Nobel Prize in Physiology or Medicine 2019: How Cells Sense and Adapt to Oxygen

This note covers the Nobel Prize in Physiology or Medicine 2019: who won it, how cells use a protein called HIF to sense how much oxygen is around them, how William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza pieced the mechanism together, how the discovery unfolded over nearly three decades, and why it matters for anaemia and cancer treatment.

What was the Nobel Prize in Physiology or Medicine 2019 awarded for?

The Nobel Prize in Physiology or Medicine 2019 went jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza "for their discoveries of how cells sense and adapt to oxygen availability".

This is the official citation of the award, announced by the Nobel Assembly at Karolinska Institutet on 7 October 2019.

In plain words, the three scientists worked out how a living cell "notices" that the amount of oxygen around it has dropped, and then switches on the right genes to cope with that shortage.

Every animal cell uses oxygen to turn food into usable energy, and oxygen levels inside the body are never perfectly constant: they fall during hard exercise, at high altitude, in a healing wound, or inside a growing tumour.

The laureates found the molecular switch that detects these changes and adjusts gene activity in response.

The prize is formally called the Nobel Prize in Physiology or Medicine, and this edition was shared equally, one third each, among the three winners.

Their work answered a question that had puzzled scientists for most of the twentieth century: oxygen was known to be essential for life, but nobody understood, at the level of genes and proteins, exactly how a cell could tell whether it had enough oxygen and then do something about a shortage.

Who are the laureates?

All three laureates worked largely independently in the 1990s before their findings converged on the same molecular pathway in the early 2000s.

William G. Kaelin Jr

William G. Kaelin Jr was born on 23 November 1957 in New York, NY, USA.

At the time of the award he was affiliated with Harvard Medical School, Boston; the Howard Hughes Medical Institute, Chevy Chase, Maryland; the Dana-Farber Cancer Institute, Boston; and Brigham and Women's Hospital, Boston. He received one third of the prize.

Kaelin studied chemistry and mathematics at Duke University, earned his medical degree there in 1982, and trained at Johns Hopkins University before becoming a professor at Harvard Medical School in 2002.

He had been studying an inherited cancer condition, von Hippel-Lindau disease, and showed that the gene responsible, VHL, acts to prevent cells from switching on hypoxia genes when oxygen is plentiful.

Sir Peter J. Ratcliffe

Sir Peter J. Ratcliffe was born on 14 May 1954 in Lancashire, United Kingdom. His affiliations at the award were the University of Oxford and the Francis Crick Institute, London. He received one third of the prize.

Ratcliffe studied medicine at Cambridge, trained in nephrology, and completed his doctorate in 1987 before building his research career at Oxford, later also directing clinical research at the Francis Crick Institute from 2016.

His group, working alongside Semenza's, showed that the oxygen-sensing machinery for the hormone erythropoietin works in almost every tissue, not only in the kidney, and later proved that the VHL protein is required to remove HIF when oxygen is normal.

Gregg L. Semenza

Gregg L. Semenza was born on 12 July 1956 in New York, NY, USA. At the time of the award he worked at Johns Hopkins University, Baltimore. He received one third of the prize.

Semenza studied biology at Harvard, trained in medical genetics and paediatrics, and earned his doctorate from the University of Pennsylvania in 1984 before settling at Johns Hopkins.

He discovered the protein complex that switches on hypoxia genes and named it the hypoxia-inducible factor, or HIF.

What problem were the laureates trying to solve?

Oxygen accounts for roughly one fifth of the Earth's atmosphere, and animal cells use it inside structures called mitochondria to convert food into usable energy.

This basic fact had been known for a long time, and earlier Nobel Prizes had already honoured pieces of the oxygen story: the 1931 prize to Otto Warburg for showing that this energy conversion is driven by enzymes, and the 1938 prize to Corneille Heymans for showing how a structure called the carotid body, near the neck's large blood vessels, senses blood oxygen and signals the brain to change breathing rate.

What remained unknown was a slower, more fundamental kind of adaptation: how do individual cells, everywhere in the body, change which genes they switch on when oxygen is scarce? Scientists already knew that low oxygen triggers the kidney to release more of the hormone erythropoietin (EPO), which tells the bone marrow to make more red blood cells so the blood can carry more oxygen.

But how oxygen levels controlled the EPO gene itself, at the level of DNA, was a mystery that had lasted most of the century. Solving it needed a way to find the actual molecular "sensor" hidden inside cells.

How does the HIF switch sense oxygen?

Semenza traced the DNA region next to the EPO gene that responds to low oxygen (a state called hypoxia) using genetically modified mice, and both Semenza's and Ratcliffe's groups found that this same oxygen-sensing mechanism was active in cell types far beyond the kidney, which showed the system was general rather than specific to one organ.

