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Two California-based scientists won the 2021 Nobel Prize in medicine or physiology on Monday for their discoveries of receptors for heat, cold, and touch.

David Julius of the University of California, San Francisco, and Ardem Patapoutian of the Scripps Research Institute in La Jolla, Calif., figured out how stimuli are converted into nerve impulses so that temperature and pressure can be perceived — essential to humans’ survival. Julius’ work involved experiments with capsaicin, the substance that makes hot peppers hot, to identify a sensor in the nerve endings of the skin that responds to heat. Patapoutian unlocked the molecular basis for sensing temperature or mechanical force working with cold and used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs.

Together their work explains how we interpret heat, pain, touch, and location and movement of our bodies in space, called proprioception, the Nobel Prize committee said.

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“The Nobel Prize news reflects the great interest in the senses that all human beings have, including the Nobel Committee,” Jeremy Berg, professor of computational and systems biology at the University at Pittsburgh and former director of the NIH’s National Institute of General Medical Sciences, told STAT in an email.

Capsaicin in hot peppers is among the properties found in natural products that Julius, 65, has explored to discover temperature-sensitive ion channel receptors that allow sensory nerve fibers to detect hot or cold temperatures. These channels, called TRP (pronounced “trip”) channels, also respond to chemical stimuli that evoke sensations of heat or cold: The TRPV1 receptor responds to heat and the TRPM8 receptor responds to either cool temperatures or the chemicals that make up menthol.

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These TRP receptors are important in medicine because they are plentiful in pain pathways, making them targets for biotech and pharmaceutical companies searching for drug candidates that might control pain without the drawbacks of opioids.

Patapoutian, born in 1967, has also focused on ion channels activated by changes in heat — acting like molecular thermometers in the body. Some of these channels, such as TRPA1, respond to chemical substances, playing a role in pain and inflammation (one compound blocking that channel is now in clinical studies). His lab has also identified different pathways, including the cation channels Piezo1 and Piezo2, that are activated by mechanical force. That’s important in touch and pain, but they also regulate biological processes such as blood pressure, breathing, and bladder control.

“The identification of those sensory ion channels was a major step forward,” Eric Honoré, director of research at the Institute of Molecular and Cellular Pharmacology, in Valbonne, France, who studies the mechanobiology of diseases like hypertension and obesity, told STAT via email.

This morning, many of you will wake up and start your coffee-making routine. You’ll tread across your kitchen floor, feeling the tile or wood or linoleum underfoot. Perhaps you’ll wince at the too-early sound of grinding beans, but it will be soon soothed by caffeine-promising aromas and the curve of a favorite mug, now warm to the touch. Let your attention stray, however, and a scalded tongue may be in store. These impressions of temperature, touch, movement, sound, smell, and yes, sometimes, pain, are essential for navigating our constantly changing surroundings.

Most mechanisms for sensing the environment have already been recognized by the world’s most prestigious science award. In 1961, a Nobel went to Georg von Békésy for hearing; George Wald for vision in 1967; Richard Axel and Linda Buck for smell in 2004; as well as Roderick MacKinnon with Peter Agre for the underlying signaling systems such as ion channels for the senses in 2003. With today’s award, touch and temperature join the club.

“It’s been the last main sensory system to fall to molecular analysis,” Julius said at a press conference convened by UCSF Monday. The eye is an easier organ to study, he said. And pharmacology gave scientists clues about the kinds of molecules responsible for transmitting smells. “But for things like temperature and pressure sensors, we really didn’t have examples of the types of molecules that we could look for.”

In the late 1940s, Hungarian researchers discovered that if you rubbed high doses of capsaicin onto mice and rats, it acted like an analgesic. In subsequent decades, scientists found lots of connections between the substance and lowering body temperature, increasing vasodilation, and reducing inflammation. But it wasn’t until the 1990s, when Julius’ group at UCSF set out to systematically find the molecules responsible for capsaicin-sensing, that anyone understood how it really worked.

Julius and his colleagues surveyed the sensory neurons which react to pain, heat, and touch to see which genes they expressed. Then they assembled a massive library of millions of DNA fragments corresponding to those genes and cloned them into cultured cells that normally don’t react to capsaicin. The exhaustive search turned up a single gene that was able to make cells capsaicin-sensitive. Further experiments showed that the gene encoded a novel ion channel protein, later named TRPV1.

Patapoutian then worked to see if similar ion channel receptors might be involved with sensing mechanical forces. Using a search method that involved systematically switching off the genes of a cell line that emitted electricity when poked with a micropipette, they identified the crucial protein for sensing pressure, an ion channel they named Piezo1, after the Greek word for pressure.

