At preschool, children learn that there are five senses: sight, touch, smell, taste and hearing. But only one of these senses is shared by all living organisms, from bacteria to humans, and that sense is touch. It’s also the only sense that can be triggered by any part of our body. Touch is the essential survival tactic. We sense temperature and pressure because our nervous system responds to these physical cues, but how is this communicated by the body at a molecular level?
David Julius and Ardem Patapoutian were jointly awarded the 2021 Nobel Prize in Physiology or Medicine, “for their discoveries of receptors for temperature and touch”. Both scientists noted that touch and pain are taken for granted, and that this important feature of physiology was unknown from a chemical point of view. It was “the elephant in the room”, said Patapoutian in an interview.
From Chili Peppers to Drugs Targeting Pain
Transient receptor potential (TRP, pronounced “trip”) channels are proteins built into cell membranes which act as sensors. First discovered in fruit flies in 1969, TRP wasn’t properly identified until over two decades later. In the mid-1990s, David Julius and his colleagues decided to look for the receptor for capsaicin, the chemical compound that gives chili peppers its spiciness. It was known that capsaicin switches on nerve cells responsible for recognizing pain, by increasing calcium in their membranes. The receptor for capsaicin was cloned from nerve cells found in the root of a spinal nerve, and was later found to also become activated by pain-producing heat (over 43°C). This new receptor was classified as belonging to the TRP family of ion channels and named TRPV1. By knocking out the genes responsible for TRPV1 in mice, Julius and his team were able to demonstrate that mice without TRPV1 were resistant to pain caused by heat.
Julius went on to identify other TRP channels using natural products. Menthol from peppermint activates TRPM8, the receptor for cold (this was also independently discovered by Ardem Patapoutian and his team). TRPA1, known as the wasabi receptor, is stimulated by a range of plant chemicals, notably mustard and horseradish. “Keeping the sources of natural products around is really critical”, said Julius in a telephone interview soon after the announcement of the Nobel Prize. Many TRP modulator drugs have entered clinical trials, not only those focusing on pain, but also those that aim to manage a wide range of diseases.
Chemical signaling is one form of communication between cells, but physical force as a signaling mechanism had long been “a mystery,” said Ardem Patapoutian. In 2009, Patapoutian and his postdoc Bertrand Coste designed an experiment using cells that produced an electric signal when poked with a micropipette. The candidate genes for ion channels were knocked out in each batch of cells, and a search began for the cell that would not respond to touch. “It was a grueling and difficult project,” recalled Patapoutian. It took over a year to identify the gene, which was named Piezo1. Shortly afterwards, a similar gene, Piezo2 was found, indicating that, like TRP, Piezo proteins constitute a family of ion channels. To see the real-life effects of eliminating Piezo genes, the research group conducted a series of experiments comparing mice with and without the Piezo2 gene, which involved sweeping their paws with a cotton swab, or sticking a piece of tape to their backs (mice with Piezo2 tried to shake the tape off their backs).
What began as a lengthy cell-poking experiment in basic science has ballooned into an array of potential applications. People who lack Piezo genes suffer from various illnesses, which may have been misdiagnosed before the discovery of Piezo. One such disorder is the lack of proprioception – the awareness of where our limbs are in relation to the rest of our body. For example a blindfolded person without proprioception isn’t able to walk properly. Treatment for these diseases may not yet be around the corner, but knowing their cause is a significant step.