About the 2021 Nobel Prize in Physiology or Medicine
[Fig. 1] The temperature-sensing receptor reacted with capsaicin[1].
The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius and Ardem Patapoutian for the discovery of temperature and tactile sensory receptors. This article introduces the discovery of each receptor and interesting facts about it.
Discovering receptors through screening
The existence of neurons that are responsible for stimuli such as pain, temperature, and touch has been known for a long time. However, scientists did not know which molecule acts as sensory receptors. In 1997, David Julius, a professor at the University of California San Francisco (UCSF), came up with an idea to figure out which molecules are responsible for producing temperature sensory receptor proteins.
All cells in a person’s body have the same deoxyribonucleic acid (DNA). However, the role and the characteristic of the cells are different due to the ribonucleic acids (RNA) that are expressed. Using this point, Julius proposed an idea that if every mRNA sequences can be obtained from sensory cells, then they should be able to find the receptor.
They created a complementary DNA (cDNA) library of sensory neuron cell bodies that are activated by capsaicin. cDNA is a newly synthesized DNA by using mRNA as a template strand, and has a nucleotide sequence complementary to mRNA. This cDNA is inserted into a vector1) for cloning, and the formed aggregate is the cDNA library.
The created cDNA library is divided into several cDNA pools and then each one is injected into the cell line2). If a capsaicin ligand, a molecule that binds complementarily to a receptor, is treated, the cell line will not express the sensory receptor, preventing any response to capsaicin. If there is a cDNA that decodes a sensory receptor among the injected pool, it will have a response to capsaicin.
[Fig. 1] is visualization of the receptor response to capsaicin. The case where capsaicin was not treated is (-) and a reaction is (+). Because only the small part of the cDNA reacts to capsaicin (‘pcDNA’ in Fig. 1), only few cells will be injected with the cDNA that have reactivity. Extract the cDNA from the activated group, amplify, dilute, and retest the reactivity. After repeating this experimental process, a single cDNA clone that has reactivity will be obtained. This whole progress is called ‘screening3).’ Then the identity of the receptor is determined by DNA sequencing.
The name of discovered receptor is VR1. Further research showed that it is responsible for responses to high temperatures. Since then, several researchers have discovered other receptors that respond to a wide range of temperatures.
Using the knockdown method
Ardem Patapoutian, a professor at Scripps Labs, identified the receptor responding to touch in a different way.
There are two methods to test the function of gene: ‘gain of function’ and ‘loss of function.’ The ‘gain of function’ is a variation that specific conditions are satisfied. In the case of a temperature receptor, while mRNA expression does not normally occur, used the fact that the cell activates by the additionally injected receptor gene. Conversely, the ‘loss of function’ is a variation that loses function due to a specific condition. The discovery of the tactile receptor was based on loss of function.
Tactile receptors use the characteristics of the loss of function. Here, a knockdown method was used. When a complementary sequence is attached to a single strand mRNA, it is regarded as an external enemy mRNA factor so the strand is cut. That is, the mRNA, formed from DNA, is not translated into a protein. This phenomenon is called RNA interference (RNAi), and it is one of the knockdown methods. Researchers used RNAi testing to target candidate genes in Neuro2A (a cell line responsible for tactile response).
From the 72 candidate genes, repeat RNAi to finally find the gene. The discovered receptor that gene expressed is PIEZO1. [2]
Interesting facts about sensory receptors
Capsaicin is a particle that causes pain from a spicy food. However, the sensory receptor discovered through capsaicin was for temperature, not for pain. Why was capsaicin used to discover temperature receptors?
To answer this question, recall the experience when you ate spicy food. When you eat fairly spicy food, you might feel that your tongue is burning. The temperature receptors are activated even though we have not eaten hot food, but we feel burning. This is the result of capsaicin, which reacts with temperature receptors.
This is also the reason why you feel cool when you eat mint. Because menthol, main component of mint, reacts with the low temperature receptor., So mint feels cool.
Tactile receptors are attributed to proprioception in the body. Proprioception is a kind of sense that allows us to know where our body is and how we move, even when we close our eyes, which is important for people to interact with the world.
The presence of sensory receptors is very important. If there were no receptors, we would not feel the pain of hot or cold, which is essential to prevent cellular harm and abnormalities in the body. However, avoiding pain is also important, not distinguishing, so sometimes we confuse pain with hot or cold.
Why this research was awarded the Nobel Prize
This year, the Nobel Prize in Physiology or Medicine was awarded for the discovery of sensory receptors and not-as most people expected-for the development of mRNA vaccine. Song Mi-ryoung, a professor at the School of Life Sciences, provided some reasons for the research awarded the Nobel Prize. She explained, “The efficiency of a vaccine development as well as some potential latent sides effects cannot be recognized immediately. It requires time to prove to be efficient and beneficial to human so the mRNA vaccine development is probably on a long Nobel Prize waiting list.”
She also emphasized the importance of discovery of receptors. Song said, “The discovery of sensory receptors is important because it can be combined with various fields of life science. At GIST, related research is being conducted in various lab such as drug development, neural circuits, and gene expression analysis.”
The senses are one of the essential elements for life, and the discovery of sensory receptors has served as a cornerstone for current neuroscience research. Through this research, people can expect further development of neuroscience in the future.
[Terminology]
1) vector: DNA molecule as a transporter, carry foreign genetic material into another cell so that it can be replicated or expressed
2) cell line: a group of cells that can be maintained in culture with identical genetic characteristics
3) screening: an experimental technique used to identify and select cells expressing an interested protein from the mutated population
[References]
[1] Caterina, M. J., and D. Julius. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 1997. 389(6653): p.816-824.
[2] Coste, B., and A. Patapoutian. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 2010. 330(6000): p.55-60.
