2019 Nobel Prize in Physiology or Medicine: Kaelin, Ratcliffe, and Semenza Uncover the Cell's Oxygen Sensing Circuit

What You'll Learn in This Article

The 2019 Nobel Prize in Physiology or Medicine was awarded to three scientists who elucidated how each cell in our body senses and responds to oxygen levels in real time—that is, the cellular hypoxia sensing circuit. Gregg Semenza of Johns Hopkins University discovered the transcription factor HIF-1, which induces a hypoxic response. Peter Ratcliffe of Oxford University revealed that the tumor suppressor gene VHL is responsible for degrading HIF-1α. William Kaelin of Dana-Farber Institute demonstrated that prolyl hydroxylase domain (PHD) acts as an oxygen sensor. These three discoveries, when combined, revealed the complete picture of an elegant polling loop that automatically degrades the protein when oxygen is present and accumulates it when oxygen is absent, thereby activating responsive genes. This circuit is the foundation for understanding renal cancer, anemia, cardiovascular disease, high-altitude adaptation, and fetal development, and it is also the conceptual basis for anemia treatments like roxadustat, a PHD inhibitor.

A Story Different from Common Sense: Each Cell Has Its Own Oxygen Gauge

The common understanding that "oxygen is inhaled by the lungs and transported by the blood" is a description at the system level. In reality, each cell individually senses and responds in real time to how much oxygen it is currently receiving. This sensing system was a mystery until the late 20th century, and the three laureates completed the puzzle.

The key principle is surprisingly elegant. The transcription factor HIF-1α is constantly produced inside cells, but it is quickly degraded under normal oxygen conditions. When oxygen is present, prolyl hydroxylase domain (PHD) uses oxygen to hydroxylate specific proline amino acids in HIF-1α, and the hydroxylated HIF-1α is recognized by von Hippel-Lindau (pVHL) protein, which tags it with ubiquitin for degradation by the proteasome. In other words, HIF-1α disappears as soon as it is produced when oxygen is available.

When oxygen levels drop, this process stops. Because PHD cannot hydroxylate without oxygen, HIF-1α is not degraded and accumulates. The accumulated HIF-1α moves to the nucleus and activates responsive genes such as EPO (erythropoietin, which stimulates red blood cell production) and VEGF (vascular endothelial growth factor, which promotes the formation of new blood vessels). The body responds by increasing red blood cell production and increasing the number of blood vessels to increase oxygen supply.

If we frame this in a CS framework, it is a combination of a polling loop and auto-cleanup. HIF-1α is a constantly increasing counter, PHD is a sensor that detects oxygen levels, and VHL is a garbage collector (GC) that resets the counter. When oxygen is sufficient, the counter is continuously reset, and no response signal is generated, but when oxygen is insufficient, the reset stops, and the counter exceeds a threshold, triggering a response process. This elegant negative-feedback architecture is built into each cell in the body.

The Landscape of the Time: The Cho Kuk Scandal, the Hong Kong Protests, and the Pandemic Approaching in the Dark

In 2019, South Korea was in turmoil due to the Cho Kuk scandal. After the nomination of Cho Kuk as Minister of Justice in August, controversies over his daughter's academic credentials, private equity investments, and the direction of prosecutorial reform erupted, leading to large-scale rallies in Gwanghwamun and Seocho. Although Minister Cho Kuk resigned on October 14, the situation subsided, but it was an event that clearly revealed the generational and political divisions in Korean society.

Japan's export restrictions on three major semiconductor materials (photoresist, hydrogen fluoride, and polyimide) in July exacerbated the Japan-Korea conflict. South Korea aggressively pursued a policy of domesticating materials, components, and equipment, and this trend determined the direction of industrial policy for the following years. On June 30, an impromptu meeting between Trump and Kim Jong-un was held at the Panmunjom. President Moon Jae-in also joined, creating the first scene in history where the three leaders stood together at Panmunjom.

In the world, protests against the extradition bill began in Hong Kong in June and escalated over half a year, becoming the focus of international attention. It expanded as a front in the US-China conflict, intensifying the international debate on Hong Kong's autonomy and China's governance.

On April 10, the first photograph of a black hole was released. It was an image of the shadow of the supermassive black hole at the center of the M87 galaxy, captured through international collaboration by the Event Horizon Telescope (EHT). It was a visual confirmation of Einstein's theory of general relativity after 100 years and became a symbolic moment for collaborative science.

In the United States, an impeachment investigation began in September over allegations of President Trump pressuring Ukraine. This led to the House of Representatives' impeachment of Trump in early the following year. The Amazon rainforest fire in August intensified international environmental debate, and the Brazilian Bolsonaro government's response came under fire. Brexit renegotiations and the appointment of Prime Minister Johnson reshaped British politics in October.

And in December, cases of an unidentified pneumonia began to be reported in Wuhan, China. Local medical staff observed SARS-like symptoms and expressed concern, but the international community was not yet aware of the severity. The pandemic that would shake the world was beginning in the quiet darkness of that winter.