Semenza then purified the protein complex that binds this DNA region in cultured liver cells and called it the hypoxia-inducible factor (HIF).

By 1995 he had identified the genes for its two parts: an oxygen-sensitive protein named HIF-1α, and a stable partner protein called ARNT.

The basic switch works like this, as later experiments by all three laureates established:

1. When oxygen levels in a cell are low, the HIF-1α protein is not broken down, so it builds up and moves into the cell's nucleus.
2. Inside the nucleus, HIF-1α pairs up with ARNT and attaches to specific DNA sequences in hypoxia-regulated genes, switching them on.
3. When oxygen levels return to normal, a cell structure called the proteasome rapidly breaks down HIF-1α instead, so the hypoxia genes switch off again.
4. This on/off control happens because oxygen itself is needed to chemically tag HIF-1α for destruction, so without oxygen the tag cannot be added and HIF-1α survives.

Draw a cell with two conditions side by side. On the low-oxygen side, show HIF-1α joining ARNT in the nucleus and binding a DNA sequence labelled HRE, switching a gene on.

On the normal-oxygen side, show HIF-1α being broken down inside the proteasome, after small hydroxyl (OH) groups have been added to it and the VHL protein has grabbed hold of it.

This explains why the same molecular machinery can work in almost any tissue: HIF-1α is present everywhere, and its fate depends only on the local oxygen level, not on which organ the cell belongs to.

How is HIF marked for destruction by VHL?

The missing piece was how oxygen controlled the tagging of HIF-1α for destruction. Kaelin had been studying von Hippel-Lindau disease, an inherited condition that raises the risk of certain cancers.

He showed that the VHL gene makes a protein that normally stops cancer from developing, and that cancer cells missing a working VHL gene had abnormally high levels of hypoxia genes switched on, even when oxygen was normal.

Putting a working VHL gene back into those cells restored normal control. This showed VHL was somehow involved in shutting HIF down.

Other groups then found that VHL is part of a larger protein complex that attaches a small tag called ubiquitin to proteins, marking them for destruction inside the proteasome.

Ratcliffe's group made the key connection: they showed that VHL can physically grip HIF-1α and is needed for its breakdown when oxygen is normal. The final question was what signalled VHL to grip HIF-1α only when oxygen was present.

In 2001, Kaelin's and Ratcliffe's groups separately published the answer at almost the same time: when oxygen is available, enzymes called prolyl hydroxylases attach hydroxyl groups to two specific points on HIF-1α, and only this modified version of HIF-1α is recognised and gripped by VHL.

Draw a human figure with arrows pointing to muscles (exercise adaptation), blood vessels (new vessel growth), bone marrow (red blood cell production), the immune system, and a tumour, with a label noting that drugs are being developed to either switch the oxygen-sensing machinery on, for example to treat anaemia, or switch it off, for example to slow cancer growth.

How did the discovery unfold?

The breakthroughs did not arrive together; each laureate followed a separate thread of research for years before the pieces connected.

Why does this discovery matter?

The oxygen-sensing pathway built around HIF turns out to control far more than the EPO gene.

The Nobel Assembly's press release noted that the mechanism affects fundamental processes such as the formation of new blood vessels, how cells adjust their metabolism during intense exercise, and parts of immune function, as well as normal development of blood vessels and the placenta before birth.

Because the pathway is so central, faults or imbalances in it are linked to many diseases.

Patients with chronic kidney failure often develop anaemia because their kidneys make too little EPO, and drugs that block the prolyl hydroxylase enzymes (keeping HIF switched on) can raise EPO levels and have already shown clinical benefit in trials for this kind of anaemia.

In the opposite direction, many cancers hijack the same machinery to switch on blood vessel growth and reshape their metabolism so tumour cells can multiply faster, which makes blocking HIF activity, or targeting VHL-related pathways, a promising strategy against some cancers.

Researchers are also exploring the pathway's role in stroke, heart attack and pulmonary hypertension. The broader open question that remains is how to safely tune this very finely balanced switch, since both too much and too little HIF activity can cause harm in different diseases.

How does this connect to what you study?

This discovery sits exactly where a school biology course meets real research: it builds on basic ideas about cell respiration (using oxygen to release energy from food), gene expression (how a gene is switched on or off), and protein structure.

If your biology lessons cover cellular respiration, enzymes, or how genes are regulated, the HIF story is a working, real-world example of all three ideas acting together inside a single cell.

It also shows how a study of a rare inherited cancer syndrome, von Hippel-Lindau disease, led to a universal discovery about how all animal cells, not only cancer cells, respond to oxygen.

