How does your body know where your limbs are when you are not looking at them? How does it sense when it is time to go to the bathroom or whether a touch is soothing or painful?
All these abilities rely on a mechanism for sensing touch or pressure. And this week Ardem Patapoutian of Scripps Research in La Jolla, Calif., was awarded a Nobel Prize in Physiology or Medicine for contributing to the discovery of such mechanisms, which detect these sensory inputs and convert them into neural impulses the brain can perceive. He shared the prize with David Julius of the University of California, San Francisco, whose work revealed how we sense heat and pain.
Patapoutian and his colleagues identified pressure-sensitive ion channels known as Piezo1 and Piezo2—specialized protein molecules embedded in the membranes of some cells that enable them to transmit signals in response to touch or pressure. To find them, the researchers methodically deactivated individual genes in pressure-sensitive cells until they found ones that instruct the cells to make these ion channels, turning off the cells’ ability to respond to touch. Then they inserted those genes into cells that were not sensitive to touch and showed that the cells had gained this sensitivity.
This mechanism is critical for everything from knowing the position of one’s limbs in space—a sense called proprioception—to detecting bladder fullness and the amount of air in the lungs. Understanding it is a breakthrough for basic science and could one day lead to treatments for disorders of touch or internal organ sensing.
Scientific American spokes with Patapoutian about how he learned he had won a Nobel Prize, why the sense of touch has remained a mystery for so long and why these discoveries are so important for human physiology.[An edited transcript of the interview follows.]
How did you find out you had won a Nobel?
My phone was on “do not disturb” mode, so I almost didn’t get the news. My dad is 94 years old, and he lives alone with my mom in Los Angeles. They have a landline, so they got the call. And he was able to call me, so I heard it from my dad—which was a really special moment, actually. I mean, they didn’t tell him. He just said, “I think you got it,” because of the fact that they called him. But it was a wonderful moment. Even if you think it’s a possibility, it’s still a complete shock to hear. And it’s also two in the morning, so you’re worried that you’re not coherent at all.
It’s been a crazy 24 hours, but I’ve enjoyed it. This is not just about me but about people in my lab, my institute, the whole field that studies touch. Everybody’s having a great time with it.
Why are the senses of temperature and touch so important?
I always like to emphasize that my colleagues and I study we do because of just the interest in basic science. I think it’s fascinating how, when we started this, one of the major five senses mechanistically—how we sense touch—was not understood. It’s something so unique because everything else—whether you’re talking about smell or taste, which are based on chemicals, or hormones being secreted from your body, such as insulin—is chemical sensing. So here is a phenomenon that’s completely different, and it’s based on sensing physical stimuli such as pressure.
But I also find super fascinating this idea of proprioception: the sense of where your limbs are, compared with the rest of your body. I consider it perhaps your most important sense. I would say the majority of people have probably never even heard of it or have never stopped to think about this sense. Your sensory neurons innervate all the muscles in your body, and from how much your muscles are stretched, you have a very visual—without actually looking—image of where your limbs are. This is how I can close my eyes and touch my nose. This is proprioception. I think, partly, people take it for granted because you can never turn it off. It’s not like your vision, where you can close your eyes and say, “This is what the world is like without seeing.”
The fact that the senses of temperature, touch and pain are all related and that they’re done by the same neuronal [machinery] makes a very compelling case for why it was interesting to study.
Can you give an overview of the research that led to your prize?
The idea was very simple. We knew that for touch to be initiated, there are these pressure-activated ion channels that do something very basic: they’re either closed or they’re open. And when they open, ions (for example, sodium) come in. That’s a language that neurons understand because [the flood of sodium ions] depolarizes a neuron and sends a signal called an action potential, which can then talk to the next neuron. But the identities of these pressure sensors [or receptors] were just not known. That has been the focus of my life for the past 10 years. When we first found the Piezo receptors in 2010, it was because we took a very reductionist approach. We said, “We know there are these pressure sensors in our bodies, but we don’t know what they are.” And we said, “The easiest way to find them is to find a cell line—a cell that grows in a culture dish—that responds to pressure.”
So my [then] postdoctoral scholar Bertrand Coste found a cell line that responds to pressure this way. And he made a list of candidate genes and, one by one, knocked them down [deactivated them] and tried to see if this pressure-sensing response was still there. It was very laborious. It took him about three days to test each candidate, so he had a whole year of negative data. And then, finally, candidate number 73—when he deleted or knocked it down, this pressure response was gone. And so we knew we had something interesting on our hands.
What did you do next to prove that these genes were actually necessary for sensing pressure?
The big experiment was now to take those genes and make a full-length protein and put it in a cell that was not mechanosensitive [touch sensitive]—and every cell we put it in became mechanosensitive. So that’s what we call “necessary and sufficient.” The two experiments together made a very convincing case that this was the sensor.
What are some of the practical applications of this work?
Within a few years, we showed that these ion channels are the principal sensors for touch sensation, for proprioception, for a specific type of pain sensation that is common in chronic pain conditions. We’ve also shown that they play a big role in interoception, which is sensing of internal organs. Take bladder fullness: every time you feel like you have to go, it’s a mechanical sense—the bladder stretches, and it tells you when you have to go. This seems to be Piezo2-dependent. Every time you breathe, Piezo channels are monitoring how much your lungs are inflating. The list goes on and on. We’ve also shown that these ion channels sense blood pressure in your blood vessels and are part of a feedback loop to keep your blood pressure constant.
We also collaborate with Alexander Chesler and his colleagues at the National Institutes of Health, who have access to studied individuals who lack Piezo2. Their major phenotype is that they are uncoordinated—they don’t learn to walk until they’re five years old or older, and even then, they need help doing it. Chesler and his team quickly realized, when they did tests, that these individuals cannot discriminate touch, and their proprioception is completely nonfunctional. They have the same kind of deficits as people with some forms of allodynia, which is when touch becomes painful (for example, if you get a sunburn, just wearing your shirt or touching your shoulder hurts). People who suffer from neuropathic pain experience this phenomenon chronically, and there are really no good medications for it. We’ve done some tests to show that these conditions are Piezo2-dependent. This is why we think it actually might be an interesting drug target in the future.
There are challenges; these are not easy molecules to target. But more importantly, deactivating Piezo2 all over your body with a pill taken orally is not a good idea. That’s going to knock down your sense of touch, proprioception and everything else. So any modulation of this has to be done locally, maybe just within the bladder. Or if you have a very severe neuropathic pain in your elbow or some other body part, I can imagine a topical drug. We’re not anywhere close to that yet, but it could be useful.
You grew up in Lebanon during a period of war and violence. How has that influenced your life and career?
I’m of Armenian origin. I grew up in Lebanon, and I pretty much fled to the U.S. when I was 18. I think it has had a huge influence on me. You know, growing up in a war-torn country, I couldn’t even imagine having a career in science. Coming here was a great shock, but at the same time, I think it’s always been in me not to take things for granted because of my tough childhood and all the things that I experienced. I think that’s helped me in appreciating what I have and knowing what a privilege it is to get the education I’ve gotten here—to have the government fund basic science, which I think is a no-brainer in the sense that not only are discoveries great, but all practical applications come from basic discoveries. And I think the U.S. is still one of the best places in the world that encourages this.