Could Nobel Prize 2021 findings lead to new drug discoveries?

The 2021 Nobel Prize in Physiology or Medicine has been jointly awarded to David Julius and Ardem Patapoutian for their discoveries of receptors for temperature and touch. David Julius utilised capsaicin, a compound from chili peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat. Ardem Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs.

Our ability to sense heat, cold and touch is essential for survival and underpins our interaction with the world around us. In our daily lives we take these sensations for granted, but how are nerve impulses initiated so that temperature and pressure can be perceived? This question has been solved by this year’s Nobel Prize laureates.

Julius and Patapoutian’s breakthrough discoveries launched intense research activities leading to a rapid increase in our understanding of how our nervous system senses heat, cold, and mechanical stimuli.

At the University of California, in the 1990’s, Julius saw the possibility for major advances by analysing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chili peppers. Research and experiments revealed that an identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1. When Julius investigated the protein’s ability to respond to heat, he realised that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful (Figure 2).

The discovery of TRPV1 was a breakthrough which led to the unravelling of additional temperature-sensing receptors. Independently of one another, both Julius and Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures. Many laboratories pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipulated mice that lacked these newly discovered genes.

While the mechanisms for temperature sensation were unfolding, it remained unclear how mechanical stimuli could be converted into our senses of touch and pressure. Researchers had previously found mechanical sensors in bacteria, but the mechanisms underlying touch in vertebrates remained unknown. Patapoutian, working at Scripps Research in La Jolla, California, USA, wished to identify the receptors that are activated by mechanical stimuli.

Patapoutian and his collaborators first identified a cell line that gave off a measurable electric signal when individual cells were poked with a micropipette. After searching, Patapoutian and his co-workers succeeded in identifying a single gene whose silencing rendered the cells insensitive to poking with the micropipette. A new and entirely unknown mechanosensitive ion channel had been discovered and was given the name Piezo1. Through its similarity to Piezo1, a second gene was discovered and named Piezo2. Sensory neurons were found to express high levels of Piezo2 and further studies firmly established that Piezo1 and Piezo2 are ion channels that are directly activated by the exertion of pressure on cell membranes (Figure 3).

The discoveries of the TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us. The TRP channels are central for our ability to perceive temperature. The Piezo2 channel endows us with the sense of touch and the ability to feel the position and movement of our body parts. TRP and Piezo channels also contribute to numerous additional physiological functions that depend on sensing temperature or mechanical stimuli.

Intensive ongoing research originating from this year’s Nobel Prize awarded discoveries focusses on elucidating their functions in a variety of physiological processes. This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain (Figure 4).