This is a useful example for understanding how biomedical research often finds general principles while investigating one specific, narrow problem.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2019 went to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza for discovering how cells sense and adapt to oxygen availability.

It was announced on 7 October 2019 by the Nobel Assembly at Karolinska Institutet, which awards this prize through its Nobel Committee. Each laureate received an equal, one-third share of the prize.

Kaelin was affiliated with Harvard Medical School and other Boston institutions in the United States, Ratcliffe with the University of Oxford and the Francis Crick Institute in the United Kingdom, and Semenza with Johns Hopkins University in the United States.

Their work centres on a protein switch called HIF, which is controlled by the VHL protein and the oxygen-dependent prolyl hydroxylase enzymes, and its links to anaemia and cancer treatment.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Hypoxia — a state in which the oxygen available to a cell or tissue is lower than normal.
• HIF (hypoxia-inducible factor) — a protein complex, made of HIF-1α and ARNT, that switches on genes when oxygen is low.
• HIF-1α — the oxygen-sensitive part of HIF; it is destroyed quickly when oxygen is normal but survives when oxygen is low.
• ARNT — the stable partner protein that pairs with HIF-1α to form the active HIF complex.
• VHL protein — a tumour-suppressing protein that grips oxygen-modified HIF-1α and marks it for destruction.
• Ubiquitin — a small protein tag attached to other proteins to mark them for breakdown in the proteasome.
• Proteasome — a cell structure that breaks down proteins tagged with ubiquitin.
• Prolyl hydroxylase — an oxygen-dependent enzyme that attaches hydroxyl groups to HIF-1α, allowing VHL to recognise it.
• Erythropoietin (EPO) — a hormone, mainly made in the kidney, that stimulates the bone marrow to produce red blood cells.
• Erythropoiesis — the process of making new red blood cells.
• Carotid body — a structure near the neck's major blood vessels that senses blood oxygen and signals the brain to adjust breathing.
• Von Hippel-Lindau disease — an inherited condition caused by a faulty VHL gene that raises the risk of certain cancers.
• Angiogenesis — the growth of new blood vessels, one of the processes the oxygen-sensing pathway controls.

Common errors and misconceptions

• Misconception: The three laureates worked together as one team from the start. Correct: They worked largely independently, with Semenza and Ratcliffe studying the EPO gene and Kaelin studying a cancer gene, before their findings converged.
• Misconception: HIF is only important for red blood cell production. Correct: HIF also affects blood vessel growth, metabolism, immune function and development, besides erythropoietin regulation.
• Misconception: VHL only matters in cancer patients. Correct: VHL is the normal mechanism that destroys HIF-1α in every cell once oxygen is restored to normal levels.
• Misconception: Low oxygen destroys HIF-1α. Correct: Low oxygen protects HIF-1α from destruction; it is normal, high oxygen that leads to its breakdown.
• Misconception: This is the first Nobel Prize connected to oxygen biology. Correct: Earlier prizes, to Otto Warburg in 1931 and Corneille Heymans in 1938, had already honoured other parts of the oxygen story.
• Misconception: The hydroxylation step adds oxygen to DNA. Correct: The hydroxylation is a chemical modification added directly to the HIF-1α protein, not to DNA.
• Misconception: The pathway is only relevant to rare diseases. Correct: It is relevant to common conditions such as anaemia from kidney failure and many cancers.

Exam-style questions with model answers

Q1. State the official citation for the Nobel Prize in Physiology or Medicine 2019. [2 marks]

1. The laureates were honoured "for their discoveries of how cells sense and adapt to oxygen availability", as stated in the official citation.

Q2. Name the three laureates and their affiliations at the time of the award. [2 marks]

1. William G. Kaelin Jr was at Harvard Medical School and related Boston institutions; Sir Peter J. Ratcliffe was at the University of Oxford and the Francis Crick Institute; Gregg L. Semenza was at Johns Hopkins University.

Q3. Explain what HIF is and how its level changes with oxygen. [4 marks]

1. HIF, the hypoxia-inducible factor, is a protein complex made of HIF-1α and a stable partner protein called ARNT.
2. When oxygen is low, HIF-1α is not broken down, so it accumulates and pairs with ARNT inside the nucleus.
3. The paired complex then binds specific DNA sequences and switches on hypoxia-response genes.
4. When oxygen returns to normal, HIF-1α is rapidly destroyed by the proteasome, so the hypoxia genes are switched off again.

