by Vivian Chou
figures by Anna Maurer
What do sushi and pain therapy have in common? The answer lies in a tiny protein in our bodies called TRPA1, nicknamed the “wasabi receptor.” For over a decade, scientists have been fascinated by the TRPA1 receptor, which allows us to taste the stinging, burning flavors of the popular Japanese condiment wasabi. This last April 2015, TRPA1 shot to the spotlight when scientists at UCSF announced a new discovery: a remarkably detailed structure of the receptor using a specialized type of microscopy known as cryo-EM. Besides being important to the field of science, the discovery of the TRPA1 structure may also represent a step forward in the field of chronic pain therapy. Despite the prevalence of chronic pain and its serious impacts on patients, effective treatments are very limited. Now, scientists are hopeful that studies into how TRPA1 is responsible for the curious phenomenon of spicy wasabi may lead to a new generation of pain medications.
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If you have ever eaten Japanese food, you have likely encountered wasabi, a pale-green paste often used in sushi dishes that packs a pungent, spicy, and fiery flavor-punch. Our ability to detect these distinct, potent sensations has captured the curiosity of the scientific world, and for years now, researchers have worked to unlock the secrets of wasabi. A breakthrough in this field occurred in April 2015, when researchers at UCSF published an exciting new finding on the shape and appearance of the “wasabi receptor” [1, 2].
More formally called TRPA1, the wasabi receptor is a special protein in our bodies responsible for the distinct, sometimes unpleasant sensations we experience in response not only to wasabi, but also to other irritants like smoke and onions. Interestingly, there are even hopes that this discovery may have important medical applications – specifically in pain therapy – making wasabi a fascinating bridge between the worlds of science, healthcare, and culinary art.
What’s really in that green stuff?
Before diving into the specifics of the science, let’s begin with what started it all: wasabi.
Wasabi is an edible plant in the cabbage family, which also includes horseradish and mustard  [Figure 1]. To prepare the paste, the stem of the wasabi plant is simply grated and mixed. Outside of Japan, the wasabi plant is far more rare and costly, so in these countries the paste is usually prepared from other related plants, most commonly horseradish .
Figure 1: Wasabi. Wasabi paste (left) is often eaten with sushi. Pale-green in color, wasabi paste is associated with pungent, stinging, and spicy flavors. The paste is made by grating the stem of a wasabi plant (right). The process of grating breaks down the plant and releases the flavors of a substance within the wasabi plant known allyl isothiocyanate (“mustard oil”). Images are from iStockPhoto and Wikipedia Commons.
Whether wasabi paste is prepared from a proper wasabi plant or a similar crop, there is a similar scientific reason behind its distinctive kick. Plants like wasabi, horseradish, and mustard produce a substance called allyl isothiocyanate, which is more commonly called “mustard oil” . Mustard oil is produced as a natural defense mechanism against plant-eating animals. Ordinarily, the oil is stored in a harmless, inactive form  in the plant’s cells, which function as microscopic storage-packets. However, when an unlucky animal tries to eat the plant, the cells of the plant are broken down by the animal’s teeth, spurring chemical reactions that convert the non-spicy form to become stinging, pungent mustard oil that repels the would-be diner .
By contrast, the heat of mustard oil is what makes wasabi so attractive to humans. In fact, we actively seek to release the flavor of wasabi by grating the plant into paste, which mimics the chewing action of animals.
TRPA1, the wasabi receptor
While it is a crucial ingredient, the mustard oil in wasabi paste alone is not enough to account for the striking flavors. There must be something in the nerves of our bodies to detect the oil — the TRPA1 wasabi receptor. TRPA1 is found in our neurons or nerve cells, which are what allow us to sense the world through sight, touch, sound, and, in the case of wasabi, smell and taste.
To understand this, imagine the TRPA1 receptor as a tiny smoke detector, and the mustard oil in wasabi as the smoke. This TRPA1 receptor is embedded in the membranes of the nerve cells found in our mouth and tongue [Figure 2]. When the wasabi “smoke” is present in the mouth, it sets off the TRPA1 “detector” in the nerve, which then sends alarms to our brain to tell us that something is stinging and burning [Figure 2].
