David Julius and Ardem Patapoutian receive Frontiers of Knowledge Award for identifying the sensors that enable us to feel pain, temperature and pressure

The jury's citation underscores that it is a line of research that holds out exciting medical possibilities. Currently, several pharmaceutical laboratories are working to identify molecules that act on these receptors with the aim of treating different forms of chronic pain, for example, those associated with inflammatory processes like arthritis “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 citation. “Julius and Patapoutian provided a molecular and neural basis for thermosensation and mechanosensation.”

These findings have opened an area of research with the power to transform how we understand the physiological processes that govern our bodies’ functioning, with important medical implications. In this sense, this new field, ‘mechanobiology’, is taking a first look at the role of pressure receptors inside the body, in systems such as in the excretory system, for instance, to indicate a full urinary bladder, or the circulatory system, to control blood pressure

Taste and touch sensors

David Julius (New York, 1955) found that the receptor that triggers a burning sensation in the mouth on ingesting capsaicin – the pungent ingredient in chili peppers – is also responsible for sensing heat. Thus, the signal emitted by this receptor reaches the brain, which determines whether the heat is strong enough to burn tissue and, if so, produces the sensation of pain.

“Plants defend themselves by generating substances that cause predators pain, and we thought we could use these tools to try and understand the sense of pain on a molecular scale,” says Julius, after being notified of the award. His research team succeeded in identifying the gene of the receptor for the hot ingredient of chili peppers, but the real surprise came when they began looking at the same protein’s function in humans. “We realized that heating the cells produced an intense activation of the receptor,” the new laureate recalls. “It was a truly thrilling moment.”

They continued researching along this line trying to identify the receptor that governs our body’s perception of cold and they discovered that it resembles the one that detects capsaicin. “These findings told us that nature uses a common strategy that enables our nervous system to detect changes in temperature through a family of similar molecules,” said the scientist.

Later on, Julius also identified a receptor that mediates in the perception of wasabi and they verified that this same receptor is also implicated in the stinging of the eyes experienced when chopping an onion, and is also activated by the toxins of certain animals, among them the scorpion. “The crucial point” about this mechanism, explains the researcher, is that “it is important for understanding the pain of an inflammatory injury” and may serve “to understand how tissue injury generates not only acute but persistent pain, leading on to chronic pain syndromes.”

Pressure receptors on the skin

Ardem Patapoutian (Libano, 1967) discovered the receptors for the mechanical forces that sense pressure on the skin and in blood vessels, thus advancing “mechanobiology,” a new field of science that intersects biology, engineering and physics The discovery of the capsaicin receptor gene was published in 1997. By that time, Patapoutian had already begun to study the molecular bases of sensory perception

The starting point for Patapoutian’s research was the observation that touch is the only sense based on the translation of a physical signal, like pressure, into the chemical language that the body understands. “When 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 doesn’t: They sense physical forces like temperature and touch. There is really very little known about how the body translates these physical forces into a chemical language,” explained Patapoutian.

His team looked for cells that reacted electrically in a lab culture to the physical stimulus of pressure. Once found, they systematically suppressed the expression of candidate genes via RNA interference until they had isolated the receptor. “We knew there were proteins involved in the perception of pain, touch, heating or blood pressure, but no one had any idea that a single family, the Piezo 1 and Piezo 2 receptors discovered by our group, could explain all these processes,” he noted.

This breakthrough was the first in a chain of discoveries in this research field. Patapoutian’s group has since revealed the three-dimensional structure of the Piezo receptors, helping to elucidate their mechanical functioning. Patapoutian elaborates further: “Piezo 2 is required for a very specific subset of pain. “The pain of being hit with a hammer has little to do with this receptor, but if you get sunburn, for example, and just touching your shoulder hurts, that form of pain seems to be Piezo 2 dependent. This could be important for the treatment of neuropathic pain. I believe it will be interesting to see what the next five or ten years bring in terms of the medical repercussions of these findings.”

Patapoutian is confident that mechanobiology will uncover additional means of inter-cell communication, with potentially enormous implications for biomedical research: “Until now we have treated life mainly as a bag of chemicals that talk to each other by chemical synthesis, but more and more we are realizing that mechanobiology, mechanical forces, play important roles in everything from cell division all the way up to hearing, touch and pain. What we have discovered so far is very exciting, but it’s just the tip of the iceberg of this new science.”