Editor’s Note (10/4/21): David Julius, interviewed in this story from September 2019, is the co-recipient of the 2021 Nobel Prize in Physiology or Medicine for discoveries related to how the human body senses temperature and touch.
David Julius knows pain. The professor of physiology at the University of California, San Francisco, School of Medicine has devoted his career to studying how the nervous system senses it and how chemicals such as capsaicin—the compound that gives chili peppers their heat—activates pain receptors. Julius was awarded a $3-million Breakthrough Prize in life sciences on Thursday for “discovering molecules, cells, and mechanisms underlying pain sensation.”
Julius and his colleagues revealed how cell-membrane proteins called transient receptor potential (TRP) channels are involved in the perception of pain and heat or cold, as well as their role in inflammation and pain hypersensitivity. Much of his work has focused on the mechanism by which capsaicin exerts its potent effect on the human nervous system. His team identified the receptor responsive to capsaicin, TRPV1, and showed that it is also activated by heat and inflammatory chemicals. More recently, he has revealed how scorpion venom targets the “wasabi” receptor TRPA1. Drug developers are now investigating whether these receptors and others could be targeted to create nonopioid painkillers.
Besides his findings on pain, Julius has discovered a receptor for the brain-signaling chemical serotonin. He is also interested in other types of sensory reception, such as infrared sensing in snakes and electroreception in sharks and rays.
Scientific American spoke with Julius about his work on understanding pain, why we need it and how it can go awry.
[An edited transcript of the conversation follows.]
How did you first get interested in studying pain?
When I did my postdoctoral work, I became interested in the nervous system. I was interested in understanding how neurotransmitters such as serotonin work in the brain and what the receptors for these neurotransmitters look like and in using genetics and molecular biology to try and get some handle on that. I really got so fascinated with this whole idea of folk medicine and health and how scientists have exploited natural products to understand physiology. I got interested in questions such as how hallucinogens work—how people discover things such as peyote and use that in ritualistic fashion. Chemists, of course, had discovered the active ingredients and how these things work and act on the nervous system. And I just got really enthralled by that whole approach, where people study some human behavior and take that into the chemical realm and then use those chemicals as clues and tags to understand how the nervous system works. That eventually led me to ask about how some of these agents in our environment generate pain—[chemicals] such as capsaicin and wasabi. And so, for me, that was kind of a natural segue from wanting to use natural products to understand the nervous system.
I heard you got the idea to study capsaicin while you were in the supermarket. How did that happen?
[Laughs] I was looking at these shelves and shelves of basically chili peppers and extracts (you know, hot sauce) and thinking, “This is such an important and such a fun problem to look at. I’ve really got to get serious about this.” My wife was down the aisle—she’s also a scientist—and she looked at me and said, “What are you doing?” And I said, “I’m really frustrated. I really need to figure out how we can tackle this problem.” She said, “Well, stop fiddling around. Why don’t you get going?” It's like everything else: it takes the right time, the right people, the right technology to come along. And [Michael] Caterina, who was in my lab at the time as a fellow, he’s the person who said, “Yeah, I’ll take that challenge.” And he did a fantastic job. And so, you know, that’s the way science is: at the right moment, things come together.
You and your colleagues discovered that capsaicin activates a receptor called TRPV1. How does that help us sense pain?
It’s a protein that sits on the surface of nerve cells. It’s mostly found on nerve cells that are involved in pain sensation. And it’s an ion channel that, in essence, forms a “doughnut” in the [cell] membrane, where the central hole is closed until something activates it. And then ions can flow from the outside of the cell to the inside. (The ions that we're talking about here are mostly sodium and calcium ions.) When this happens, it sets up electrical currents in the cell and initiates action-potential firing. So it sends the electrical signal from the periphery—let's say, your lips or your eye, wherever you feel the hot chili pepper—and it takes the signal to the spinal cord. And then, in the spinal cord, those neurons (what we call primary afferent sensory neurons and nociceptors), they send the signal to a second neuron in the spinal cord. Then, through a relay of neurons, this eventually gets taken to the brain to centers where you perceive it as being something noxious and painful.
What’s interesting about this ion channel is, one, it’s activated by heat, so it plays a role in our ability to sense things that are hot. So that’s the sort of convergence of information, that a chili pepper is mimicking a heat stimulus. But the channel doesn’t only detect heat; it also detects agents that our body makes in response to inflammation.
Why do we have the ability to feel pain?