Figure 2: TRPA1 “wasabi receptor” in nerve cells allows us to detect mustard oil. When we eat wasabi (green dots, A), our tongue can taste the food (B) because there are nerve cells (C) in our tongue. These nerve cells in our tongue have the TRPA1 wasabi receptor (yellow) embedded in them (D), which allows us to sense the mustard oil. Once TRPA1 in the nerves of our tongue sense the mustard oil, it sends a signal to the brain (E).
The role of TRPA1 as the wasabi “smoke detector” was first identified in 2006 through experiments in mice [5,6,7]. It is worth noting that TRPA1 also acts as a “smoke detector” for many substances, not just wasabi. Onions and even smoke itself are just a few other examples of the many things that can trigger the TRPA1 alarm. Thus, TRPA1 is important not just to our ability to taste spicy Japanese food, but to detect pain and irritants in general.
A recent look at the wasabi smoke detector
TRPA1 made the news in April 2015 when researchers at UCSF published the latest development in the story of the receptor: the 3D structure of TRPA1, nearly to the level of resolution of individual atoms. For comparison, this means researchers could distinguish objects that are as small as the thickness of a credit card divided by 2 million .
How did the researchers figure out the exact shape and appearance of a protein with such precise detail? The researchers used a technique called cryo-electron microscopy (cryoEM). In a nutshell, this involved rapidly freezing the protein, and then using electrons – one of the tiny particles that make up atoms – to detect the shape of the protein, which is then captured by a specialized camera. [For more information on how cryoEM works, visit http://bsp.med.harvard.edu/node/221]
So what did researchers see when in their snapshots of TRPA1? It turns out that it looks something like a donut: it is a disk with an opening in the middle that can squeeze shut. This ability of TRPA1 to change shape explains how it can act as a “smoke detector” for wasabi and allow nerves to send “alarms” to our brains. When there is no wasabi present, TRPA1 stays squeezed shut, and no alarm occurs [Figure 3, top]. However, when wasabi consumed, the mustard oil will bind to TRPA1, so that TRPA1 is no longer squeezed [Figure 3, bottom]. This change in shape tells the nerve cells of the mouth and tongue to signal the brain and sound the alarm.
Figure 3: TRPA1 is like a smoke detector for mustard oil. In scenario A, there is no wasabi, TRPA1 in the mouth is squeezed/turned OFF, and no alarm is sent from to the brain. In scenario B, wasabi is present, TRPA1 is not squeezed/turned ON, and the pain alarmis sent from the mouth to the brain.
From 3D structures to pain therapies
The solving of the TRPA1 structure was a breakthrough for the scientific community because scientists had never before used cryoEM to create such a detailed protein structure. Prior efforts to use cryoEM produced protein structures that appeared as “blobs.” The April 2015 discovery of the TRPA1 structure bucked the trend of “blobby” cryoEM structures and spotlighted cryoEM as a powerful method for solving protein structures in the future.
Beyond its intellectual impacts, this discovery is interesting even for those with no connection to academic research, because it may pave the way towards a more relatable application: new and innovative ways to treat pain .
We are no strangers to pain and its many unpleasant effects. Most of us have experienced acute, or short-term pain, throughout our lives. Though not an enjoyable sensation, pain is not necessarily bad. Just like real smoke detectors warn us of potential fires, receptors like TRPA1 in our bodies warn us that something is going on in our bodies that we need to be careful of, such as illness or injury. Thus, despite the inconvenience of pain, it is very important to our body’s alarm system and for keeping us from further harm.
However, in special cases pain detectors in our bodies can sometimes go awry and set off alarms, even when there is no danger. An estimated 100 million Americans are thought to suffer from chronic pain, which is pain that lasts for at least six months, even after the original injury or illness is healed [10,11]. Because very little is understood about why pain can occur even after the original problem is gone, effective treatments for chronic pain have been limited to a small number of medications, including opioids (such as morphine) and non-steroidal anti-inflammatory medications (such as ibuprofen or aspirin). Now, scientists are hoping research into TRPA1 may lead to the development of a new generation of painkillers, and novel approaches to treating chronic pain .
