David Julius discovered molecular mechanisms that explain how we perceive pain and temperature. He has identified members of the Transient Receptor Potential (TRP) ion channel family; these proteins are at the heart of responses to diverse sensory stimuli, including temperature, pain, osmolarity, pheromones, and taste. TRP channels also play important roles in calcium adsorption and tissue development.
For decades, fundamental mechanistic questions about how pain and other somatosensory stimuli were detected and decoded went unresolved. David Julius resolved the mystery by identifying the VR1 (TRPV1) channel. This was a landmark finding that was published in Nature (1997).
In this work Julius showed that VR1 is a calcium-permeable, non-selective cation channel that is activated directly by capsaicin, the pungent natural ingredient in hot chili peppers, or by heat. Moreover, he and his colleagues showed that the thermal activation threshold matched that of sensory nerve fibers. Importantly, this discovery of TRPV1 as a thermal sensor did not make use of the prior cloning of TRP channels by others, but instead relied on a functional expression cloning strategy based on capsaicin sensitivity. The expression library was made from mouse sensory neurons known to respond to thermal and chemical stimuli. The transfected cells were exposed to capsaicin and a single clone conferring sensitivity to capsaicin was identified. The striking cover of Nature is impossible to forget. This discovery provided the first definitive molecular basis for the selective nature of capsaicin action, while validating the ‘specificity theory’ of nociception first suggested by Sherrington more than 100 years ago.
The use of capsaicin showcases Julius’s strategy for seeking out important signaling molecules. He tracks them with the help of natural products or drugs that trigger the same sensations and perceptions, for example, for temperature or pain. Similarly, he and his coworkers used pharmacological tools (menthol and other cooling agents) to identify a cold receptor (TRPM8), which turned out to be in the same family as VR1/TRPV1 (Nature, 2002). Together, these discoveries showed that TRP channels are general detectors of ambient temperature spanning a wide physiological range. Subsequent to these initial discoveries, Julius has revealed other key fundamental and fascinating intricacies of the function of TRP channels, including their roles in pain and injury-evoked pain hypersensitivity. One cannot fail to mention beautiful studies of the molecular basis of infrared detection by snakes and vampire bats (Nature, 2010 and 2011) that used transcriptome profiling to identify TRP channels as sensory detectors in these systems. More recently his lab has published another highly lauded landmark study using electron cryo-microscopy to visualize 3-dimensional structures of TRPV1 at atomic resolution, revealing how distinct conformations underlie activation of this channel (Nature, 2013). This has paved the way towards elucidating structural changes at different temperatures and understanding how drugs modulate TRP channel function.
Julius is one of the most creative and respected neuroscientists of his generation. He uses a very broad multidisciplinary approach to his research ranging from biochemistry, biophysics, and therapeutics, to evolution and molecular structure.
Caterina, M., Schumacher, M., Tominaga, M., Rosen, T., Levine, J., and Julius, D. (l997) The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 389: 816-824
McKemy, D., Neuhausser, W., and Julius, D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52-58
Bautista, D., Jordt, S., Nikai, T., Tsuruda, P., Read, A., Poblete, J., Yamoah, E., Basbaum, A., and Julius, D. (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124: 1269–1282
Gracheva, E.O., Ingolia, N.T., Kelly, Y.M., Cordero-Morales, J.F., Hollopeter, G., Chesler, A.T., Sánchez, E.E., Perez, J.C., Weissman, J.S. and Julius, D. (2010) Molecular basis of infrared detection by snakes. Nature 464: 1006-1011
Cao, E., Liao, M., Cheng, Y., and Julius, D. (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504: 113-118
A short biography
David Julius graduated in 1977 from the Massachusetts Institute of Technology (MIT) with a bachelor’s degree in Life Sciences and in 1984 he received his Ph.D. in Biochemistry from the University of California, Berkeley. He joined the faculty of the University of California, San Francisco (UCSF) in 1990. He is Professor and Chair of the Department of Physiology at UCSF. He is a member of the National Academy of Sciences (United States) and the American Academy of Arts and Sciences, and has received the Yngve Zotterman Prize of the Physiological Society of Stockholm (2003); the Kerr Basic Science Research Award of the American Pain Society (2006); the K.J. Zülch Prize for Basic Neurological Research of the Max Planck Society (Germany, 2006); the Edward Scolnick Prize in Neuroscience of the McGovern Institute for Brain Research at MIT (USA, 2007); the W. Alden Spencer Award of the Center for Neurobiology and Behavior at Columbia University (2007); the Julius Axelrod Prize of the Society for Neuroscience (2007); the Unilever Science Prize (USA, 2007), the Passano Foundation Award (USA, 2010), and the 2010 Shaw Prize and Prince of Asturias Award.