The discovery was a long time coming, Patapoutian told reporters at a briefing held by Scripps Monday. One of his postdocs at the time, Bertrand Coste, had spent more than a year knocking out dozens of genes with one negative result after another. But the 72nd candidate wiped out the pressure-sensing. “We were so excited, literally jumping up and down,” he said.

Since then, scientists have flocked to understand how these two types of ion channels are involved in healthy body functions and disease.

“Both these discoveries really opened the floodgate,” said Jorg Grandl, an associate professor of neurobiology at Duke University who studies mechanical transduction. “In the last 10 years there have been so many physiological processes that have been uncovered involving these ion channels, that no one really had on the map.”

It’s not just our neurons and the cells on our skin that possess these temperature and pressure-sensing proteins. There are cells that sense how stretched your lungs are, and cells that sense how wide your blood vessels have opened. When cells migrate, they have to navigate around their neighbors, and when they divide, that’s a mechanical process mediated by these same proteins. In fact, researchers have found them in nearly every type of cell in the human body. What exactly they do in each type of tissue is still an active area of investigation. “These fields were almost nonexistent before these discoveries and now they are moving fast and really thriving,” said Grandl.

Patapoutian said at the briefing that his lab is now working with Calibr, the California Institute for Biomedical Research, a Merck-backed nonprofit in San Diego, to develop treatments for neuropathic pain — where even a slight touch can cause stabbing pains or a burning or tingling sensation. “We really don’t have drugs that address this,” said Patapoutian. It’s still early days, and any treatment would have to be topical, so as not to impact all the other tissues where these proteins do other jobs. But Patapoutian is optimistic. “We believe from our data and others that blocking one of these receptors could really help these patients.”

Julius and Patapoutian shared the 2020 Kavli Award in Neuroscience for their discoveries. The prize recognized Julius’ extensive classification of the TRP family of proteins and Patapoutian’s work identifying pressure-sensitive proteins, which “opened the door to understanding mechanobiology.”

Julius was also honored for his studies of the TRP family of receptors with the 2020 Breakthrough Prize in Life Sciences. Established by tech billionaire Yuri Milner in 2012, the so-called science Oscars is often seen as a precursor to the Nobel. Last year’s Nobel winners in chemistry — Jennifer Doudna and Emmanuelle Charpentier, for their discovery of the revolutionary gene editing tool CRISPR-Cas9 — had received a Breakthrough Prize in 2015.

Berg remembers the excitement associated with the discovery of the capsaicin receptor as a key clue into touch, a finding that has now been in textbooks for decades. Touch had largely been a black box until this discovery.

“The approach of using a chemical that we associate with hot peppers was quite clever since the addition of a chemical is more specific and readily controlled than temperature or mechanical forces,” he said. “Once identified, this ion channel protein was shown to be sensitive to temperature and opened up the field. We all have likely experiences related to these channels as, for example, the pain we feel when a cut or burn is exposed to higher temperatures.”

Thomas Perlmann, secretary of the Nobel Committee and professor of molecular development biology at the Karolinska Institute, announced the award at a ceremony in Stockholm.

“The laureates identified critical missing links in our understanding of the complex interplay between our senses and the environment,” the committee said in a statement. “The groundbreaking discoveries … by this year’s Nobel Prize laureates have allowed us to understand how heat, cold, and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us.”

At the press conference Monday, Julius said that it was a great honor to receive the award on behalf of the team of researchers in his lab who have worked on this question for more than two decades now.

“We don’t go into this thinking we’re going to win prizes, we just do it for the thrill of discovering something,” he said. “There’s a time when you make a discovery when you’re the only person on the planet — or at least you think you’re the only person on the planet — who knows the answer to a particular question, and that’s a really thrilling moment. That’s what most of us live for.”

Julius, originally from New York, and Patapoutian, who was born in Beirut and moved to the U.S. as a teenager, will share 10 million Swedish kronor, or about $1.35 million. Their names are added to a list of medicine Nobel winners that includes 224 men and 12 women.

Perlmann said it was tough to get in touch with the laureates before the announcement but was able to “with the help of one father and one sister-in-law.” He said both were very happy and surprised in their brief conversations.

Covid-19 came up during the Nobel Academy’s press conference. One prize committee member said there is a link between research begun decades ago and the present pandemic.

“This is not directly related to Covid, but as you know, during the last year, we have been socially distancing from each other,” Abdel El Manira, professor of neuroscience at Karolinska Institute, said. “We have missed the sense of touch, the sense of the warmth that we give to each other, like … when hugging each other.”

This story has been updated with background and comment on the winning research.

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