4 October, 2021
David Julius, of the University of California, San Francisco, and Ardem Patapoutian, of The Scripps Institute in La Jolla (United States) were in Bilbao on September 21 to attend the Frontiers Awards presentation ceremony.
The two researchers received the Frontiers Award for discovering new families of sensors that enable us to perceive temperature, pain and pressure. As the Frontiers citation states, these stimuli “are part of our sense of touch, perhaps the least understood of the five main human senses.” Julius and Patapoutian’s findings, it continues, “provide a molecular and neural basis for thermosensation and mechanosensation.”
Patapoutian, who began his career in the United States after fleeing war in his native Lebanon, looked back at his origins during his acceptance speech in Bilbao: “I could never have imagined as a refugee from Lebanon to the United States that I could have a life in the sciences. Perhaps because of my background I try not to take things for granted and I consider myself privileged to be a scientist.”
Distinguishing the prick of a cactus from a gentle breeze
He also explained how his research elucidates how the human body distinguishes between a gentle caress and the prick of a cactus. And spoke about the “last frontier” in sensory biology:
“We are being recognized today for our work on identifying receptors that our bodies use to sense the physical forces that we experience. How do we sense stimuli of the physical dimension, such as temperature and pressure? These senses help us recognize a gentle breeze or the prick of a cactus. They also tell us when our blood pressure is increased, or when our bladders are full. This is a fundamental question of sensory biology, the last frontier to be described.”
“We began our work for the love of pure science, but are also uncovering unexpected medical implications, in areas such as pain, hypertension, atherosclerosis, and osteoporosis.”
From “hot” food to new analgesics
David Julius talked the public at the Frontiers ceremony through his research journey from the sensing of pungency in food to the potential development of new analgesics.
“What types of molecules enable nerve fibers to respond to physical factors, such as heat and cold, or to chemical irritants, such as acid? And if such molecules exist, how are their properties altered following physiological insults, such as inflammation or nerve damage, that promote chronic pain?”
“…we asked two simple questions: (i) what specific molecular mechanisms enable us to appreciate the pungent ‘heat’ of chili peppers or the refreshing ‘coolness’ of mint, and (ii) how do such mechanisms relate to our normal sensations of temperature and pain? Answers to these questions led to the discovery of heat- and cold-activated ion channels (TRPV1 and TRPM8 respectively), which (…) validate the sensory nerve fiber as a rational and selective target for novel analgesics.”
“The value of understanding how we perceive the world”
Neuroscientist Óscar Marín, secretary of the Frontiers committee and Director of the MRC Centre for Neurodevelopmental Disorders at King’s College London (United Kingdom), talking after the award decision, in February 2021, emphasized “the immense value that comes with understanding from a fundamental standpoint how we perceive the world.”
“Although we have yet to see practical applications from these discoveries, their potential is so great as to mark a transformative milestone,” he added. “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, more specifically, how we knew only the part of the nervous system that processes the information, but not the molecular sensors it employs. 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.”
From hallucinogenic compounds to the study of pain
David Julius began investigating the molecular bases of pain out of an interest in medicinal plants and hallucinogenic compounds. “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,” he explained shortly after hearing of the Frontiers award.
Research elsewhere had suggested a connection between pain sensation and capsaicin, the molecule responsible for the burn in chili peppers. Julius managed to identify the capsaicin receptor that allows our body to detect its presence. But the truly thrilling moment, he says, came with the realization that the same protein also responded to heat: “We found that heating the cells produced an intense activation of the capsaicin receptor.”
The next step was to look for the cold receptor, using menthol this time for the icy sensation it evokes. The result was another win: the receptor for menthol and low temperatures was one and the same, and “the truly fascinating thing was that it was very close genetically to the receptor for capsaicin and heat.”
Julius went on to identify the receptor for the pungent compound wasabi, which is also activated by the chemicals given off by onions – hence the weeping eyes – and by scorpion venom. We now know that it is also associated with inflammatory pain, and may help us understand how certain injuries give rise to a persistent pain.
Pressure in skin and blood vessels
The discovery of the capsaicin receptor gene was published in 1997. By that time Ardem Patapoutian, an Armenian immigrant fleeing the war in Lebanon, had also begun studying sensory perception. The two laureates coincided at the University of California, San Francisco, where their research would transition from competing to complementary as they increasingly specialized in different receptors.
Patapoutian’s started from the observation that touch is the only sense based on the translation of a physical signal, like pressure, into the chemical language the body understands. “When studying the peripheral nerves that help us feel touch and pain, we realized something very special, which is that 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.”
He and his group found cells that reacted electrically in a lab culture to being pressed with a pipette. They then looked for the genes implicated in this response, suppressing candidate genes one after another and observing whether the cells ceased to respond. After almost a year’s worth of measurements, in 2009 they identified the Piezo1 gene, named after the Greek word for pressure. This was followed not long after by the discovery of Piezo2. And so was born a new and still expanding avenue of research – mechanobiology – described in the Frontiers citation as “an emerging field of science that intersects biology, engineering and physics.”
The Piezo genes quickly became the subject of hundreds of research papers. Activated by tension, the mechanical force of stretching, they intervene in multiple systems, from the excretory – warning when the urinary bladder is full – to the circulatory, where they regulate pressure sensing in the blood vessels. As such, said the Frontiers committee, “their importance in health and disease extends beyond the sense of touch.”
The discovery came as a surprise, admitted Patapoutian: “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 Piezo1 and Piezo2 receptors, could explain all these processes.”
We now know that it is Piezo2 that detects when the skin is brushed lightly or caressed. Or warns when it is inflamed by sunburn. It also plays an essential role in proprioception, our ability to feel the relative position of the parts of our body. A sense, he explains, that “we largely ignore because we cannot turn it off,” but which we rely on to remain standing, and when learning to walk or play a musical instrument.
Patapoutian is confident that much remains to be learned. “More and more we are realizing that mechanobiology plays important roles in everything from cell division all the way up to hearing, touch and pain. What we have discovered so far is merely the tip of the iceberg of this new science.”
17 Frontiers of Knowledge Awards laureates have won the Nobel Prize
Following today’s award to David Julius and Ardem Patapoutian, a total of 17 Frontiers of Knowledge Awards laureates have gone on to win the Nobel Prize in several different categories.
Emmanuelle Charpentier and Jennifer Doudna, winners of the 2020 Nobel Prize in Chemistry, received with the Frontiers Award in Biology and Biomedicine in 2017. In the same edition, the Noble Memorial Prize in Economic Sciences was bestowed on Paul Milgrom and Robert Wilson, Frontiers awardees in Economics, Finance and Management in 2013 and 2016 respectively.
In 2019, four Nobel prizes went to researchers previously distinguished with a Frontiers of Knowledge award: Abhijit Banerjee and Esther Duflo in Economics (2008 Frontiers laureates in Development Cooperation) and Didier Queloz and Michel G. E. Mayor in Physics (2011 Frontiers laureates in Basic Sciences). In earlier editions, Shinya Yamanaka and James P. Allison, winners in the Biomedicine category of the awards, received the Nobel Prize in Medicine in 2012 and 2018 respectively; and Robert J. Lefkowitz, another Biomedicine laureate, won the Chemistry Nobel in 2012. In Economics, Finance and Management, three Frontiers laureates besides Milgrom and Wilson were subsequently awarded the Economics Nobel: Lars Peter Hansen (2013), Jean Tirole (2014) and Angus Deaton (2015). And finally, William Nordhaus received the 2018 Nobel in Economics after winning the Frontiers Award in Climate Change earlier that year.