David Julius and Ardem Patapoutian receive the Frontiers of Knowledge Prize in Biology and Biomedicine

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The BBVA Foundation Frontiers of Knowledge Award in Biology and Biomedicine was presented in this thirteenth edition to David Julius, of the University of California, San Francisco, and Ardem Patapoutian, of the Scripps Institute, La Jolla (United States), “for have identified the receptors that allow us to feel temperature, pain and pressure. “

“Temperature, pain and pressure are part of our sense of touch, perhaps the least understood of the five main senses of humans,” read the opening words of the quote. “Julius and Patapoutian provided a molecular and neural basis for thermosensation and mechanosensation.”

This line of research offers interesting medical possibilities, because “it sheds light on how to reduce chronic and acute pain associated with a range of diseases, injuries and their treatments”. Indeed, several pharmaceutical companies are working to identify molecules that act on these receptors in order to treat different forms of chronic pain, for example those associated with inflammatory processes such as arthritis.

But the committee also underlined “the immense value that comes with understanding a fundamental point of view of how we perceive the world”, in the words of Óscar Marín, secretary of the committee and director of the MRC Center for Neurodevelopmental Disorders at King’s College London (United Kingdom). “Although we have yet to see practical applications from these findings, their potential is so great that it marks a milestone.

Understanding how our bodies feel about changes in temperature or pressure is so conceptually important that it’s surprising how much we knew until recently, or rather, how we knew which part of the nervous system processes information, but not the molecular sensors it uses. This is the kind of discovery where it’s difficult to grasp the full extent of its potential applications, although work is already underway on some, such as chronic pain management and blood pressure control. “

For Marín, the award is also a timely reminder of the importance of basic science: “Think back 20 years to researchers working on RNA biology. They couldn’t even imagine they had found the key to ‘a new generation of vaccines like those of today. deployed against Covid 19. “

The findings of the two laureates have opened up an area of ​​research with the power to transform the way we understand the physiological processes that govern the functioning of our bodies, with important medical implications.

This new field, mechanobiology, takes a first look at the role of pressure receptors inside the body. In the excretory system, for example, to indicate a full bladder, or the circulatory system, to control blood pressure.

Taste and touch sensors

The first surprise came when David Julius discovered that the receptor that triggers a burning sensation in the mouth when ingesting capsaicin – the pungent ingredient in chili peppers – is also responsible for sensing heat. Julius, said the committee, “identified the gene encoding the first temperature sensor, the TRPV1 ion channel, using capsaicin, and found that TRPV1 is also activated by high temperatures.” The signal from this receptor reaches the brain, which determines whether the heat is strong enough to burn tissue and, if so, produces the sensation of pain.

Julius explained after hearing about the price that while the link between the burning sensation of spicy food and the high temperature was “obvious in hindsight,” it was not at the time. It was his basic curiosity about how we use natural products that drew him to this area of ​​research, ultimately leading him to investigate the molecular basis of pain.

“Plants defend themselves by generating substances that cause predators pain, and we thought we could use these tools to try to understand the meaning of pain on a molecular level,” says Julius. His research group began by studying the molecular basis for perceiving capsaicin, which research elsewhere has shown may be related to the sensation of pain. They managed to identify the receptor gene for the hot ingredient in chili pepper, but the real surprise came when they began to examine the function of the same protein in humans. “There was no way,” Julius said, “that we would have it just to enjoy the spicy food.”

They discovered in cultured cells that heat also activates the capsaicin receptor. “We realized that heating the cells produced intense activation of the receptor,” recalls the new winner. “It was a really exciting time.”

They decided to continue this line of research and to search for the receptor of the cold. Armed with their knowledge of the link between temperature and certain taste reactions, they turned to menthol, an ingredient in mint associated with a cool or icy sensation. Indeed, they found that the receptor for menthol and low temperature was the same. And, to Julius’ amazement, it looked like capsaicin.

