How did chili pepper and mint win the “Nobel Prize in Food”?

The 2021 Nobel Prize in Physiology or Medicine was awarded to two scientists who discovered temperature and touch receptors. How did they open up a new research field from the senses that people are accustomed to?

When you eat hotpot, how do you feel the spiciness and heat in your mouth? When the weather gets colder, how do you feel the coolness? In fact, it's all the human body's sense of touch at work.

Whether it is the perception of touch or temperature, people are already accustomed to it. But for two scientists, David Julius and Ardem Patapoutian, this is a brand new field of research.

This year's Nobel Prize in Physiology or Medicine has just been awarded to these two scientists for their discovery of temperature and touch receptors, which opened the door to knowledge for us. The human ability to perceive heat, cold and touch is essential for survival and is the basis for human interaction with the world around us. Without touch, we would not know if we are "on the ground"; if we cannot feel the temperature, we may be in a dangerous environment without knowing it.

▲Julius (left) and Pataptian (Photo source: Nobel Prize official website)

"Imagine a summer morning, walking barefoot in a field. You can feel the warmth of the sun, the coolness of the morning dew, the gentle summer breeze, and the touch of the grass under your feet," the Nobel Prize website said. The two scientists' research not only explains how these external heat, cold and touch trigger signals in the human nervous system, but can also be used to develop treatments for various diseases, including chronic pain.

Chili peppers open the "channel" for feeling hot and cold. In fact, scientists have long proved that nerve cells are highly specialized and can be used to identify and transmit different types of stimuli. Joseph Erlanger and Herbert Gasser, winners of the 1944 Nobel Prize in Physiology or Medicine, discovered that different types of sensory nerve fibers can respond to different stimuli, such as painful and non-painful touch.

However, our understanding of how the nervous system perceives and interprets the surrounding environment has always contained a fundamental unresolved question: How are physical temperature and mechanical stimuli converted into neural electrical impulses?

In the 1990s, David Julius, who was good at receptor cloning, became interested in the molecular mechanisms of somatic perception and pain. After arduous searches, Julius and Michael Caterina, a postdoctoral fellow in the team, discovered a gene that can make cells sensitive to capsaicin in 1997. Further experiments showed that the gene encodes a new ion channel protein, and this newly discovered capsaicin receptor was later named TRPV1.

▲Our perception of temperature and pressure depends on ion channel proteins (Image source: Nobel Prize official website)

What are ion channels? The reason why we have different responses to different stimuli depends on the ion channels on the nerve cell membrane. The opening and closing of these channels affect the entry and exit of ions inside and outside the cell, and then affect the cell membrane potential.

A normal cell membrane maintains a potential difference of "positive outside and negative inside". If a large amount of cations flow in or anions flow out, it will cause a change in the cell membrane potential. When this potential change reaches a certain level, it will induce nerve impulses and ultimately produce "feelings" in the cerebral cortex.

As Julius studied the TRPV1 protein's ability to respond to heat, he realized something: they had discovered a heat receptor that could be activated by temperatures above 43°C.

▲ Capsaicin causes the illusion of "heat"

This is the first temperature-sensitive ion channel discovered. This discovery confirmed for the first time that natural chemical stimulation such as capsaicin and physical stimulation such as temperature can be converted into electrical signals through the TRPV1 channel on the cell membrane, allowing us to understand how temperature differences generate electrical signals in the nervous system and updating our understanding of somatic sensations.

▲TRPV1 protein structure diagram. High temperature can activate it, and some spider toxins (the purple molecule above the picture) and capsaicin molecules (the small red molecule in the picture) can also activate it, thus producing a "burning" feeling (Image source: quanta)

Since then, scientists have discovered at least eight more TRP channels that respond to heat and cold. For example, Julius and Ardem Patapoutian's teams independently identified TRPM8 as a molecule that responds to menthol and cold, and that the channel can be activated by harmless low temperatures of 8°C to 28°C.

