From Peppers to Pain

What David Julius’ Breakthrough Prize-Winning Research Means for the Future of Pain Management

By Samantha Yammine

Have you ever wondered why spicy peppers seem “hot” even though they’re room temperature?

This seemingly simple curiosity about our world led researcher David Julius to a 2020 Breakthrough Prize in Life Sciences, and to a world of discovery about one of the most mysterious and common natural phenomena: pain.

Think of the last three times you felt pain: how did they feel? Were they the exact same?

Despite how common it is, the changing and heterogeneous nature of pain makes it difficult to describe, let alone treat. As Julius says, “chronic pain is not just one thing, it’s a collection of syndromes.” From heartbreak and psychological pain to acute pain resulting from an injury or chronic pain — pain has many causes and manifests in different ways all around the body.

While it’s something we may wish to never experience, there is a utility to feeling some amount of pain. In fact, it’s thought pain evolved to help us avoid things that can cause serious damage to our bodies, like hot surfaces or sharp objects.

It’s when pain is felt without an imminent threat (called allodynia), disproportionately for a given painful stimulus (hyperalgesia), or chronically, that it can severely impact one’s quality of life. With over 28% of adult Americans estimated to be living with chronic pain and a rampant opioid crisis gripping the country, it’s a topic deserving of medical attention.

To begin addressing this, we go back to the chili pepper and David Julius’ early research.

Julius marveled at how eating spicy peppers led to a sensation of painful heat even though they are not actually high in temperature.

The pain-causing molecule in peppers has long been known as capsaicin, named after the Capsicum pepper from which it derives. We even knew capsaicin activates pain-sensing nerve endings in the peripheral nervous system, called nociceptors.

But Julius’ work was the first to identify the structure of the protein receptor through which capsaicin signals, the TRPV1 receptor. TRPV1 sits in the outer tips of sensory nerves mostly in the peripheral nervous system. While it is indeed activated by capsaicin, it also responds to heat greater than 110 degrees Fahrenheit. In the presence of either stimulant, TRPV1 lets sodium and calcium ions flow into the nerve through its pore, triggering a cascade of electrochemical messages from the nerve to the central nervous system, leading to the perception of “heat” pain in the brain.

Julius’ team has since characterized other related nociceptors belonging to the same family of proteins, including TRPM8, which senses cold temperatures or menthol (which therefore has a characteristic cool feeling); and TRPA1, which is what helps you sense the kick in wasabi, and is also involved in some pain due to inflammation.

This research started out of genuine interest of simple “how” questions about our bodies, but is now central to Julius’ future research tackling some of the biggest challenges in pain management. While we have many analgesic drugs that can reduce pain, many of them act broadly, causing undesirable side effects throughout the body. For example, opioids can often effectively treat pain, but they can also cause sedation, dizziness, vomiting, constipation, respiratory depression, and — central to the current opioid crisis — physical dependence and addiction.

The more we know about the protein receptors involved in the sensation and perception of pain, the more likely we’ll be able to engineer more targeted pain medications that treat unwanted pain but still allow helpful everyday sensations like if your coffee is too hot to drink. Julius calls this selective targeting “biased agonism,” which depends on his pioneering research in structural biology for which he won the 2020 Breakthrough Prize.

But even once we can engineer more targeted drugs, we’ll still be left with another challenge: how do we measure their success objectively when pain can be such a subjective experience?

To this end, Julius’ team is trying to find better ways of defining pain biologically by searching for hallmarks of pain in the blood or other easy-to-access tissues. These are called “biomarkers” and would give researchers a quantitative tool for optimizing treatments, and hopefully empower patients who may have their pain experiences dismissed because of its often invisible and subjective nature.

While the road ahead for Julius and his team is riddled with many new questions and challenges, his work so far has been instrumental for “Seeing the Invisible” — the 2020 Breakthrough Prize theme.

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Laureates for the 2020 Breakthrough Prize Awards. Photo by Dale Ramos/CZI.

Julius’ work exemplifies how following our curiosities can lead to breakthrough discoveries, and help build a better future for everyone.

Samantha Yammine is a Neuroscientist & Science Communicator who received her PhD from the University of Toronto studying how stem cells build and maintain the brain. She goes by Science Sam on social media, where she shares nuanced discussions about science in accessible and entertaining ways. You can find her on Twitter @heysciencesam, and find out more about her at samanthayammine.com.

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