Q4. Describe the role of the VHL protein in regulating HIF-1α. [4 marks]

1. VHL is a tumour-suppressing protein studied by William Kaelin in connection with von Hippel-Lindau disease.
2. Kaelin showed cancer cells lacking functional VHL had abnormally high levels of hypoxia genes switched on, and restoring VHL brought levels back to normal.
3. Sir Peter Ratcliffe's group proved VHL physically binds HIF-1α and is required for its destruction when oxygen is normal.
4. VHL can only grip HIF-1α after oxygen-dependent enzymes called prolyl hydroxylases have chemically modified it, so VHL action depends directly on oxygen.

Q5. Discuss how the discoveries of Kaelin, Ratcliffe and Semenza unfolded, and why they matter for medicine today. [6 marks]

1. Semenza began in the early 1990s by tracing the DNA region controlling the erythropoietin gene's response to low oxygen, naming the responsible protein complex HIF in 1992 and purifying it by 1995.
2. Ratcliffe, working in parallel, showed the same oxygen-sensing mechanism operates in many tissues beyond the kidney, proving it was a general cellular system rather than a kidney-specific one.
3. Kaelin, studying the inherited von Hippel-Lindau cancer syndrome, discovered the VHL gene suppresses tumours and that cells without functional VHL cannot properly switch off hypoxia genes.
4. Ratcliffe's group then connected the two threads in 1999 by showing VHL physically removes HIF-1α when oxygen is normal, and in 2001 both the Kaelin and Ratcliffe groups independently showed that oxygen-triggered hydroxylation of HIF-1α is the signal VHL recognises.
5. These discoveries matter because the same pathway controls red blood cell production, new blood vessel growth and metabolic adjustment, and it is disrupted in common diseases such as kidney-related anaemia and cancer.
6. Drugs that block the oxygen-sensing enzymes to raise HIF activity have already shown benefit for anaemia, while drugs that block HIF activity are being explored against certain cancers, showing that basic cell biology discoveries can lead directly to new treatments.

Q6. Which earlier Nobel Prizes also concerned oxygen, and what did they recognise? [3 marks]

1. The 1931 Nobel Prize in Physiology or Medicine went to Otto Warburg for showing that the conversion of food into energy using oxygen is an enzymatic process.
2. The 1938 Nobel Prize in Physiology or Medicine went to Corneille Heymans for showing how the carotid body senses blood oxygen and controls breathing rate by signalling the brain.

Q7. What date was the 2019 Nobel Prize in Physiology or Medicine announced, and what is the prize amount? [2 marks]

1. It was announced on 7 October 2019, and the prize amount was 9,000,000 Swedish kronor, shared equally among the three laureates.

Key takeaways

• The 2019 Nobel Prize in Physiology or Medicine went jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza for discovering how cells sense and adapt to oxygen levels.
• The central molecule is HIF, a protein complex of HIF-1α and ARNT that switches hypoxia-response genes on when oxygen is scarce.
• HIF-1α is destroyed by the proteasome when oxygen is normal but survives and accumulates when oxygen is low.
• The VHL protein, discovered through research on an inherited cancer syndrome, marks HIF-1α for destruction, but only once oxygen-dependent hydroxylation has modified it.
• The pathway controls red blood cell production, new blood vessel growth, metabolism and immune function across virtually all tissues.
• Disruption of this pathway is linked to kidney-related anaemia and to many cancers, making it a target for new drugs.
• The discoveries built on, and extended, two much earlier Nobel Prizes concerning oxygen physiology, from 1931 and 1938.

Test yourself

What does HIF stand for?

HIF stands for hypoxia-inducible factor, the protein complex that switches on genes when a cell's oxygen supply is low.

Which laureate discovered and named HIF?

Gregg L. Semenza discovered and purified the HIF protein complex while studying the erythropoietin gene at Johns Hopkins University.

What happens to HIF-1α when oxygen is normal?

When oxygen is normal, HIF-1α is chemically modified and recognised by the VHL protein, then broken down by the proteasome.

How did a study of cancer lead to the discovery of VHL's role in oxygen sensing?

William Kaelin studied von Hippel-Lindau disease and found that cells lacking a working VHL gene wrongly switched on hypoxia genes, linking VHL to oxygen sensing.

Name one disease linked to faults in the HIF-VHL pathway.

Chronic kidney failure can cause anaemia because the kidneys make too little erythropoietin, a hormone controlled by this oxygen-sensing pathway.

Where was Sir Peter J. Ratcliffe based at the time of the award?

Sir Peter J. Ratcliffe was based at the University of Oxford and the Francis Crick Institute in London, both in the United Kingdom.

What prize amount did the 2019 Nobel Prize in Physiology or Medicine carry?

The prize carried 9,000,000 Swedish kronor, shared equally, one third each, among the three laureates.