The five senses we use to perceive our environment are hearing, sight, smell, taste and touch. David Julius discovered molecular mechanisms by which the sense of touch allows us to perceive pain, temperature and other sensations.
The ability to feel pain is essential to our health and survival as it allows us to avoid direct contact with agents that can produce injury. Following injury, the skin becomes hypersensitive and even light touch or warm temperatures can be painful. This hypersensitivity has the positive function of protecting the skin from further injury. However, it sometimes has a negative effect, causing the development of chronic pain syndromes that can be physiologically and psychologically devastating. In pioneering studies conducted over the past fifteen years, David Julius and his coworkers have uncovered mechanisms by which we sense pain and temperature as well as mechanisms that underlie pain hypersensitivity. His work has provided insights into fundamental mechanisms underlying the sense of touch as well as knowledge that opens the door to rational drug design for the treatment of chronic pain.
Julius’ strategy for seeking out molecules that play a critical role in signalling a painful touch or temperature is to track them down with the help of natural products or drugs that trigger the same sensations and perceptions. In a groundbreaking study published in 1997, Julius along with his students and postdoctoral fellows sought to discover how a component of chili peppers, called capsaicin, provokes the spicy hot and burning sensation when applied to our skin. The research led to the identification and cloning of the specific ion channel that is responsible, named TRPV1.
TRPV1 is a specialized ion channel located at the tips of sensory nerves. Ion channels are pores that open and close to govern the movement of electrically charged atoms – called ions – across cell membranes. Nerve cells transmit electrical signals along their length as a result of transient changes in electrical potential from the successive opening and closing of ion channels. The rapid changes in electrical potential enable the sensory signal to travel through the cell’s connection to the spinal cord, which then relays these signals to the brain. TRPV1 is triggered not only by capsaicin but also by temperature higher than 43 °C. The ion channel also contributes to the hypersensitivity to heat felt in injured tissue, such as sunburned skin. When tissue is hypersensitive the stimulus is perceived as burning hot, thus alerting us to avoid further injury. Julius delineated the mechanisms by which this channel became hypersensitive under pathophysiological conditions.
Subsequently, Julius successfully cloned and identified other ion channels responsible for perception of other sensations. One called TRPA1 is activated by wasabi and other mustard oils that cause pain, irritation and inflammation. Importantly, TRPA1 is also the target of environmental irritants, such as acrolein, that account for the toxic and inflammatory actions of tear gas, vehicle exhaust and metabolic byproducts of cancer drug treatments. He also discovered a channel called TRPV2 that is activated at a higher temperature than TRPV1, and another called TRPM8 that detects painful cold sensations and menthol.
Together, the discoveries of David Julius and his colleagues constitute a major contribution to our knowledge of a fundamental biological function and its medical implications. An indication of the importance of this work to medicine is the current intense interest in TRP channels as potential targets for the development of novel analgesic agents.
(Adapted in part with permission from an article by Jeffrey Norris, UCSF Public Affairs)
Life Science and Medicine Selection Committee
The Shaw Prize
27 May 2010, Hong Kong