Ardem Patapoutian (Lebanon, 1967) earned his BS from the University of California, Los Angeles (UCLA) in 1990, then went on to complete a PhD in Biology at California Institute of Technology (Caltech) in 1996, followed by a postdoctoral fellowship at the University of California, San Francisco. In the year 2000, he joined the faculty of the Scripps Research Institute, where he now combines a professorship in the Department of Neuroscience at the Dorris Neuroscience Center with his work as a Howard Hughes Medical Institute (HHMI) Investigator. He also held a series of posts at the Genomics Institute of the Novartis Research Foundation between 2000 and 2014. Author of more than a hundred published papers in scientific journals, he belongs to the American Association for the Advancement of Science (2016), the U.S. National Academy of Sciences (2017), and the Society for Neuroscience.
“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.”
This line of research holds out exciting medical possibilities, because “it sheds light on how to reduce chronic and acute pain associated with a range of diseases, trauma and their treatments.” In fact, 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.
But the committee also highlighted “the immense value that comes with understanding from a fundamental standpoint how we perceive the world,” in the words of Óscar Marín, committee secretary and Director of the MRC Centre for Neurodevelopmental Disorders at King’s College London (United Kingdom). “Although we have yet to see practical applications from these discoveries, their potential is so great as to mark a transformative milestone. Understanding how our bodies sense changes in temperature or pressure is so conceptually important that it is surprising how little we knew until recently, or rather, how we knew which part of the nervous system processes the information, but not the molecular sensors it uses. This is the kind of finding where it is hard to grasp the full scope 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 the researchers working on RNA biology. Not even they could imagine that they had found the key to a new generation of vaccines likes those now being deployed against Covid 19.”
The two laureates’ 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.
This new field, mechanobiology, is taking a first look at the role of pressure receptors inside the body. In the excretory system, for instance, to indicate a full urinary bladder, or the circulatory system, to control blood pressure.
Taste and touch sensors
The first surprise came when David Julius 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. Julius, says the committee, “identified the gene encoding the first temperature sensor, the ion channel TRPV1, using capsaicin, and discovered that TRPV1 is also activated by high temperatures.” 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.
Julius explained after hearing of the award that though the link between the burning sensation of spicy food and high temperature was “obvious with hindsight,” it was not so at the time. It was his basic curiosity about how we use natural products that attracted him to this area of research, eventually 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 and understand the sense of pain on a molecular scale,” says Julius. His research group started by studying the molecular bases for the perception of capsaicin, which they knew from research done elsewhere could be linked to pain sensation. They were successful in identifying the gene of the receptor for the hot ingredient of chili, but the real surprise came when they began looking at the same protein’s function in humans. “There was no way,” says Julius, “that we would have it just to enjoy spicy food.”
They discovered in cultured cells that heat too would activate the capsaicin receptor. “We realized that heating the cells produced an intense activation of the receptor,” the new laureate recalls. “It was a truly thrilling moment.”
They decided to pursue this line of research and search for the cold receptor. Armed with their knowledge of the link between temperature and certain taste reactions, they turned to menthol, an ingredient of mint associated with a cool or icy sensation. In effect, they found that the receptor for menthol and low temperature was one and the same. And, to Julius’s astonishment, it resembled that of capsaicin.
“What was really fascinating about this discovery was that that molecule is very close genetically to the receptor activated by the capsaicin of chili peppers and by heat. So together 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.”
Wasabi and inflammatory pain
Julius then went on to identify the receptor for wasabi, the pungent compound belonging to the mustard family. Again the clues were found in nature: “Extracts from mustard have been used for many years in pain tests: a physician would rub a tincture of mustard oil on a patient’s skin to generate a sense of irritancy that tests acute pain response, 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, such as you would feel with an arthritic joint. We asked how this process worked and identified a receptor in the nerve cells that is the mechanism through which wasabi and other mustard plants produce a pungent sensation.”
It has since been found that the wasabi receptor is 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. But “the crucial point” about this mechanism, Julius explains, 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 in 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 had come to the USA to become a doctor but quickly “fell in love with research” – had also begun to study the molecular bases of sensory perception.
The two laureates, who coincided at the University of California, San Francisco, during Patapoutian’s postdoctoral stay, described their relationship as moving from “competitive” to “complementary” as they began specializing in different receptors. Patapoutian, the citation says, “identified the genes encoding a family of stretch-activated ion channels.” Known as Piezos, these proteins “are responsible for pressure sensing in the skin and blood vessels, so their importance in health and disease extend beyond the sense of touch.”
“These findings,” it continues, “opened the door to understanding mechanobiology, an emerging field of science that intersects biology, engineering and physics.”
Touch and neuropathic pain
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.”
Patapoutian and his group 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. At this stage, they still had no inkling of how this finding might relate to other physiological processes: “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,” said Patapoutian yesterday.
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. They are, it turns out, large proteins that move repeatedly in and out of cell membranes, like an elastic band fastened to the membrane that alternately stretches and contracts. Last October, an article in Nature described how Piezo 2 indicates when the urinary bladder is full. It is also Piezo 2 that detects when the skin is brushed lightly or caressed. Or warns that the skin is inflamed by sunburn.
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 [when pain lasts for a long time after the original injury has gone away]. 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.”
The Scripps Institute investigator has also shown that these sensors play an essential role in “proprioception,” our ability to feel the relative position of the parts of our body. This is a sense, he points out, that we largely ignore “because we cannot turn it off,” but that we rely on completely to do such simple things as stand up or walk.
He 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.”
Image: ©Sandy HuffakerAP Images for HHMI