The question of how we sense the environment around us has fascinated humans for centuries. The first attempts at a theoretical understanding of the senses were discovered in the writings of early Greek thinkers in the sixth and fifth centuries BCE. However, the gap between our theories and our understanding of how our senses work is continuing to shrink. This year, the Nobel Prize in Physiology or Medicine was awarded jointly to Dr. David Julius and Dr. Ardem Patapoutian, two scientists who independently discovered mechanisms of how we sense temperature and touch.
This work goes back to the early 1900s, when it was discovered that there are different types of sensory nerve fibers that react to distinct stimuli. Nerve fibers are the axons (long, slender projections from a nerve cell) that conduct electrical impulses to communicate with other neurons (a type of cell of the nervous system). In fact, nerve cells are highly specialized for detecting and converting different types of stimuli into electrical impulses, thereby allowing us to sense a broad range of perceptions from our surrounding environment. But there was a major hurdle in understanding how our senses actually work; how are temperature and mechanical stimuli translated into electrical impulses in the nervous system?
In the late 1990s, Dr. Julius at UC San Francisco had the idea of using capsaicin (the chemical compound responsible for the burning sensation you feel when eating a pepper) as a way to parse out the mechanism of temperature sensation. He reasoned that because capsaicin elicits a similar burning sensation as actual heat does, the mechanism may be the same. Using a library of DNA fragments extracted from a sensory neuron known to react to capsaicin, he and his co-workers individually expressed these fragments in a culture of cells known not to react to capsaicin, hypothesizing that one of these DNA fragments corresponded to the protein responsible for the cells’ reaction with capsaicin. Eventually, using one of these DNA fragments, they were able to make normally unreactive cells capable of reacting to capsaicin. This DNA fragment corresponded to a novel ion channel protein, which they called TRPV1. When Dr. Julius investigated the protein’s ability to confer a temperature response, he discovered that TRPV1 is responsible for sensing temperatures above a certain threshold that is perceived as painful (>43°C, or >109°F).
This breakthrough led to a dynamism of research in the field. Independently, Dr. Julius and Dr. Patapoutian used chemical substances to identify another heat receptor, TRPV8, which is responsible for sensing colder temperatures (<20°C or <68°F). Other laboratories used genetically modified mice to identify additional receptors that are responsible for conferring sensation across a broad range of temperatures, but Dr. Patapoutian also wanted to know how mechanical stimuli were converted into electrical impulses. Thus, influenced by the methods Dr. Julius used to investigate heat sensation, he implemented a similar approach to study mechanical sensation.
Dr. Patapoutian at the Scripps Research Institute identified a cell line that gave off measurable electrical signals when poked with a micropipette (a small scientific tool). Hypothesizing that, similar to heat sensing, mechanical sensing is also conferred by an ion channel, he examined proteins that were predicted to be ion channels (click here for more information about ion channels and how they work). However, instead of individually expressing these genes in another cell type, he individually knocked-down these genes in the identified cell line. Eventually, he identified a gene that, when knocked down, conferred insensitivity to poking with a micropipette, which he called Piezo1. While continuing to knock-down other candidate genes, he discovered another gene called Piezo2, which makes cells insensitive to poking.
These groundbreaking discoveries enable us to better understand how we perceive the world, whether it’s our capacity to feel differences in the texture of a surface or our ability to distinguish between a comforting warmth and a scorching heat. Since their discovery, these genes have been implicated in a variety of physiological processes. This research has also prompted other scientists to investigate these mechanisms as potential targets for therapeutics.
References:
Baltussen, H. (2019). Early theories of sense perception. In R. Skeates & J. Day (Eds.),The Routledge Handbook of Sensory Archaeology. Abingdon: Routledge.
Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., & Julius, D. (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 389, 816-824.
Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., Koltzenburg, M., Basbaum, A. I., & Julius, D. (2000). Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288, 306-313.
Coste, B., Mathur, J., Schmidt, M., Earley, T. J., Ranade, S., Petrus, M. J., Dubin, A. E., & Patapoutian, A. (2010). Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 330, 55-60.
McKemy, D. D., Neuhausser, W. M., & Julius, D. (2002). Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 416, 52-58.
Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., Story, G. M., Earley, T. J., Dragoni, I., McIntyre, P., Bevan, S., & Patapoutian, A. (2002). A TRP channel that senses cold stimuli and menthol. Cell, 108, 705-715.
Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., & Julius, D. (1998). The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron, 21, 531-543.
The Nobel Prize (2021). “The Nobel Prize in Physiology or Medicine 1906.” NobelPrize.org.
Edited by Dan Myers and Ben Greulich
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