An Essay on the Prize in Life Science and Medicine 2010
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 and temperature.
The ability to detect painful stimuli 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 touches 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 outcome, 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 and opened the door to rational drug design for the treatment of chronic pain syndromes.
The sense of touch is initiated by sensory neurons that have nerve endings in the skin to detect tactile and painful stimuli and temperature. The sensory neurons transmit signals to the spinal cord, which then relays these signals to the brain. In groundbreaking work published in 1997, David Julius discovered how sensory neurons detect capsaicin, a component of chili peppers that induces burning pain sensations when applied to the skin. He showed that capsaicin is detected by an ion channel on a subset of sensory neurons. Binding of capsaicin to the channel causes the channel to open, leading to an influx of cations that causes the neuron to transmit signals to the spinal cord. This channel, now called TRPV1, belongs to the TRP family of ion channels, whose members are structurally related but serve different functions. Surprisingly, Julius found that TRPV1 is activated not only by capsaicin, but also by temperatures above 43 C, which are perceived as painful. By recording currents from single TRPV1 channels in isolated membrane patches, he further showed that both capsaicin and high temperatures directly open TRPV1 channels. Interestingly, he found that birds have a TRPV1 with a slightly different structure so that they are insensitive to the capsaicin in chili pepper seeds and therefore capable of carrying these seeds to spread chili pepper and similar plants. Tarantula bites can cause severe pain as their venom also targets this channel. Together, these discoveries provided the first insights into the molecular mechanisms by which we detect environmental stimuli through the sense of touch.
Julius subsequently discovered that TRPV1 also plays a central role in the hypersensitivity to pain resulting from tissue injury. Tissue injury results in a local increase in protons and the release of inflammatory mediators, such as bradykinin, that cause inflammation and pain hypersensitivity. Julius found that both protons and bradykinin lower the threshold for activating TRPV1, thereby stimulating the transmission of pain signals in response to innocuous and much milder stimuli, such as warm temperatures. Thus, TRPV1 not only detects painful heat and environmental chemicals, but is also capable of enhancing pain sensitivity in the setting of injury and inflammation. In addition to providing insight into a basic biological system, these discoveries open the way to the development of drugs to treat pain hypersensitivity and chronic pain syndromes.
Julius also studied a second ion channel on sensory neurons that detects other painful stimuli. This channel, 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 chemotherapeutic agents.
Julius has also provided important insights into the molecular mechanisms by which we perceive other stimuli by his discovery of other TRP-related channels. Thus, he discovered TRPV2, a related but distinct TRP-type channel that is activated at a higher temperature than TRPV1. This suggested that thermosensation might involve different TRP channels that are activated by different temperatures. Another channel discovered by Julius and another group led by Ardem Patapoutian was TRPM8 that detects painful cold temperatures as well as menthol, a chemical that causes cool sensations when applied to the skin.
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. His work has revealed molecular mechanisms that explain how one of our five senses, the sense of touch, detects changes in temperature and environmental stimuli that we perceive as painful. In addition, he has elucidated molecular mechanisms that underlie hypersensitivity to pain, thereby providing new targets for the design of drugs to treat chronic pain syndromes that affect many in our society.
Life Science and Medicine Selection Committee
The Shaw Prize
28 September 2010, Hong Kong