From The Kitchen To The Lab: How Sushi Dinners May Lead To New Pain Therapies

If you have ever eaten Japanese food, you have likely encountered wasabi, a pale-green accompaniment to sushi dishes that packs a pungent and fiery flavor-punch. Scientists have been intrigued by our ability to detect these distinct, potent sensations and have been working to unlock the secrets of why the flavors of wasabi are so distinct. Researchers at the University of California, San Francisco (UCSF) published a finding in April 2015, a discovery which has been considered a breakthrough among scientists in the field of structural biology, on the shape and appearance of what has been nicknamed as the body’s “wasabi receptor.”

More formally called TRPA1 (Transient Receptor Potential Ankyrin), 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 irritants like smoke and onions. Beyond helping us sense irritants, TRPA1 is also a key part of the body’s pain response. Though scientific knowledge of TRPA1’s roles in detecting sensations, both positive and negative, has been developing for at least a decade now, the April 2015 discovery of its structure represents a major step forward in understanding the protein.

Intriguingly, these new insights into TRPA1 structure may have an application in discovering new pain therapies. Some degree of pain is present in all of our lives, and for over 100 million Americans, it is a chronic problem lasting months. Despite the prevalence of pain in both its shorter-lived and chronic forms, there are very few effective strategies for treating pain. For about a decade now, scientists have been interested in understanding TRPA1 and related proteins in terms of their role in the body’s pain system; however, progress in using knowledge of TRPA1 to develop effective medications has still been slow. Now, there are hopes that the April 2015 discovery of TRPA1 structure may provide a key piece of knowledge that will help accelerate pain research efforts – in addition to demystifying the powerful flavors of wasabi.

What’s really in that green stuff?

Figure 1

Wasabi is an edible plant in the cabbage family, which also includes horseradish and mustard. To prepare the paste, the green stem of the wasabi plant is grated and mixed. Outside of Japan, the wasabi plant is far more rare and costly – fetching 160 USD, or even more, per kilogram – so the paste is usually prepared from other related plants like horseradish.

Whether wasabi paste is prepared from a proper wasabi plant or a related crop, there is a similar scientific reason behind its distinctively spicy kick. Plants like wasabi, horseradish, and mustard produce a substance called allyl isothiocyanate, better known as mustard oil. Mustard oil acts 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: grating the plant into paste mimics the chewing action of animals.

TRPA1, The Wasabi Receptor

The mustard oil in wasabi paste alone is not enough to account for the striking flavors we experience when we eat wasabi. The TRPA1 receptor, found primarily on nerve cells, allows us to detect the smell and taste of the mustard oil in wasabi paste.

Illustration by Anna Maurer

We can envision TRPA1 to be a tiny smoke detector, with the mustard oil in wasabi acting as the smoke. TRPA1 is embedded in the membranes of the nerve cells found in our mouth and tongue. When the wasabi “smoke” is present in the mouth, it sets off the TRPA1 “detector” in the nerve, which then alarms our brain to tell us that something is stinging and burning.

The role of TRPA1 as the “smoke detector” was first identified in 2006 through experiments in mice, in which they applied mustard oil to the animals paws and observed whether they showed a response, or not, to the oil. It was found that normal mice, which do have TRPA1, flick their paws in response to mustard oil, while mice that were genetically engineered to lack TRPA1 did not respond. This finding showed that TRPA1 was a key component in allowing mice – and humans – to sense mustard oil.

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

More recently, scientists at UCSF figured out the three dimensional structure of TRPA1 nearly to the level of resolution of individual atoms. For reference, an individual atom is as small as the thickness of a credit card divided by two million.

The researchers figured out the exact shape and appearance of TRPA1 using a technique called cryo-electron microscopy (cryoEM), which involves 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, Harvard has published a guide.)

Illustration by Anna Maurer

It turns out that TRPA1 looks something like a donut: it is disk-shaped, with an opening in the middle that can squeeze shut. TRPA1 can change its shape in response to “smoke:” when there is no wasabi present, TRPA1 stays squeezed shut, and does not send an alarm to the brain. However, when there is smoke, TRPA1 will no longer remain squeezed shut. This change in shape tells the nerve cells of the mouth and tongue to sound the alarm and alert the brain.

From 3D structures to pain therapies

Solving of the TRPA1 structure with such precision was a breakthrough for the scientific community because scientists had never before used cryoEM to model such a detailed protein structure. Prior efforts to use cryoEM produced protein structures that appeared as “blobs.” However, advances in both equipment – particularly in the camera used to detect electrons – and computer software have vastly improved the quality of cryoEM images. The resolution of the TRPA1 structure was one instance in particular that bucked the trend of “blobby” cryoEM structures and spotlighted cryoEM as a powerful method for solving protein structures in the future.

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 it is not a particularly enjoyable sensation, pain is not necessarily bad. Just as real smoke detectors warn us of potential fires, receptors in our bodies like TRPA1 notify us that something unusual is going on and warn us that there is something we need to avoid illness or injury. Therefore, the feeling of pain can protect 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 defined as pain that lasts for at least six months even after the original injury or illness has been resolved. Because researchers don’t quite understand why pain persists after the original problem has healed, effective treatments for chronic pain are 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 hope that research on TRPA1 may lead to the development of a new painkillers and novel approaches to treating chronic pain.

Though scientists who study pain have been excited about TRPA1 and related molecules for about a decade now, progress in designing painkillers has been limited because scientists had yet to discover the receptor’s structure, which would guide their research like having a “roadmap” for navigating a new and complicated city. Even without knowledge of the protein structure, scientists have already tried to develop painkillers targeting TRPA1, but those efforts involved a lot of guesswork and wrong turns.

Now, even though we are still a long way from effective pain medications that target TRPA1, the new, detailed knowledge of TRPA1’s structure of TRPA1 jump-starts the is process by providing the missing map and cutting out a lot of the guesswork, allowing researchers to focus their efforts and design medications that target 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 our environment, and how we can manipulate our 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.

Figure legends

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.

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).

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.

Further reading

• UCSF press release on the discovery of the TRPA1 structure

• “Chronic Pain Management” (WebMD)

• “How does an electron microscope basically work?” (Harvard Medical School)

• Farley, Pete. “First Look At ‘Wasabi Receptor’ Brings Insights For Pain Drug Development” (Science Daily)

• Hamilton, Jon. “Sushi Science: A 3-D View Of The Body’s Wasabi Receptor.” (NPR)

• Nelsen, Eleanor. “Teaching the Nervous System to Forget Chronic Pain.” (NOVA)

• Palca, Joe. “Unlocking the Science of Wasabi.” (NPR)

• Paulsen, Candice E., Jean-Paul Armache, Yuan Gao, Yifan Cheng, and David Julius. “Structure of the TRPA1 ion channel suggests regulatory mechanisms” (Nature)

• Spiegel, Alison. “Think You’ve Been Eating Wasabi All This Time? Think Again.” (Huffington Post)

• Stockton, Nick. “The Burn of Wasabi May Lead To New Pain Meds” (Wired)

Image Credit:

Featured Image: Calgary Reviews via flickr

Figure 2 and 3: Anna Maurer