals

Axel Hugo Theodor Theorell was born in Linköping, Sweden. He trained in medicine at the Karolinska Institute and then built his biochemistry career at Uppsala, Berlin, and Stockholm. In 1937, he established his own laboratory at the Karolinska and led research there for over 40 years.

A key difference in his methodology compared to others was his focus on obtaining enzymes in crystalline form. Until that time, most enzyme research was conducted with partially purified samples, leading to low reproducibility. Theorell obtained several enzymes in 99%+ pure crystals, allowing him to precisely measure their structure and activity.

He made three key discoveries:

First, he elucidated the structure of "yellow enzyme," a flavoprotein. He established that this enzyme contains riboflavin (vitamin B2) and that this coenzyme is the actual executor of the oxidation-reduction reaction. These coenzymes are now known as FAD/FMN (flavin adenine dinucleotide/flavin mononucleotide).

Second, he purified and characterized alcohol dehydrogenase (ADH). This enzyme catalyzes the oxidation of alcohol to acetaldehyde, the first step in human alcohol metabolism. This discovery laid the theoretical foundation for today's clinical studies related to alcohol metabolism.

Third, he obtained crystals of myoglobin and elucidated its oxygen-binding properties. Myoglobin, an oxygen-storage protein in muscle, became one of the first successful targets for X-ray crystallography (leading to John Kendrew's 1962 Nobel Prize in Chemistry).

The Oxidoreductase Pipeline: A CS Framework

Let's now summarize Theorell's discoveries using the language of computer science.

The oxidoreductase pipeline of cellular respiration can be roughly described as follows:

Glucose → (Glycolysis + Krebs Cycle) → NADH, FADH2 → Electron Transport Chain → Oxygen → Water

Electrons are transferred at each stage. NADH or FADH2 carry electrons, which are then transferred through various enzyme complexes (Complex I, II, III, IV) in the inner mitochondrial membrane to the final electron acceptor, oxygen. Each complex has its own coenzyme (flavin, heme, iron-sulfur cluster, etc.), and each stage releases a small amount of energy.

This architecture is precisely a middleware pipeline. Each stage has its own interface (electron accepting and releasing capabilities), allowing it to connect with the preceding and succeeding stages. If an enzyme in any stage fails, the entire pipeline stops. In reality, many mitochondrial diseases are caused by defects in specific complexes.

Flavoenzymes (enzymes containing FAD/FMN) play a special role in this pipeline. They receive electrons from various substrates (fatty acid, amino acid metabolites, etc.) and transfer them in a standardized form (FADH2). They act as adapters, converting diverse inputs into a standard format. Various metabolic pathways are ultimately connected to the central electron transport chain through these flavoenzymes.

Clinical Legacy

There are several ways in which Theorell's discoveries continue to be relevant in clinical practice today.

Clinical Implications Related to Alcohol Metabolism: Genetic variations in alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) create individual differences in alcohol metabolism. In particular, the ALDH2 variant, found in approximately 30-50% of East Asians, is the cause of the flushing reaction that occurs after drinking alcohol. It has been recently confirmed that individuals with this variant are at higher risk of stomach and esophageal cancer, and it is now a target for genetic testing and personalized advice.

Metabolic Diagnostics: Various enzyme activities are used as diagnostic markers in clinical chemistry tests. AST/ALT (liver cell damage), LDH (tissue damage), and CK (muscle damage) are representative examples, and understanding the precise characteristics of each enzyme is a prerequisite for establishing these tests. Theorell's crystalline purification methodology laid the foundation for this clinical chemistry.

Mitochondrial Diseases: It has since been discovered that defects in each complex of the electron transport chain are the cause of various genetic diseases. LHON (Leber's hereditary optic neuropathy), MELAS (mitochondrial encephalomyopathy), and various myopathies are among them. The detailed knowledge of the electron transport pipeline established by Theorell is essential for the diagnosis and understanding of these diseases.

Why It Matters

What Theorell left behind is a clear example of the principle that “accurate tools enable accurate understanding.”

Until then, oxidoreductase research had been conducted with partially purified samples, but Theorell's establishment of a crystalline purification methodology propelled this field into reproducible experimental science. Subsequently, many researchers used this methodology to purify other enzymes, completing the detailed chemistry of cellular metabolism.

This principle is also repeated in computer science. Once a good development tool is established, the research using that tool becomes more reproducible. The explosive growth of open-source collaboration after the establishment of Git, and the standardization of data science after the establishment of Jupyter Notebook, are the same patterns. The accuracy of the tool determines the accuracy of the science.

Another implication is the power of middleware architecture. The fact that cells convert electrons from various metabolic pathways into a standard format (FADH2, NADH) and process them through a single pipeline is an optimized system design that evolution has discovered over a long period of time. Computer science developers use the same principles when designing middleware pipelines today, and there is much that the two fields can learn from each other.

The Nobel Committee's award in this year was a recognition of the final piece that completed the overall picture of metabolic pathways. Krebs provided the framework for the cycle, Lipmann provided the connectors, and Theorell filled in the detailed chemistry of each stage. The awards to these three individuals together create the heart of the cellular metabolism textbook.

1955 Theorell Summary: Established a methodology for purifying oxidoreductases in crystalline form. Purified and elucidated the structure and function of yellow enzyme (flavoprotein), alcohol dehydrogenase (ADH), and myoglobin. This detailed chemistry is the theoretical foundation of today's clinical enzymology, alcohol metabolism, and mitochondrial disease diagnostics.

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