Though scientists who study pain have been excited about TRPA1 for years , progress in designing painkillers has been limited because scientists lacked the crucial information–the receptor’s structure. The April 2015 discovery is important because having a protein structure is like having a “roadmap” in a new, huge, and complicated city. Scientists have for some time tried to develop painkillers targeting TRPA1 , but before the discovery of the TRPA1 structure, this was somewhat like trying to navigate in a new city without a roadmap: it involved a lot of guesswork, wrong turns, and wasted time and effort. Now, even though we are still a long way from effective pain medications that target TRPA1, the new, detailed structure of TRPA1 jump-starts this process by providing the missing map and cutting out a lot of the guesswork, thus allowing researchers to focus their efforts and design medications against TRPA1 in a strategic manner.
Sushi dinners are probably not the first place one would expect to find thought-provoking scientific ideas. However, our curiosity about how and why wasabi packs such a distinct flavor has led to a deeper understanding of why we taste wasabi the way we do. Moreover, our curiosity about this spicy paste has furthered our scientific knowledge of how we sense many other sensations in our environment, and how we can manipulate these sensations to find new, innovative ways to alleviate the symptoms of those who suffer from chronic pain. Though the story of wasabi and TRPA1 is far from over, it has already shown how a closer peek into seemingly ordinary phenomena can unlock fascinating insights into the natural world.
Vivian Chou is a Ph.D. student in the Biological and Biomedical Sciences (BBS) Program at Harvard Medical School.
For further reading
UCSF press release on the discovery of the TRPA1 structure http://www.ucsf.edu/news/2015/04/124956/first-look-wasabi-receptor-brings-insights-pain-drug-development
Wired article on the solving of the TRPA1 receptor structure (non-technical) http://www.wired.com/2015/04/burn-wasabi-may-lead-new-pain-meds/
Science Daily article on the solving of the TRPA1 receptor structure (more technical) http://www.sciencedaily.com/releases/2015/04/150408133042.htm
Harvard Medical School webpage on how electron microscopy works http://bsp.med.harvard.edu/node/221
WebMD article on chronic pain http://www.webmd.com/pain-management/guide/understanding-pain-management-chronic-pain
 Paulsen, CE, Armache, J-P, Gao, Y, Cheng, Y, Julius, D. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature. April 2015. http://www.nature.com/nature/journal/v520/n7548/full/nature14367.html
 Hamilton, J. Sushi Science: A 3-D View Of The Body’s Wasabi Receptor. NPR. April 8, 2015. http://www.npr.org/blogs/health/2015/04/08/398065961/sushi-science-a-3-d-view-of-the-bodys-wasabi-receptor
 Guimaraes, MZP, Hordt, S-E. TRPA1 : A Sensory Channel of Many Talents. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. 2007. http://www.ncbi.nlm.nih.gov/books/NBK5237/
 Spiegel, A. Think You’ve Been Eating Wasabi All This Time? Think Again. Huffington Post. March 26, 2014. http://www.huffingtonpost.com/2014/03/26/real-wasabi_n_5027341.html
 Bautista, DM et al. TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents. Cell. March 2006. http://www.sciencedirect.com/science/article/pii/S0092867406002406
 Carroll, SB. As Genes Learn Tricks, Animal Lifestyles Evolve. New York Times. August 27, 2012.
 Chadwick, A, Julius D. [Interview] Unlocking the Science of Wasabi. NPR. March 23, 2006. http://www.npr.org/templates/transcript/transcript.php?storyId=5297157
 Farley, P. First Look at ‘Wasabi Receptor’ Brings Insights for Pain Drug Development. UCSF News. April 8, 2015. http://www.ucsf.edu/news/2015/04/124956/first-look-wasabi-receptor-brings-insights-pain-drug-development
 Brederson, JD, Kym PR, Szallasi, A. Targeting TRP channels for pain relief. European Journal of Pharmacology, September 2013. http://www.ncbi.nlm.nih.gov/pubmed/23500195
 Boyles, S. New Study Shows That Pain Costs Billions of Dollars a Year in U.S. Web MD. June 29, 2011. http://www.webmd.com/pain-management/news/20110629/100-million-americans-have-chronic-pain
 Nelsen, E. Teaching the Nervous System to Forget Chronic Pain. NOVA Next. August 2014. http://www.pbs.org/wgbh/nova/next/body/chronic-pain/