Understanding why mint tastes cool and chilli is hot could bring new cures for chronic pain, obesity and even cancer
IT STARTS out as a pleasant tingle, before growing into a burning sensation that feels like your whole mouth is ablaze. You sweat, you cry, and your nose streams. You gasp for water, but it feels like nothing can douse the flames. Once the pain has subsided, however, you suspect you'll seek out an even more extreme fix the next time around.
Anyone who enjoys a curry knows this feeling – and chefs have been using the sensation of chillies and other peppers to spice up their culinary experiments for centuries. But it is only in the last decade or so that scientists have begun to understand how we taste piquant foods. Now they have found the mechanism that not only explains the heat of chillies and wasabi, but also the soothing cooling of flavours like menthol.
The implications of this discovery extend far beyond cuisine. The same mechanisms build the body's internal thermometer, and some animals even use them to see in the dark. Understand these pathways, and the humble chilli may open new avenues of research for conditions as diverse as chronic pain, obesity and cancer.
The story begins in earnest in 1997, with David Julius at the University of California, San Francisco. Although people had long speculated about the source of the chilli's fire, his team was the first to discover how its key component, capsaicin, sets our mouth aflame. Most of our sensory perception depends on specific "channels" on the surface of certain cells, each responding to a different kind of stimulation. When the channel is activated, its pores open up, allowing electrical charge in the form of ions – charged particles – to flow in. These ion channels are often found on nerves, where this influx of ions triggers an electrical impulse.
There were many candidates for the channel that responds to capsaicin, but with some nifty genetics work, Julius was able to pin it down. It is called TRPV1. Crucially, he then showed that the channel also responds to uncomfortably hot temperatures – about 43 °C or higher – that would be enough to damage tissue. This neatly explains why chillies feel like they are burning the mouth.
Other TRP (pronounced "trip") channels had previously been implicated in different kinds of sensory perception, but this was the first to represent our internal thermometer (see diagram). It didn't take long for other, related protein channels to emerge that explain our sensitivity to other temperatures and food ingredients. In 2002, for instance, Julius discovered the TRPM8 channel, which is activated by relatively cool temperatures, between about 10 and 30 °C. This channel is also triggered by menthol, giving it that cooling sensation.
Just chillin'
Having identified the TRPM8 channel, Julius and his colleagues went on to create a strain of genetically engineered mice that carried two defective copies of the gene that normally codes for its protein. They then tested the animals' sensitivity to cold by placing them in a box containing two chambers, each with a different ambient temperature, and compared their behaviour with that of their normal littermates.
The normal mice showed a strong preference for the chamber kept at 30 °C, but the genetically engineered animals happily stayed in the colder chamber for long periods of time, preferring the warmer one only when the temperature dropped to below 15 °C. They were also far less able than their littermates to distinguish between cool and warm surfaces.
The researchers are now filling in the other gaps in our understanding of the body's thermostat. As they do so, it is becoming clear that in some animals these mechanisms have evolved in surprising ways. For instance, in pit vipers and vampire bats, a super-sensitive variant of the TRPA1 channel, which responds to temperatures of around 10 °C, has been co-opted for infrared-based thermal imaging.
A new understanding of the senses was only half the cause for excitement, however, as it soon emerged that these channels' responsibilities are wide-ranging, potentially implicating them in a range of disorders. Of particular interest is the fact that they are found on nerves that respond to painful stimuli – and that they can act as a kind of switch that amplifies or damps down the nerve's sensitivity. When that mechanism backfires, thanks to certain mutations, even the slightest changes in temperature can produce devastating pain (see "Worse than childbirth"). But the flip side is that these channels open promising avenues of research for new kinds of analgesics that could potentially use the pathway as an entry point.
Initially, most research focused on TRPV1 – the first channel that Julius discovered. Unfortunately, finding ways to alter pain perception through this route was much more difficult than it first seemed, since the potential drugs were quickly found to have unwanted and potentially dangerous side effects. Because TRPV1 is involved in detecting hot temperatures, anything that blocked its function made people less sensitive to painful heat. That meant they were more prone to injury, by scalding themselves in a hot shower for instance. And, due to its involvement in regulating the core body temperature, drugs that block the channel can cause a dangerously high fever. "Every major pharmaceutical company piled in," says pain researcher John Wood at University College London, "and something like $60 billion was spent trying to make drugs based on TRPV1. We made hundreds and characterised them really carefully, but none were any good."
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