▲A 2017 study found that hamsters and squirrels are insensitive to cold environments due to mutations in TRPM8 (Image source: Cell Reports)

In 2003, Julius' team discovered the cold-sensing channel TRPA1, which can be activated by mustard oil and can also be activated by ultra-low temperatures (

A recent study called TRPA1 the "cough switch": researchers used acrolein and other substances in cigarette smoke to test and found that both mice and volunteers would cough after inhaling these substances, and the greater the amount inhaled, the more severe the cough. However, if drugs were used to inhibit the TRPA1 receptors in the body, their coughing would be significantly reduced.

▲Scientists have found a variety of TRP channels that respond to cold and heat with the help of various natural ingredients that produce a "spicy" or "cool" feeling (Image source: "Membranes")

Interestingly, many discoveries in this field are inseparable from common condiments in the kitchen. In a telephone interview with the Nobel Prize Committee, Julius said, "We are able to carry out relevant research because we started looking for (clues) in the natural world."

▲Several key TRP proteins discovered by Julius' team interact with the ingredients of seasonings (Image source: iBiology.org)

Exploring the Secret of "Pressure" Pataptian and Julius were studying the problem of touch receptors at almost the same time. After discovering the receptors for mint and mustard oil, he decided to launch an attack on the search for the more challenging mechanical force receptors.

The study of mechanical force receptors is extremely difficult, firstly, it is necessary to find a suitable stimulation method, and secondly, it is difficult to record the weak current generated. During the research, Pataptian found cells of a glioma cell line that can be grown in a laboratory dish. These cells respond to the pressure changes caused by light touch by generating electrical signals.

▲Exerting pressure on the cell membrane surface will open some ion channels (Image source: Nobel Prize official website)

The research team selected more than 300 candidate genes that were highly expressed in this type of cell from more than 20,000 coding genes in humans, and then cultured cells with these genes knocked out. The samples were then tested to find genes that would cause cells to lose their sensed current when missing.

After painstaking research, Patapoutian and his colleagues succeeded in identifying a gene whose knockout rendered cells insensitive to the light poking of microtubules. They discovered a completely new and unknown force-sensitive ion channel and named it PIEZO1, which comes from the Greek word for "pressure" (piesi).

▲3D printed PIEZO transmembrane channel protein model (Photo credit: Pataptian)

Subsequently, they discovered a second gene through sequence similarity to PIEZO1 and named it PIEZO2. Scientists found that sensory neurons expressed high levels of PIEZO2, and further studies confirmed that PIEZO1 and PIEZO2 ion channels can be directly activated by applying pressure to the cell membrane.

The discovery of PIEZO channel proteins has opened the door to mechanobiology, an emerging scientific field that intersects biology, engineering, and physics, focusing on studying how changes in the physical forces and mechanical properties of cells and tissues affect health and disease. Studies have found that PIEZO channel proteins are not only important for touch, but can also sense pressure through nerve endings distributed in blood vessels and lungs, affecting red blood cell volume and vascular physiology, and their abnormalities can cause a variety of human genetic diseases.

Pataboutian said in an interview that he had experienced a long period of slow progress in his research career, and he even thought about changing his career. But fortunately, he "resisted the pressure" and persisted. "This is a very fascinating journey. PIEZO channel proteins take us from biology and pathophysiology, and then take us to new and unknown areas."

▲ From the popular dishes, Patabotian can see what PIEZO protein looks like

The discovery of the capsaicin receptor TRPV1, which was discovered by the Nobel Prize winner, confirmed that spiciness is not a taste, but a pain sensation. Subsequently, the mystery of "pepper analgesia" surfaced: research found that when the ion channel properties of TRPV1 are continuously activated, cations will continue to flow into the cell. For the sake of self-protection, the cell will feedback-close the TRPV1 channel and "desensitize" the nociceptive neurons to capsaicin and even other noxious stimuli, reducing the generation of pain signals and thus inhibiting the pain sensation.

