Nobel Prize in Physiology or Medicine
D. Indumathi, The Institute of Mathematical Sciences, Chennai

The Nobel Assembly at the Karolinska Institute has awarded the 2021 Nobel Prize in Physiology or Medicine to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch”.
Winter is approaching and the days are getting colder. Your skin feels the cold, your bladder wishes to empty itself several times a day, and your nose smells the fresh and cold air around you. Your eyes see the fog on a winter's morning, or the sun on a hot summer day. This is how we perceive the world around us throough our senses.
We have always known this. But what is the exact mechanism by which we feel hot or cold, or the sensation of pressure or touch? How exactly do our nerves respond so that we sense these things? This is the subject of research for which the Nobel laureates won the physiology prize this year.

How do we perceive the world?
In the 17th century, the philosopher René Descartes imagined that different parts of the skin were connected by threads with the brain. In this way, a foot touching an open flame would send a mechanical signal to the brain. These cells were later found to exist and were called nerve cells or neurons. Each of these neurons were highly specialised to detect changes in our surroundings, such as light, sound, heat.
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. For example, different fibres respond to painful and non-painful touch. So, a pat on the cheek will not be confused for a blow to the face.

The science heats up!
We all know that if you touch chillies and then touch your eyes or even your skin, you feel a burning sensation. This is because of the chemical called capsaicin in chillies. The hotter the chilli, the more capsaicin it contains. Why does touching capsaicin cause us to feel pain? This was solved by David Julius, who was working at the University of California, San Francisco, USA, in the late 1990s. 

DNA and genes
DNA is a molecule called Deoxyribonucleic acid. DNA carries genetic instructions for the functioning, growth and reproduction of all known organisms. All living cells contain DNA. The instructions for growth and reproduction is coded into genes. Genes are made up of DNA. A gene is the basic physical and functional unit of heredity. Genes are made up of DNA. Some genes act as instructions to make molecules called proteins.
When a gene is activated, we say that it is expressed. When neurons respond to pain or heat, certain genes in them are expressed. Julius and his colleagues created a library of millions of DNA fragments. Each of them corresponded to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. Julius thought that there should be at least one DNA fragment that contains the actual protein which reacts to capsaicin.
After hunting through this library, they finally found a single gene that was able to make cells capsaicin sensitive (see Figure). The gene for capsaicin sensing had been found!

The capsaicin gene TRPV1
You may know that sensations travel through neurons as electrical signals (of a few millivolts). These electrical signals are created by having charged sodium and potassium ions that move across the nerve membrane. So for a nerve impulse to be transmitted, it is necessary to have special "gates" in the membrane where these ions can cross into or out of the nerve. These are called ion channels. In fact, these channels are specialized proteins that open and close to provide a passage for the charged ions.
The gene that had just been discovered actually encoded (produced) a new ion channel protein called TRPV1. This acts as a capsaicin receptor (it responds to the presence of capsaicin). Julius studied the effect of heat on this protein. He found that this protein is a heat-sensing receptor. It is activated at temperatures felt to be painful; hence, the effect of eating or touching capsaicin (or chillies) is the same as touching something hot! See the figure. You can see that when the temperature increases, the new ion channel closes and the nerve signals the brain indicating the presence of painful heat. So the work of Julius showed how temperature can induce electrical signals in the nervous system.

Hot or cold
The discovery of TRPV1 was a major breakthrough and led to the discovery of additional temperature-sensing receptors. Independently of one another, both David Julius and Ardem Patapoutian used the chemical substance menthol to identify the receptor TRPM8. This was shown to be activated by cold. All of you must have felt the cold sensation when you eat mint peppermints! Now you know, this is due to TRPM8!!
Many more ion channels were found that are activated by different range of temperatures. The procedure was the same in all cases: start with a cell that does not respond to temperature, introduce a gene from the library, and see if that generates a new response/sensation to temperature. Genetically modified mice were used to study many such genes. 

Research under pressure!
So much for chillies and heat. What about touch? Pressure applied on the skin can also be felt by our sense of touch. How does this happen? Are there also genes for this?
Ardem Patapoutian, working at Scripps Research Institute in California, USA, tried to identify the receptors that are activated by a mechanical stimulus such as pressure. Patapoutian and his collaborators first poked individual cells with a micro-pippette. One such cell gave a measurable electric signal when poked. They assumed that this receptor is an ion channel and listed 72 possible candidate genes that were responsible for encoding (producing) this channel. 
Each gene was inactivated one by one and it was tested again. If this is the gene sensitive to touch, then there will be no electrical signal in the nerve when it is inactivated. They found a completely new and unknown ion channel that was responsible for sensitvity to touch/pressure. It was given the name name Piezo1 (piezo means pressure in Greek). Soon a second gene called Piezo2 was found. Both are activated (that means sensory neurons in your skin express these genes) when you exert pressure on cell membranes (see the figure).
Soon it was found that the Piezo2 ion channel is essential for the sense of touch. It also plays a key role in the critically important sensing of body position and motion. This is called proprioception. Later, Piezo1 and Piezo2 channels have been shown to regulate other important physiological processes including blood pressure, respiration and urinary bladder control.

It all makes sense!
Thus the efforts of the Nobel laureates and the discovery of the TRPV1, TRPM8 and Piezo channels helped us understand how heat, cold and mechanical force can trigger nerve responses. This in turn allows us to sense and adapt to the world around us.
The TRP channels are needed for our ability to perceive temperature. The Piezo2 channel gives us the sense of touch and the ability to feel the position and movement of our body parts. Both the TRP and Piezo channels also contribute to numerous additional physiological functions that depend on sensing temperature or mechanical stimuli.
These led to more research in trying to understand their functions in different physiological processes. For example, this knowledge is being used to develop treatments for a wide range of disease conditions, including chronic (constant) pain (see figure).
Adapted from the popular information on the Nobel Prize pages