An interview with the Nobel Prize 2021 winners

Talha Burki speaks with Ardem Patapoutian and David Julius, winners of the 2021 Nobel Prize in Physiology or Medicine for their discoveries of the receptors for temperature and touch.

David Julius and Ardem Patapoutian

Ardem Patapoutian had his mobile phone on silent when the 2021 Nobel Prize in Physiology or Medicine was announced (it was 2:30 AM in California). It was his 94-year-old father who eventually brought the news of his award. “It was a pretty amazing experience to hear it from him”, Patapoutian told The Lancet. David

Julius was woken by a text message from

his sister-in-law, saying that one Thomas Perlmann (secretary of the Nobel Committee for medicine) was trying to get hold of him. She added that she had looked up Perlmann on the internet and he seemed legitimate.

Patapoutian (Scripps Research, La Jolla, CA, USA) and Julius (University of California San Francisco, San Francisco, CA, USA) were jointly awarded the prize for discovering the receptors for temperature and touch. “The laureates identified critical missing links in our understanding of the complex interplay between our senses and the environment”, noted the Nobel Committee in a statement announcing the award, on Oct 4, 2021.

“We tend to take touch more for granted than our other senses”, points out Julius. “You can close your eyes and know what it is like not to have vision, or put on a pair of earplugs and know what it is like not to hear. But touch and temperature sensation seem like something built into our skin—we do not think about them that much.”

Julius used capsaicin, the chemical that causes your mouth to burn after eating a chilli pepper, to pinpoint the sensor that reacts to heat. “I have always been fascinated by the whole idea of natural products”, he said. “I guess you could call it chemical anthropology.

Civilisations have consistently identified plants and animals that they can use for medicinal, culinary, or ritualistic purposes; then scientists come along and ask ‘what is going on here? How can we identify the specific compound that is causing the effect?’” He reels off a roster of drugs derived from the natural world, including morphine (from poppies), aspirin (from willow), and ACE inhibitors (from pit vipers). “There are plenty of reasons to preserve the biodiversity that we have left, but one of them is that we cannot afford to lose these sources of inspiration for new types of medicine; there is a lot there that has yet to be discovered”, Julius told The Lancet.

Julius began wondering whether the chilli pepper, a fruit people have been cooking with for thousands of years, could help elucidate a vital physiological process. He hypothesized that there had to be a specific gene that encoded the protein that responded to capsaicin. If he could identify this protein, and describe the associated pathway, he could start to come to grips with the mechanism by which human beings detect pain. Julius’ team put together a library of millions of fragments of DNA. After testing combinations of genes against cultured cells that typically do not respond to capsaicin, they found the one that conferred capsaicin sensitivity. It encoded an ion channel protein that they named TRPV1.

Ion channels sit on the surface of the nerve cell. They are either open or closed. When the channel is open, ions such as calcium or sodium flow into the cell, at a rate measured in millions per second. This initiates an electrical current, setting off a chain of reactions that culminate in signals to the brain. Aside from capsaicin, TRPV1 is activated by temperatures higher than 43°C. It plays a key role in interpreting different types of pain. Julius and Patapoutian, working independently, used menthol to identify TRPM8, an ion channel activated by cold temperatures. They also discovered TRPA1, the ion channel that allows us to detect the eye-watering active ingredient in things like mustard oil, horseradish, and garlic, as well as pain and inflammation.

In the laboratory upstairs from Julius’, biophysicist Yifan Cheng was working with cryo-electron microscopy, a remarkable technique for examining the atomic structure of molecules. “I wandered into his lab and told him who I was and that I had these proteins we had discovered and could he help us have a look at them”, recalls Julius. He has been working with Cheng ever since. In 2013, they published a paper showing TRPV1 in exquisite detail. “We could see where the atoms were located and how the channel appeared when it was closed, and how it appeared when it was open. We started to get a picture of the lifecycle of this protein. It was a huge advance, not just for us but for anyone who wants to understand the structure of proteins, especially those that live in membranes”, said Julius.

The findings open a route towards a novel approach to drug discovery. “We can look at all the nooks and crannies of these proteins to see how drugs work and where new drugs could go”, explained Julius. “We want to understand the basis for different types of pain. If we can make sense of the pathways and molecules that are involved, then we can start thinking about a more rational and less hit-and miss way of finding drugs.”

The intention of Patapoutian’s team was to figure out the receptors involved in responding to pressure. They identified a cell line from mice that transmitted an electrical signal when an individual cell was prodded with a micropipette. They assembled a collection of 72 candidate genes, one of which they assumed would encode the relevant ion channel. They knocked out each gene one by one, and eventually discovered the one that conferred mechanosensitivity on the cells.

“It was a pretty low-key moment, I had a post-doc researcher working on it, Bertrand Coste, and he came into my office and told me he may have found what we were looking for”, remembers Patapoutian. “Bertrand soon confirmed his findings and we were very excited. But I did not for a moment think we had found something that plays such a dominant role across the nervous system and beyond.”

The ion channel was given the name Piezo1, after the Greek word for pressure. Patapoutian’s team subsequently discovered a related channel they called Piezo2. These receptors are key to the system of touch and proprioception—the understanding of how our bodies are situated. It is how I know, without looking, that I am making contact with the keys of the laptop, but not so hard as to damage it, and my back is resting against the chair and both feet are flat against the ground. It is how blood cells can squeeze through capillaries half their diameter, how the brain knows when the bladder is full, and when the lungs are inflated. “Wherever Piezo1 and 2 are expressed, we know there is a mechanosensory role”, said Patapoutian. “It points us to a whole new biology that has not been studied.”

Patapoutian is of Armenian descent and grew up in Lebanon. When he was 8 years old, the country descended into civil war. “There were a lot of tough times; it really taught me not to take anything for granted”, he said. At 18 years old, Patapoutian emigrated to the USA. “I was oblivious to the idea of science as a career; I did not really know careers like that existed, and I certainly did not think they existed for people like me”, he said. Patapoutian’s primary intention, when he took up laboratory work as a pre-medical student at the University of California, Los Angeles, was to obtain a letter of recommendation. “It did not take long for me to fall in love with the discovery process; I realised I had found my calling”, said Patapoutian. He would end up working with researchers from all over the world to discover a physiological pathway fundamental to every human being.

“I am very proud of the culture we have in science; it is a wonderful place to think and find out new things”, said Patapoutian. “There is a melding of ideas and nationalities, which is important not just for science but for society”. Julius’ grandparents emigrated to the USA from the shtetls of Czarist Russia. “As a scientist, you never think about borders or ethnicities”, he said. “You may have scientific competitors, or collaborators who come from the same or different fields, but we are all in it together for discovery.”

The Nobel Prize in Chemistry, which was announced on Oct 7, went to Benjamin List (Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany) and David MacMillan (Princeton University, NJ, USA) for independently developing a new way to construct molecules, known as asymmetric organocatalysis. Their efforts have overturned the assumption that there could only be two types of catalysts, enzymes and metals. Asymmetric organocatalysis can help streamline the production of drugs.

“Organocatalysis has developed at an astounding speed”, stated the Nobel Committee. “Organic catalysts can be used to drive multitudes of chemical reactions. Using these reactions, researchers can now more efficiently construct anything from new pharmaceuticals to molecules that can capture light in solar cells. In this way, organocatalysts are bringing the greatest benefit to humankind.”

Talha Burki