After grasping the relationship between TRPV1 receptors and analgesia, scientists are also exploring it as a new important drug target for the treatment of various chronic pains. In fact, as early as the late 1980s, consumer-grade low-dose capsaicin ointments had already appeared, but the effect was minimal. In 2009, pain researchers developed a patch with a higher concentration of capsaicin for patients with chronic neuralgia. It contains 8% capsaicin, which is more than 100 times the concentration of the original capsaicin ointment, and the effect is better than the previous ointment.

▲8% high-concentration capsaicin patches have been approved in Europe and the United States for the treatment of certain types of neuralgia (Image source: Therapeutic Advances in Neurological Disorders)

After discovering more channel proteins in the TRP family, Julius' team worked with the laboratory of Chinese scientist Cheng Yifan to analyze the three-dimensional structures of multiple TRP proteins. Subsequently, they used methods such as gene knockout technology to explore the relationship between the structure and function of these proteins. This provides a reference for future scientists to develop targeted drugs.

The researchers also found that TRPV1 is very sensitive to chemicals produced during inflammation, which could help solve the problem of cancer pain and other diseases in the future. In other words, after finding out the cause, inhibiting the relevant ion channels with drugs could alleviate certain types of chronic pain.

On the other hand, as a pressure receptor in the sensory neurons of the autonomic nervous system, the discovery of PIEZO protein also brings good news to patients with hypertension. Patients with baroreceptor reflex dysfunction usually experience postural hypotension, that is, a severe drop in blood pressure when standing, which leads to dizziness or even fainting. Impaired baroreceptor function may also lead to arrhythmias and early death in patients with myocardial infarction and heart failure.

▲Arterial baroreceptors continuously monitor arterial blood pressure through sensory nerves expressing PIEZO1 and PIEZO2 receptors

Although the concept of arterial baroreceptor reflex was described more than 80 years ago, people have always been at a loss as to how changes in blood pressure are converted into electrical signals transmitted by nerves.

Studies have found that PIEZO1 is significantly expressed in the human cardiovascular system, while PIEZO2 is a key molecule in human "proprioception". "Proprioception" allows us to perceive the position of our body in space and plays an important role in a person's standing, walking and even performing various actions in the dark.

▲PIEZO2 is crucial to human proprioception (Image source: kavliprize.org)

Although it is still in the basic research stage, the research on pressure receptors provides a basis for the development of new drugs that activate piezoelectric channels to inhibit excessive sympathetic nerve activity. In addition, Pataboutian's team also found that red blood cells in the blood can sense pressure and change the volume of cells; related receptors on immune cells can regulate the iron content in the blood. In other words, PIEZO receptors may have a breakthrough in immunotherapy.

References:

[1]Waxman SG, Zamponi GW. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014;17(2):153-163. doi:10.1038/nn.3602

[2] Stevens RM, Ervin J, Nezzer J, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Intraarticular Trans-Capsaicin for Pain Associated With Osteoarthritis of the Knee. Arthritis Rheumatol (Hoboken, NJ). 2019;71(9):1524-1533. doi:10.1002/art.40894

[3] I was so spicy that I became a masochist, but you told me that chili peppers can relieve pain?

https://www.sohu.com/a/328319835_119097

[4] 2021 Nobel Prize | How do we perceive the world?

https://www.163.com/dy/article/GLG48R550511D3CN.html

[5] 2021 Nobel Prize in Physiology or Medicine: Using chili peppers as a key to unlocking the mystery of bodily sensations

http://www.myzaker.com/article/615ad6a68e9f093f5b2527d7

[6] Science published: The century-old mystery of blood pressure has been solved, good news for patients with hypertension!

https://www.cn-healthcare.com/article/20190307/content-515471.html

Written by reporter Lai Tianying and Ding Lin Edited by Ding Lin

Produced by: Science Central Kitchen

Produced by: Beijing Science and Technology News | Science Plus Client

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