Making sense of the senses: The 2021 Nobel Prize in Physiology or Medicine

By Dominika Pasztetnik

What do spicy food, menthol lozenges and walking around blindfolded have in common? They all activate protein receptors discovered by Professors David Julius and Ardem Patapoutian, the winners of the 2021 Nobel Prize in Physiology or Medicine.

Edited by Breana Galea & Juulke Castelijn

Issue 2: December 10, 2021

Illustration by Casey Boswell

Stimuli are changes to our environment, such as heat, cold and touch, that we recognise through our senses. We are all constantly bombarded with thousands of these stimuli from our surroundings. Despite this disorder, we are somehow able to perceive and make sense of the world. The protein receptors discovered by Professors Julius and Patapoutian make this possible. Located at the surface of the nerve cell, these receptors convert an external stimulus to an electrical signal. This signal then travels along nerve cells to the brain, allowing us to sense the stimulus.

Based in California, Julius and Patapoutian are scientists in the fields of neuroscience and molecular biology. The main interest of their work has been identifying and understanding the protein receptors involved in detecting stimuli. For Julius, his major focus has been to identify the receptors involved in the sensation of pain (1). For Patapoutian, it has been to identify the protein receptors involved in detecting mechanical stimuli, such as touch (2).

For their past 25 years of research, Julius and Patapoutian were awarded the Nobel Prize in Physiology or Medicine in October 2021. The Nobel Prize was founded by Alfred Nobel, a Swedish scientist also famous for inventing dynamite. Prior to his death in 1896, Nobel allocated most of his money to the first Nobel Prizes. Since 1901, the Nobel Prize has been annually bestowed on those who, in Nobel’s words, have “conferred the greatest benefit to mankind” in different fields (3).

Notable past laureates of the Nobel Prize in Physiology or Medicine include Sir Alexander Fleming, Sir Ernst Chain and the Australian Howard Florey. They were awarded in 1945 for their discovery of the antibiotic penicillin (4). Sir Hans Krebs received the Nobel Prize in 1953 for his discovery of the citric acid cycle (5). Also known as the Krebs cycle, it is a series of reactions used to produce energy in our cells.

TRPV1: spice it up

It’s a rather chilly morning. You eye the packet of Shin Ramyun that’s been sitting in your pantry for weeks. Without a second thought, you prepare the noodles, adding all the soup powder. After a few mouthfuls, your eyes start streaming and your face matches the scarlet red of the now-empty packaging.

The culprit is capsaicin, a substance in the chilli flakes added to the soup powder. It binds to a protein receptor embedded at the surface of the nerve cells in your mouth. Julius discovered this receptor in 1997, and called it TRPV1, which stands for transient receptor potential vanilloid type 1 (6).

TRPV1 is a channel with a gate at either end that is usually closed (Figure 1, blue) (7). Capsaicin opens these gates, allowing ions, such as calcium, to move through TRPV1 and into the nerve cell (Figure 1, red). The nerve cell then signals to the brain, causing you to feel the searing heat in your mouth. TRPV1 is also found in your skin and can be activated by temperatures above 40°C, such as when you accidentally touch the kettle full of boiling water for your noodles (8).

Figure 1. TRPV1 at the surface of a nerve cell. In the absence of capsaicin or at cool temperatures, TRPV1 is closed (blue). In the presence of capsaicin or at higher temperatures, TRPV1 opens, allowing ions to flow into the nerve cell (red).

TRPM8: too cool for school

On your way to uni, you notice your throat’s a bit sore from going overboard with karaoke the night before, so you pop a lozenge into your mouth. The soothing, cool sensation is thanks to menthol. It is a compound that binds to TRPM8, which stands for transient receptor potential melastatin 8. It is another receptor found on the nerve cells in your tongue, as well as on your skin (9). TRPM8 was separately discovered in 2002 by both Julius and Patapoutian (10).

Like TRPV1, TRPM8 is a protein channel that is usually closed. In response to menthol or cool temperatures from 26 down to 8°C, TRPM8 opens and allows ions to enter the nerve cell, which then signals the cold sensation to your brain (11).

PIEZO: peer pressure

During your lunch break at uni, you and your mates decide to play blindfolded tag. Because, as we all know, that's what uni students do in their free time. In the first round, you have the misfortune of being chosen as ‘it’. Blindfolded, you walk around with your hands in front of you, trying to find your mates. Despite not being able to see anything, you can still walk and wave your arms and roughly know where your arms and legs are in space. This is due to a sense called proprioception. You lunge forward and nearly grab someone, only to feel their jacket brush your fingers.

Both proprioception and the detection of light touch, such as of the jacket brushing your fingers, are made possible by another class of protein receptors called PIEZO2. Discovered by Patapoutian in 2010, its name comes from piesi, the Greek word for pressure (12).

Like TRPV1 and TRPM8, PIEZO2 is an ion channel at the nerve cell surface. However, the structure of PIEZO2 is nothing like that of TRPV1 and TRPM8. PIEZO2 has three protruding blades, which form a dent, called a nano-bowl, in the outer surface of the cell (13). When the outside of the cell is prodded, the blades straighten and the nano-bowl flattens. This allows the channel in the centre of the PIEZO2 to open, so ions can flow into the nerve cell (Figure 2). The nerve cell then sends an electrical impulse to the brain, letting you know you’re failing at blindfolded tag.

Figure 2. PIEZO at the surface of a nerve cell. When force is applied to the surface of the nerve cell, the PIEZO channel opens, allowing ions to move into the cell.

Apart from being essential for playing blindfolded tag, PIEZO2 is also important in various other aspects of the human body’s functioning we often take for granted. For example, PIEZO2 prevents you from breathing in too much air (14). It is also present on the cells lining your digestive tract. PIEZO2 detects pressure exerted onto these cells by food, causing the cells to release hormones that help with digestion (15). Furthermore, PIEZO2 helps monitor the fullness of your bladder, saving you from embarrassment (16).

If there is a PIEZO2, what about PIEZO1? Although it has a similar structure to PIEZO2, PIEZO1’s role is quite different. PIEZO1 handles the background maintenance required to keep your body healthy. This includes bone formation (17) and preventing your red blood cells from bursting (18).

People with a particular mutated form of PIEZO1 have a reduced risk of getting malaria (19). Patapoutian found that this mutation causes red blood cells to shrivel, preventing the malaria parasite from infecting them. Many people living in malaria-affected areas, such as Africa, have this mutation. Therefore, knowledge regarding these receptors is improving our understanding of related diseases.

Drug development

Researchers are currently using information about the receptors discovered by Julius and Patapoutian to develop new drugs to treat various conditions. Knowing the identities and structures of these receptors is helping researchers design compounds that bind to them, either blocking or activating them. In this way, Julius and Patapoutian’s work is helping provide a “benefit to mankind”.

For example, during a migraine, the TRPV1 channel opens more frequently in the nerve cells of the meninges, the envelope surrounding the brain (20). These nerve cells contain more TRPV1 at their surfaces. This causes the nerve cells to send more electrical signals to the brain and so increases the sensation of pain. Using a drug to block the TRPV1 receptor could reduce the number of these electrical impulses and lessen the pain associated with migraines.

It’s been a busy day activating all these receptors, which, as it turns out, are part of your daily life as a uni student. So next time you eat chilli flakes, have a menthol lozenge or play blindfolded tag, you will know which tiny sensors to hold responsible for your pleasant — or unpleasant — experiences.