Nobel Prize in Medicine 2021 Honors Discovery of Temperature and Touch Receptors

Stockholm, Sweden · 4 October 2021

The Nobel Assembly at Karolinska Institutet announced on 4 October 2021 that the Nobel Prize in Physiology or Medicine would be awarded jointly to David Julius and Ardem Patapoutian "for their discoveries of receptors for temperature and touch." Their work solved one of the deepest mysteries in neurobiology: how the body perceives the physical world through the conversion of mechanical and thermal stimuli into electrical signals that the brain can interpret.

The Fundamental Question

How do we feel heat, cold, and pressure? For centuries, this question remained largely unanswered at the molecular level. Scientists understood that specialized nerve cells (neurons) in the skin and internal organs detect physical stimuli and transmit signals to the brain. But the specific molecular mechanisms — the biological "sensors" or "transducers" that convert a physical force into an electrical impulse — were unknown.

This was not a minor gap in knowledge. The ability to sense temperature and touch is fundamental to survival. Without it, we could not avoid burns, detect injury, or navigate our environment. The molecular identity of these sensors had eluded researchers despite decades of investigation.

David Julius and the Discovery of Temperature Sensors

David Julius, working at the University of California, San Francisco, took an innovative approach to the problem. Rather than studying nerve cells directly, he turned to a natural product that produces a sensation of heat: capsaicin, the active compound in chili peppers that causes the burning sensation we perceive as spicy.

Julius reasoned that if he could identify the specific molecule that capsaicin binds to in nerve cells, he would have found a temperature-sensing receptor. His laboratory screened a library of genes expressed in sensory neurons, looking for one that would make cells responsive to capsaicin. In 1997, they identified TRPV1 — an ion channel that opens in response to both capsaicin and temperatures above approximately 43°C (109°F), the threshold for painful heat.

Following TRPV1, Julius and his colleagues identified additional temperature-sensing channels:

The discovery of TRPM8 was particularly elegant. Just as capsaicin activates TRPV1 to produce a sensation of heat, menthol — the cooling compound in mint — activates TRPM8 to produce a sensation of cold. This parallel confirmed that the same molecular logic underlies both warm and cold sensation.

Ardem Patapoutian and the Discovery of Touch Receptors

While Julius focused on temperature, Ardem Patapoutian, working at the Scripps Research Institute in La Jolla, California, turned his attention to an even more elusive sense: mechanical sensation, or touch.

Mechanical stimuli are fundamentally different from chemical or thermal stimuli. When you press your finger against a surface, physical force deforms the cell membrane. But how does a cell detect this deformation and convert it into an electrical signal? The molecular identity of mechanosensitive ion channels in vertebrates was completely unknown.

Patapoutian's approach was methodical and painstaking. He identified a line of cells that produced a small electrical signal when poked with a microscopic pipette. He then systematically inactivated individual genes, one by one, until he found the gene whose removal eliminated the cells' ability to respond to pressure.

In 2010, Patapoutian's laboratory identified PIEZO1 and PIEZO2 — two ion channels named after the Greek word píesi, meaning "pressure." These channels open in response to mechanical deformation of the cell membrane, allowing positively charged ions to flow into the cell and generate an electrical impulse.

"These breakthrough discoveries launched intense research activities into the field of sensory biology, and our understanding of how the nervous system detects heat, cold, and mechanical stimuli has increased enormously."

— Nobel Assembly at Karolinska Institutet, 4 October 2021

The Importance of PIEZO Channels

Further research revealed that PIEZO channels do far more than mediate the sense of touch. PIEZO2 is critical for:

• Proprioception: The sense of the body's position in space, essential for coordinated movement. Mice lacking PIEZO2 in sensory neurons cannot walk normally.
• Blood pressure regulation: PIEZO1 in blood vessel walls detects changes in blood pressure and helps regulate vascular tone.
• Bladder function: PIEZO channels in the urinary tract signal when the bladder is full.
• Lung development: PIEZO1 is involved in sensing the mechanical forces that shape the developing lung.

Clinical Implications

The discoveries of Julius and Patapoutian have opened new avenues for therapeutic development:

• Chronic pain: TRPV1 is a target for pain medications, though early attempts to develop TRPV1 antagonists were hampered by side effects (including dangerous hyperthermia). More selective approaches are under investigation.
• Inflammatory pain: TRPA1 is activated by a wide range of inflammatory mediators and is a promising target for treating chronic inflammatory pain conditions.
• Mechanical allodynia: Understanding PIEZO channel function may lead to treatments for conditions where light touch becomes painful, a common symptom in neuropathic pain disorders.
• Cardiovascular disease: PIEZO1's role in blood pressure regulation makes it a potential target for treating hypertension and other vascular disorders.

The Laureates

David Julius (born 1955) is a professor and chair of the Department of Physiology at the University of California, San Francisco. He earned his PhD from the University of California, Berkeley, and conducted postdoctoral research at Columbia University. His laboratory has been at the forefront of sensory receptor biology for over two decades.

Ardem Patapoutian (born 1967) is a professor of neuroscience at the Scripps Research Institute and a Howard Hughes Medical Institute investigator. Born in Lebanon to Armenian parents, he moved to the United States in 1986. He earned his PhD from the California Institute of Technology and has focused much of his career on the molecular basis of mechanosensation.

A Nobel Season Like No Other

The 2021 Nobel Prize announcements took place against the backdrop of the ongoing COVID-19 pandemic. The traditional December ceremony in Stockholm was once again modified, though less severely than in 2020. The laureates' discoveries, while not directly related to COVID-19, underscored the importance of fundamental, curiosity-driven research — the kind of basic science that, as the pandemic had dramatically demonstrated, forms the foundation for all medical progress.

The Nobel Assembly's choice also highlighted a broader truth about sensory biology: the most fundamental questions about how we experience the world are often the hardest to answer. That Julius and Patapoutian succeeded where generations of scientists had not is a testament to the power of creative experimental design, persistence, and the willingness to tackle problems that others considered intractable.

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Sources:

• Nobel Prize in Physiology or Medicine 2021 press release, Nobel Assembly at Karolinska Institutet (nobelprize.org)
• Nobel Prize in Physiology or Medicine 2021 advanced information (nobelprize.org)
• NIH National Institute of Neurological Disorders and Stroke, summary of 2021 Nobel Prize in Medicine (nih.gov)
• Indiana University, coverage of Ardem Patapoutian's Nobel Prize (iu.edu)