In the scientific community, this prize was primarily about the fundamental discovery of cell biology. Oxygen sensing is a fundamental system shared by most multicellular organisms on Earth, and the fact that the circuit is so elegant and evolutionarily conserved is a significant story in itself.

Character Narrative: Three Cities, Two Genes, One Circuit

Gregg Semenza (1956~) was born in New York City, USA. He received his B.S. from Harvard University and his M.D.-Ph.D. from the University of Pennsylvania. He then settled at Johns Hopkins University School of Medicine. His problem was clinical: "How is the hormone EPO, produced in the kidneys, massively produced under hypoxic conditions?" EPO is a hormone that stimulates red blood cell production in the bone marrow and is explosively secreted when oxygen is scarce. The molecular mechanism of this regulation was unresolved.

Semenza's lab sought to find the protein that binds to the regulatory region (enhancer) of the EPO gene. In a 1992 paper, they discovered a new transcription factor that binds to the EPO enhancer only under hypoxic conditions, which they named HIF-1 (Hypoxia-Inducible Factor 1). HIF-1 consists of two subunits, HIF-1α and HIF-1β, with β always expressed, but it was later confirmed that α dramatically changes depending on oxygen levels.

Peter Ratcliffe (1954~) was born in Lancaster, England. He received his B.A. from Cambridge University and underwent clinical training at Oxford University, where he was a nephrologist. He then established his own lab at Oxford and delved into oxygen sensing research.

Ratcliffe's crucial discovery was that pVHL is involved in the degradation of HIF-1α. VHL is the gene that causes von Hippel-Lindau (VHL) syndrome, a hereditary tumor syndrome that causes renal cell carcinoma and central nervous system capillary hemangioblastomas. It was already known as a tumor suppressor gene. Ratcliffe observed that HIF-1α accumulates massively in kidney cancer cells with VHL gene mutations, which suggested that pVHL is responsible for the degradation of HIF-1α in normal cells.

William Kaelin (1957~) was born in New York City, USA. He received his B.A. and M.D. from Duke University and established his own lab at the Dana-Farber Cancer Institute. His problem setting also began with VHL, but with a different focus: "How does pVHL recognize HIF-1α? Why does it only happen in normal oxygen conditions?"

Kaelin's team and Ratcliffe's team made crucial observations almost simultaneously. That is, the specific proline amino acid of HIF-1α is hydroxylated when oxygen is present, and pVHL recognizes this hydroxylated proline. In other words, when oxygen is present, proline is hydroxylated and pVHL recognizes it for degradation, and when oxygen is absent, hydroxylation does not occur and HIF-1α accumulates.

Then, what enzyme uses oxygen to hydroxylate proline? The answer was prolyl hydroxylase domain (PHD). PHD is an enzyme that requires oxygen to react, so it cannot function without oxygen. This enzyme was the cell's oxygen sensor. When oxygen is present, PHD functions to degrade HIF-1α, and when oxygen is absent, PHD stops, causing HIF-1α to accumulate.

The discoveries of the three labs completed a circuit: PHD (sensor) → proline hydroxylation → pVHL (degradation signal) → HIF-1α degradation → suppression of EPO/VEGF transcription. When oxygen is absent, this entire chain stops, and HIF-1α accumulates, activating the responsive genes.

Key Achievements: An Elegant Polling Loop in a CS Framework

If we draw the cell's oxygen sensing circuit as a pipeline, it would look like this:

• Constant Production: HIF-1α is constantly synthesized in cells. At the mRNA level, it is always expressed. HIF-1α is in a state where the counter value is constantly increasing.
• Normal Oxygen Auto-Cleanup: PHD enzyme uses oxygen to hydroxylate a specific proline of HIF-1α. Hydroxylated HIF-1α is bound by pVHL and tagged with ubiquitin. The proteasome immediately degrades this tagged HIF-1α. Under normal oxygen conditions, the half-life of HIF-1α is only a few minutes.
• Hypoxia Sensing: When the oxygen concentration in the cell drops below the threshold, PHD activity decreases. The proline of HIF-1α is not hydroxylated, making pVHL recognition impossible. HIF-1α begins to accumulate.
• Response Execution: Accumulated HIF-1α binds to HIF-1β to form an active heterodimer and moves to the nucleus. In the nucleus, it binds to the hypoxia response element (HRE) and activates the transcription of several responsive genes.
• Responsive Genes: EPO (red blood cell production), VEGF (new blood vessel formation), glycolysis enzymes (metabolic rearrangement), pH-regulating proteins, etc. As a result, the body increases oxygen supply and executes metabolic adjustments to survive in hypoxic conditions.
• Recovery: When oxygen supply is restored, PHD functions again to degrade HIF-1α. The transcription of responsive genes stops, and the system returns to a waiting state.

