Ouch! Ouch! Ouch! Hot! Hot! Hot !

Naman Agrawal

  Summary: Understanding how humans perceive the world around them has been a central driving force for most of our scientific endeavours. Two key pieces of the puzzle, namely temperature and touch sensors, were discovered by Dr. David Julius and Dr. Ardem Patapoutian for which they were awarded the Nobel prize in 2021. This article aims to elucidate the methodology followed by the nobel laureates for their discoveries.

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  On a fine winter morning you wake up with a hangover, and stroll your way to the neighbourhood tea shop.. After ordering the steaming cup of fresh ginger tea, you chuckle to your atma, ‘Nice beginning to the day, huh!’. In your whimsical dopamine rush, you sip too much of the tea too soon. The seething hot tea simmers and burns your upper palate and tongue! Your pain is sudden, unforeseen and electric, and your atma shouts “Ouch! Ouch! Ouch! Hot! Hot! Hot!”.

  Okay, alright, this article is supposed to be the explainer for the Nobel Prize in Physiology and Medicine 2021 which was awarded to Dr. David Julius and Dr. Ardem Patapoutian for their discovery of sensors of heat and touch in the human body. Let us begin by travelling back in time to an unknown grocery store in San Francisco. David Julius, a professor at University of California was busy shopping with his wife. He looked at all the rows of spices and remarked to his wife “This is such an interesting problem!”, to which she replied “so do it ! “ [1]. Thereafter how Dr. Julius followed through with the problem is simple, and yet so remarkable that it once again bolsters the power of simplicity and elegance in scientific methodology. . Let us try to follow the line of thinking of Dr. Julius.

  Question - How are the spices sensed in the body ?

  Hypothesis - Spices need a “Spice Sensor” which would detect the spice’s presence and convey that information to the brain through the nervous system.

  How do we find that “Spice Sensor” ?

   Any sort of pain - noxious, thermal or mechanical - is sensed by the human body through a specialized group of neurons which are called nociceptor neurons. Incidentally, these nociceptor neurons also react to Capsaicin, which is an active component in spices like capsicum. Is it possible that these neurons might have the elusive “Spice Sensor” on their surface which enables them to react to Capsaicin?

  Dr. Julius and his students made a DNA library of the genes in sensory neurons that they thought might be responsible for making the spice sensor on the neuron surface. They artificially expressed these genes in kidney cells which natively do not respond to Capsaicin. After going through 16,000 of such candidate genes, finally he found the one which codes for the receptor of Capsaicin. Further research on this led him in figuring out that this receptor is actually a temperature sensing receptor! The receptor would open on temperatures that were perceived as “painful”. They named this gene TRPV1 (transient receptor channel protein). The elusive “Spice Sensor”, which turned out to be a temperature sensor, had been found alas![2]

  The road to discovery of mechanical sensors by Dr. Ardem Patapoutian was not very different. Dr. Patapoutian, working at Scripps Research in La Jolla, California, identified a particular cell type which upon mechanical stimulation produced miniscule but measurable electric currents. Similar to Dr. Julius, he made a DNA library of the candidate genes that he thought might code for the receptor that senses mechanical pressure in these cells. He then inactivated (silenced) these genes one by one. Silencing of one particular gene, which they later named Piezo1, made the cells insensitive to mechanical stimuli, and hence led to the discovery of the gene responsible for mechanical sensing. [3]

  It is very easy to see why these discoveries are so important. TRPV1 channels are important in detecting not just thermal pain, but also important in regulating internal body temperature and reflex actions. Similarly, Piezo channels are important not only in sensing touch, but also to have an internal sense of body parts’ location and regulating run-of-the-mill body functions that depend on crucial processes like respiration and blood pressure regulation. These discoveries are also highly valuable from a pharmaceutical point of view. If one can specifically silence the pain receptors in a particular body part, we might find new directions towards chronic pain treatment and a plethora of other related health issues.

  Our bodily pain and temperature sensing mechanisms have evolved over millions of years to protect the body from damage and ensure its survival. Thus, these discoveries as great as they are, encompass a caveat, and one needs to be cautious in perturbing such receptors which are optimized and are indispensable for our survival.

Bibliography

1. [1] - https://www.mercurynews.com/2021/10/04/ucsf-scientist-shares-in-nobel-prize-in-medicine/
2. [2] - Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997:389:816-824.
3. [3] Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell 2002:108:705-715

Naman finished his integrated BS-MS in 2020 with BS from IISER Kolkata, India and MS project from CAESAR in Bonn, Germany with Dr. Bettina Schnell. Thereafter, he took a one year break because someone ate a bat. He joined YLab in Fall 2021, where he will be looking at how the internal state of flies affect their interaction with their environment and the underlying neural circuitry for the same. In his free time, he reads some poetry, does some theatre and sends his friends obscure memes.