One of the interesting things about pain, of course, which we all know, is that when there’s injury—whether it’s tissue injury and inflammation or injury to the nerve fiber itself—there’s usually an enhancement of pain. And the reason for that, presumably, is to enhance guarding: When you sprain your ankle, you need to know that you’ve done something bad so that you can protect it and allow it to heal. People who lack that ability—for example, people who have [a common complication of] diabetes or people who have leprosy [Hansen’s disease]—they don’t have sensation in their extremities. If they injure themselves, if they have an ulcerating sore in their foot and don’t know it, they don’t know to protect themselves, and so it becomes infected. So that whole enhancement to pain sensitivity, in its best form, is there to protect us and tell us that we have to guard the site. Of course, the problem is that sometimes it gets out of control. And then we have a persistent or chronic pain syndrome.
How could we harness the capsaicin receptor and others to treat pain?
TRPV1 does not only sense heat; it also senses a lot of chemicals that are made during inflammation. The chemicals act on these pain-sensing nerve fibers to enhance their sensitivity to things such as temperature, touch and other chemicals, as part of the guarding response. This TRPV1 channel can detect a lot of those different inflammatory agents and therefore contributes to the heightened sensitivity of the nerve fiber in the context of injury. And that’s really most of the reason that people are interested in these kinds of molecules as potential sites for analgesics: because they contribute to pain hypersensitivity when there are things like injury. So you can imagine that in situations such as arthritis or bladder inflammation or gastrointestinal inflammation, with this production of a lot of these inflammatory mediators, that TRPV1 and other [channels] are important players in resetting the sensitivity of the nerve fiber in the context of injuries. What you want to do is diminish pain when it’s pathological. But you don’t want to eliminate pain that’s acute and useful, because then you don’t have a warning system, right? So that’s kind of what people want to achieve. And the idea is that maybe what you can do is block the ability of these inflammatory agents to sensitize the nerve fiber by targeting things such as TRPV1 and other such molecules—but try and do so in a way that spares the normal protective function of the pain pathway.
Could these pathways lead to an alternative to opioids? And how far off is that?
That’s a good question. I’m not working with pharmaceutical companies or anything, so I can’t tell you where the state of the art is right now. But there have been drugs that have been developed for some of these channels, such as TRPV1, the one that was first identified. They scored at least modestly well in some pain models in humans, but they’ve had what I would call on-target side effects: they decrease patients’ ability to detect things that are noxiously hot. So [pharmaceutical companies have] worried about people injuring themselves by, say, drinking hot coffee. And the other thing is that—probably because they change your sense of temperature sensation—people report at least temporarily feeling a little feverish. So far, I haven’t seen any drugs that you can go into [a pharmacy] and buy. But drug development is a long process, and I’m hopeful that some of the molecules that we’ve discovered or worked on will eventually be targets for some new analgesics that are not opioid analgesics.
Opiate receptors are expressed all over the nervous system—they’re expressed in the brain, they’re expressed in the spinal cord, they’re expressed in pain, sensory fibers. And so opiates have a lot of other effects on the nervous system that lead to things such as respiratory depression, that lead to constipation, that affect cognitive areas. So you have things such as tolerance and addiction. And so the initial goal of the work that we’ve done, and the approach that we and other people in the field are taking, is to focus on the nerve fibers in the periphery, such as in the skin, and other places that are dedicated to sensing pain responses, with the idea that if we can identify molecules that are more selectively expressed at those sites, there will be fewer side effects of drugs.
Besides pain, you’ve also studied other sensory abilities, right?
Right. We’re generally interested in sensory systems and understanding what sensory system do at large—not just the pain pathway. They allow your brain to generate an internal representation of the external world. But what I really find fascinating about sensory systems is that different animals view the world a different way. We’ve looked at [infrared sensing in] rattlesnakes, because we thought, as other people had, that it’s related to heat sensation—and because that’s close to what we work on, in terms of understanding mechanisms of pain sensation. More recently, I had a couple of guys in my lab who worked on mechanisms of electroreception [sensing electrical fields], which is something you find in aquatic animals such as rays and sharks. People have studied these animals and identified the fact that they use these systems, such as infrared sensation and electroreception, for many years and have done beautiful work on the physiology. What hadn’t been approached so much is really understanding the molecular basis for that. And now there are so many tools that we can use, such as DNA sequencing and RNA sequencing, where you can really try and make the connection between molecules and physiology. So that’s kind of where we’ve come in. We’ve taken these molecular tools and gone back and revisited these very beautiful studies to try and put a molecular framework on these behavioral and physiological systems.
What do you plan to do with the prize money?
I think I’m going to keep doing what I do. I like to give money to the community—I really like to support the arts and music and science education, so I’m going to continue to do that stuff. I do that over in [northern California’s] East Bay and other places, and so maybe I can do that on a little bit of a larger scale. I think it’s really essential for humanizing us all—and science as well. I think it makes people think broadly and openly and interact with one another.