The nature of this system is conditional polling with auto-cleanup. HIF-1α is a constantly present polling counter, the PHD-VHL axis is a garbage collector (GC) that resets this counter when the condition is met (oxygen present), and when the condition is not met (oxygen absent), the counter exceeds a threshold, triggering a response. This architecture is a natural response of hardware interrupt systems, allowing each cell to respond immediately whenever and wherever oxygen deficiency occurs, creating a distributed sensing system.

There are layers of fine-tuning. There are two prolines and one asparagine in HIF-1α that are hydroxylated, and each hydroxylation has different reaction strengths and regulatory mechanisms. There are three HIF-1α, HIF-2α, and HIF-3α α subunits, and these regulate different responsive genes in different tissues. This sophisticated layering allows the hypoxic response to be finely tuned by tissue and situation.

However, we must also point out the limitations of this analogy. The hypoxic response is not a pure binary switch, but an analog response. The amount of HIF-1α accumulated changes continuously in proportion to the continuous changes in oxygen concentration, and the expression of responsive genes is also regulated accordingly. This is different from the binary polling and triggering of software, and this analog nature makes flexible responses possible on a tissue-by-tissue and situation-by-situation basis.

Why It Matters: Renal Cell Carcinoma, Anemia, High-Altitude Adaptation, and Metabolism

First, it provides the theoretical basis for treating renal cell carcinoma. Most renal cell carcinomas have VHL gene mutations, which means that the HIF system is chronically activated. From this perspective, renal cell carcinoma is redefined as a hyperactivation of the hypoxic response circuit, and belzutifan, which specifically inhibits HIF-2α, was approved by the FDA in 2021 and is used as a treatment for VHL-related renal cell carcinoma and central nervous system hemangioblastomas. This is one of the clinical achievements that followed.

Second, a new drug for treating anemia in chronic kidney disease has emerged. Patients with chronic kidney disease suffer from anemia due to decreased EPO production in the kidneys, and they have been treated with recombinant EPO injections. However, administering PHD inhibitors orally can accumulate HIF-1α, which induces the body to produce its own EPO. Roxadustat, daprodustat, and vadadustat are oral anemia treatments developed based on this principle, and they have been approved and used clinically in several countries. This represents a shift from 20th-century EPO injections to 21st-century oral inducers, and it is one of the key clinical achievements of this story.

Third, it is connected to tumor angiogenesis. When a tumor grows, the inside becomes hypoxic, and the HIF system in tumor cells is activated, causing a large amount of VEGF to be secreted. VEGF is a signal that attracts new blood vessels to the tumor, and the tumor continues to grow through these vessels. Anti-cancer drugs such as bevacizumab (Avastin), which are VEGF inhibitors, block this pathway and inhibit tumor growth. In addition to this, various methods are being developed to target the tumor hypoxia itself.

Fourth, it is related to high-altitude adaptation genetics. Populations living at high altitudes, such as Tibetans and Bolivian Andeans, have evolved genetically distinct hypoxic adaptations compared to low-altitude populations. The Tibetan-specific variant of the EPAS1 (HIF-2α) gene has been identified as one of the key genes in this adaptation, and it has been surprisingly observed that this variant originated from Denisovans, a cousin of Neanderthals. This is a story of how the evolution of oxygen sensing systems is intertwined with the geographical distribution of human populations.

Fifth, it contributes to our understanding of myocardial infarction and stroke. In acute ischemia (blockage of blood supply), tissue hypoxia immediately induces the HIF response, which has a significant impact on the extent of tissue damage and the ability to recover. Ischemic preconditioning—a method of exposing tissues to hypoxia for a short period of time before a major ischemic event to reduce damage—is being used clinically in cardiac and renal surgery, and a significant portion of this effect is explained by the activation of the HIF system.

Sixth, it involves fetal development and the placenta. The placenta develops in a hypoxic environment, and this hypoxia acts as a normal signal for placental formation. Defects in the HIF system have been shown to be associated with placental abnormalities, fetal growth retardation, and preeclampsia, creating a new axis in obstetrics.

Seventh, it is related to metabolic reprogramming. In a hypoxic environment, cells shift their metabolism from oxidative phosphorylation (high energy efficiency but requires oxygen) to glycolysis (low energy efficiency but does not require oxygen). The switch for this reprogramming is the HIF system, which is crucial not only for normal cells but also for understanding the Warburg effect in tumor cells—the characteristic of tumors that rely on glycolysis even in the presence of oxygen.

Eighth, it provides evolutionary insights. The oxygen sensing system has existed since the very early stages of eukaryotes, and multicellular organisms, from worms to flies to fish to humans, share similar circuits. This means that oxygen sensing was a fundamental condition for the evolution of multicellular organisms, and the fact that we are still discovering the details of this system is one of the enduring fascinations of cell biology.

Each cell already had an oxygen gauge, and we now know the names of the gears in that circuit. The nineteenth Nobel Prize in Physiology or Medicine of the new century named this elegant circuit, and based on it, targeted therapies for renal cell carcinoma and oral treatments for anemia have been established clinically.

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