“What was really fascinating about this discovery was that this molecule is very close genetically to the capsaicin-activated receptor in hot peppers and by heat. So, together, these findings told us that nature uses a common strategy that allows our nervous system to detect changes in temperature thanks to a family of similar molecules. “

Wasabi and inflammatory pain

Julius then identified the receptor for wasabi, the pungent compound belonging to the mustard family. Again, the clues were found in nature: “Mustard extracts have been used for many years in pain tests: a doctor rubbed a tincture of mustard oil onto a patient’s skin to generate a feeling of irritation which tests the response to acute pain, but also generates inflammation which makes the area more sensitive to temperature and touch. So this was used as a model to understand the mechanisms associated with inflammatory pain, as you would experience with an arthritis joint. We asked how this process worked and identified a receptor in the nerve cells which is the mechanism by which wasabi and other mustard plants produce a pungent sensation. “

It has since been discovered that the wasabi receptor is involved in the tingling of the eyes felt when cutting an onion, and is also activated by toxins from certain animals, including the scorpion. But “the crux” of this mechanism, explains Julius, is that “it is important for understanding the pain of an inflammatory injury” and can be used “for understanding how tissue damage not only generates acute pain but is persistent, leading to chronic pain. syndromes. “

Pressure in the skin and blood vessels

The discovery of the capsaicin receptor gene was published in 1997. At that time, Ardem Patapoutian – an Armenian immigrant fleeing the war in Lebanon who came to the United States to become a doctor but quickly “fell in love with the research” – also had started to study the molecular basis of sensory perception.

The two laureates, who coincided at the University of California, San Francisco, during Patapoutian’s postdoctoral fellowship, described their relationship as moving from “competitive” to “complementary” by specializing in different receptors. Patapoutian, the quote says, “identified the genes encoding a family of stretch-activated ion channels.” Known as Piezos, these proteins “are responsible for sensing pressure in the skin and blood vessels, so that their importance for health and disease extends beyond the sense of touch.”

“These discoveries,” he continues, “opened the door to understanding mechanobiology, an emerging scientific field that intersects with biology, engineering and physics”.

Touch and neuropathic pain

The starting point of Patapoutian’s research was the observation that touch is the only sense based on translating a physical signal, such as pressure, into the chemical language the body understands. “By studying the peripheral nerves that help us feel touch and pain, we realized something very special, which is that they do something that the rest of the body does not. They feel physical forces like temperature and touch. There are really very few. know how the body translates these physical forces into chemical language. “

Patapoutian and his group looked for cells that reacted electrically in a laboratory culture to the physical stimulus of pressure. Once found, they systematically suppressed the expression of candidate genes via RNA interference until they isolated the receptor.

At this point, they still had no idea how this discovery might relate to other physiological processes: “We knew that there were proteins involved in the perception of pain, touch, pain. ‘heating or blood pressure, but no one knew that only one family, the Piezo 1 and Piezo 2 receptors discovered by our group, could explain all these processes, ”Patapoutian said yesterday.

This breakthrough was the first in a chain of discoveries in this area of ​​research. Patapoutian’s group has since revealed the three-dimensional structure of Piezo receptors, helping to elucidate their mechanical function.

It turns out that these are large proteins that repeatedly move in and out of cell membranes, like an elastic band attached to the membrane that alternately stretches and contracts. Last October, a Nature article described how Piezo 2 indicates when the bladder is full. It is also Piezo 2 which detects when the skin is lightly brushed or stroked. Or warns that the skin is inflamed from sunburn.

Patapoutian clarifies: “Piezo 2 is needed for a very specific subset of pain. The pain of being hit with a hammer has little to do with this receiver, but if you get sunburned, for example, and that just touching your shoulder hurts. form of pain seems to depend on Piezo 2.

It could be important for the treatment of neuropathic pain [when pain lasts for a long time after the original injury has gone away]. I think it will be interesting to see what the next five or ten years bring in terms of the medical repercussions of these discoveries. “

The Scripps Institute investigator also showed that these sensors play an essential role in “proprioception,” our ability to sense the relative position of parts of our body. It’s a sense, he points out, that we largely ignore “because we can’t turn it off,” but which we completely rely on to do things as simple as getting up or walking.

He is convinced that mechanobiology will uncover additional means of intercellular communication, with potentially enormous implications for biomedical research: “Until now, we have treated life primarily as a bag of chemicals that synthetically speak to each other, but more and more we realize that mechanobiology, mechanical forces, play an important role in everything from cell division to hearing, touch and pain. What we have discovered so far is very exciting, but it is only the tip of the iceberg of this new science. “

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