The Nobel Prize for Physiology & Medicine 2021

Posted by Phil Heler on October 31, 2021

One fundamental question in physiology has remained unsolved. This is ‘how are temperature and touch converted into electrical impulses in our nervous system?’ This question has finally been answered by David Julius and Ardem Patapoutian,  who have just been awarded Nobel Prize in Physiology this year.

Edwin Hubble ( as in Mr Hubble Space Telescope) once said ‘ equipped with the five senses, man explores the universe around him and calls the adventure science’. During his lifetime he used his five senses well. He played a crucial role in the scientific fields of astronomy and cosmology.

His observations on the cosmos proved that things that were once thought just be clouds of dust and gas were in fact ‘nebulae’ that contained other galaxies beyond the Milky Way. He also calculated that the universe was expanding (Hubble–Lemaître’s Law) which was a theory way ahead of its time.

Of the five senses that allowed Edwin Hubble to make his observations, one of the least scientifically understood is the sense of touch. This is due to its shear complexity.

The mechanisms underlying our other senses are by comparison are relatively well known. We have a good scientific understanding of how  light is detected by the eyes, how sound waves affect our inner ears, and how different chemical compounds interact with receptors in our nose and mouth generating smell and taste. Just exactly how temperature and touch  are converted into electrical signals has until very recently remained elusive.

The ability to perceive changes in environmental temperature is clearly essential for survival of all organisms. This is absolutely critical for cold blooded animals such as reptiles who have to carefully internally regulate their blood temperature. Mechanical stimuli such as touch, and vibration are also fundamental.

As we walk across a lawn in summer not only can we feel the heat of the sun, but we also feel the caress of the wind, and the individual blades of grass underneath our feet. These impressions of temperature, touch and movement are essential for our adaptation to a constantly changing surrounding.

Tactile information is our most immediate experience. While we can perceive something from a distance using our senses of vision or even sound, our most direct sensory input is picking something up and assessing it. Our touch allows us to tell if something is hot or cold, dull or sharp, rough or smooth, wet or dry. Our sense of touch is essential for survival and underpins our interaction with the world around us.

Another key pathway associated with touch is one that has an emotional and social context. Touching  is a hallmark of social interaction. This could be shaking hands or a gesture of affection such as a kiss or a hug. Touch is the first thing a new-born experiences as it touches a mother’s skin.

This sense of touch is processed in a different way. This pathway allows the processing of  social and emotional information. This activates brain regions associated with social bonding and pleasure, each of which is important for our new-born baby.

 

 

Our skin is packed with many sensory type receptors to allow all this to happen. These amazing sensory receptors for touch and temperature in our skin have  a widespread distribution all over our entire body. This is in sharp contrast to our other senses.

The receptors for these are clustered neatly in a very specific anatomical location in our cranial anatomy  close to our central nervous system (CNS). Meanwhile for the sense of touch and temperature  receptors are scattered throughout our whole body. They must convey their signals though pathways that travel to our spinal cord and then to our CNS.

Joseph Erlanger and Herbert Gasser received the Nobel Prize in Physiology or Medicine in 1944 for their discovery of different types of sensory nerve fibres in the skin that conveyed much of this information. However, one tantalizing fundamental piece of information has remained unsolved.

That simple question was ‘how are temperature and mechanical stimuli converted into electrical impulses in the nervous system?’ Put another way, how are these sensations initiated into nerve impulses so that we can perceive them? This question has finally been answered by David Julius and Ardem Patapoutian,  who have just been awarded Nobel Prize in Physiology this year.

David Julius made his discovery by using capsaicin in 1997. Capsaicin is the active component in chilli peppers that gives them their heat. It is a chemical irritant that produces a sensation of burning in any tissue with which it comes into contact with. We are all familiar with the effect of capsaicin on the mucous membranes in our mouth during a spicy curry (we have all been there!).

 

 

Essentially what David Julius did was to form a library of all genes that were known to encode for proteins that form part of our sensory pathways for touch. This is like forming of library of all the instructions manuals that manufacture proteins that are assembled to make our entire touch pathway. What he had to do was find that one instruction manual (or gene) that made a protein that reacted to capsaicin. Needle in a haystack!

As you would imagine this took time, but by tireless process of elimination he did eventually discover the gene that encoded the protein that was sensitive to capsaicin. Further experiments revealed that the isolated gene encoded for a previously unknown ion channel protein which became known as TRPV1.

He then decided to investigate how this receptor reacted to heat. Much to his surprise he discovered that this receptor  opened and closed depending on temperature and allowed ions to pass through a channel. This flow of ions then caused an electrical impulse  though a mechanism known as cell ‘membrane potential’ which was sent and processed in our CNS.

Independently of one another David Julius and Ardem Patapoutian (our second laureate) used the chemical substance menthol to identify a receptor that was shown to be activated by cold called TRPM8. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures.

While the mechanisms for how temperature is converted into an electrical signal unfolded, the race was also on to discover how mechanical stimuli (touch, pressure, and vibration) could be converted into an electrical stimulus. Ardem Patapoutian, who was working at Scripps Research in California, was also determined to identify these elusive receptors.

He assumed that the receptor activated by mechanical force was also an ion channel.  He then isolated 72 candidate genes encoding possible proteins for these receptors. After yet another arduous search, by process of elimination Patapoutian and his research team succeeded in identifying a single gene responsible for encoding for the proteins in the missing ion channel.

A new and entirely unknown mechanosensitive ion channel was discovered and was given the name Piezo1, after the Greek word for pressure (í; píesi). 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.

Piezo2 was also shown to play a key role in the critically important sensing of body position and motion, known as proprioception. In further work, Piezo1 and Piezo2 channels have been shown to regulate additional important physiological processes including blood pressure, respiration and urinary bladder control.