Nobel Prize lecture: David Julius, Nobel Prize in Physiology or Medicine 2021

Summary

Why temperature and touch matter

The 2021 Nobel Prize in Physiology or Medicine was awarded jointly to David Julius and Ardem Patapoutian for discovering receptors involved in sensing temperature and touch. Their work explains how physical stimuli are converted into electrical signals that travel through the nervous system to the brain.

Julius focuses on the peripheral beginnings of pain and temperature sensation. Pain is a vital warning system that helps prevent injury, but it can become persistent and debilitating after the initial injury has passed. Understanding how acute pain shifts into chronic pain—and how different pain syndromes arise—is important for developing better treatments.

Using natural irritants to find sensory receptors

Julius’s laboratory used naturally occurring substances to study sensory nerves. The idea was that compounds that reliably produce burning, cooling, or irritation might act on specific sensory receptors and reveal how those receptors work.

• Capsaicin, the pungent compound in chili peppers, was known to activate some pain-sensing nerve fibers. Earlier research also showed that high doses could desensitize or damage those fibers, and that capsaicin could affect body temperature.
• Menthol, from mint, produces a cooling sensation. Earlier studies found that its effects on sensory fibers depended on temperature.
• Compounds in wasabi, mustard-family plants, onions, and garlic provide additional examples of natural irritants that act on sensory systems.

This approach built on earlier work using natural products to uncover biological mechanisms, including research on opiates, aspirin-related compounds, and cannabis.

Discovering TRPV1 and TRPM8

Julius’s team used functional expression cloning to identify the capsaicin receptor:

1. They created a DNA library from sensory neurons.
2. They introduced the DNA into non-neuronal cells that would not normally respond to capsaicin.
3. They exposed the cells to capsaicin while monitoring them with a calcium-sensitive dye.
4. They used responsive cells to identify the DNA encoding the receptor.

The receptor they identified, TRPV1, is an ion channel that responds to capsaicin. The lab then used a similar strategy to identify the menthol receptor, TRPM8. Both belong to the TRP family of ion channels, as does TRPA1, a receptor activated by several pungent irritants, including wasabi-related compounds.

A key discovery was that these channels also act as temperature sensors:

• TRPV1 is activated by heat, with a threshold around 43°C, near the range at which heat becomes painful.
• TRPM8 is activated by cooling, with a threshold around 25°C, close to the range at which people begin to distinguish cool from warmer conditions.

Capsaicin and menthol can make the channels respond at less extreme temperatures. This helps explain why capsaicin feels hot and menthol feels cool even when neither changes the actual temperature.

Testing whether the channels function as thermometers

The researchers tested the channels’ roles in several ways:

• Direct biophysical testing: TRPV1 was purified, placed in a synthetic lipid membrane, and exposed to heat. It still responded, supporting the conclusion that temperature sensitivity is an intrinsic property of the channel.
• Behavioral testing: Mice lacking TRPM8 had difficulty distinguishing a warm surface from a cool one, unlike normal mice. They could distinguish the surfaces only when the cool side became much colder.
• Neural markers: TRPV1 and TRPM8 were found largely in different groups of sensory neurons. This supports the idea that some temperature information travels along relatively distinct sensory pathways, though signals are also integrated in the central nervous system.

Together, these findings support a role for TRP channels as molecular components of the body’s temperature-sensing system. They are important players, though not the only temperature-sensitive channels.

Sensory adaptation across species

Julius also discusses how temperature-sensing systems can adapt to an animal’s needs:

• Vampire bats have distinct forms of TRPV1 in sensory pathways associated with heat detection around the face and in pathways serving the rest of the body. This may help them locate warm, blood-rich areas in prey.
• TRPM8’s temperature response varies among animals with different body temperatures, including birds, mammals, and frogs.

These examples illustrate how sensory systems can be tuned to an organism’s physiology and way of life.

Injury, inflammation, and persistent pain

After tissue injury, sensitivity to heat, pressure, and chemical irritants can increase. This heightened sensitivity contributes to acute pain and can also help drive chronic pain.

TRPV1 is affected by substances released during inflammation and tissue damage. These include:

• Direct channel modulators, such as extracellular protons and certain endogenous lipids.
• Signals that act through other receptors, including bradykinin, ATP, and nerve growth factor, which can alter TRPV1 through intracellular signaling pathways.

These signals can lower the temperature threshold at which TRPV1 activates, making sensory nerves more excitable. Julius describes this as one way the “inflammatory soup” changes the gain of the pain pathway.

Therapeutic promise and risks

Because TRPV1 contributes to heat and pain detection, blocking it may help treat some pain conditions. In human testing, a TRPV1 antagonist increased the temperature at which participants detected painful heat, supporting the channel’s role in human heat sensation.

However, blocking TRPV1 can also weaken pain’s protective warning function and cause temporary increases in body temperature. Julius argues that future treatments should ideally reduce the channel’s contribution to pathological pain without shutting down its normal protective roles.

Structural studies of TRPV1

Cryo-electron microscopy made it possible to determine TRPV1’s three-dimensional structure. Structural work revealed a four-part channel with two constrictions in its ion-conduction pathway. These constrictions change as the channel opens, offering clues to how it is gated and regulated.

The structure also helped explain how protons influence TRPV1. Under acidic conditions, protons alter interactions involving an extracellular glutamate residue, making it easier for the channel to open. Understanding such molecular details could help researchers design drugs that modify specific forms of channel regulation rather than blocking the channel entirely.

Acknowledgments and scientific training

Julius closes by thanking his laboratory members, collaborators, funders, and colleagues at UCSF. He also recognizes the influence of his scientific mentors and his family, emphasizing the role of training, collaboration, and curiosity in research.

Speakers and sources featured

Speakers in the subtitles

• Ole Petter Ottersen — Introduces the Nobel lectures on behalf of Karolinska Institutet.
• Abdel El Manira — Introduces the laureates and explains the significance of their discoveries.
• David Julius — Delivers the lecture on temperature sensation, pain, and TRP channels.

Other laureate mentioned

• Ardem Patapoutian — Introduced as the co-recipient of the prize; he does not speak in this excerpt.

Principal researchers and sources named in the lecture

• Immanuel Kant — Quoted in the introduction.
• Gábor Jancsó and Áurelia Jancsó-Gábor; Herbert Hensel; Yngve Zotterman — Early work on capsaicin, menthol, and sensory nerve fibers.
• Saul Snyder, John Vane, and Raphael Mechoulam — Cited as examples of research using natural products to uncover biological mechanisms.
• Michael Caterina, Makoto Tominaga, David McKemy, and Werner Neuhauser — Associated with identifying and characterizing TRPV1 and TRPM8.
• Peter McNaughton, Mark Hoon, and Gary Lewin — Referenced in discussions of temperature sensing and sensory pathways.
• Elena Gracheva, Julio Cordero-Morales, and Ben Myers — Discussed in connection with evolutionary adaptations in temperature sensing.
• Yifan Cheng, Maofu Liao, and Kaihua Zhang — Named in connection with structural studies of TRPV1.
• Alan Basbaum — Acknowledged for contributions to Julius’s understanding of pain physiology.
• Alex Rich, David Baltimore, Howard Temin, Tom Frazier, Simon Litvak, Jeremy Thorner, Randy Schekman, Richard Axel, and Al Gilman — Cited among Julius’s mentors and scientific influences.
• Holly Ingram — Acknowledged by Julius as his wife and a scientific colleague.