Post by Lani Cupo
The quest to understand heat, cold and mechanical force
You take a bite of your curry and at once the powerful spice overwhelms you in a tidal wave of heat. Your eyes water, your nose runs, your friends laugh as your face turns red—you swear you could breathe fire to rival any dragon. Desperately you reach for a piece of bread or glass of milk—anything to quench the flame that has engulfed your head. But why does spicy food feel like fire? And why does it burn when you touch your eyes—organs that you don’t need to taste? The answers to these questions represent careers worth of work for two scientists and have recently earned them the most prestigious prize a scientist can win. In 2021, Drs. David Julius and Ardem Patapoutian were awarded the Nobel Prize in Physiology or Medicine for their work ultimately discovering the receptors providing the basis for sensing heat, cold, and mechanical force. In the following overview, we will explore exactly what the researchers discovered and why it earned them a place in the scientific halls of fame.
The Nobel Prizes were established by a Swedish chemist, engineer, and inventor Alfred Nobel, and first awarded in 1901. The prize in Physiology or Medicine is chosen “for the discovery of major importance in life science or medicine”, and the discovery must be “of great benefit for humankind”. Nominations are invited with confidential letters, then the Nobel Committee is responsible for selecting the winners, consulting with experts in the appropriate field.
Explaining thermosensation
How is heat from our environment communicated through the nervous system to the brain? To convey this information, thermal signals must be converted to electrical signals that can travel up nerves to the brain. Different neurons that carry these electrical signals respond to different types of sensory information based on the molecular receptors and ion channels that the neurons express.
Born in New York and educated at Massachusetts Institute of Technology, the University of California, Berkeley, and Columbia University, Dr. Julius first became interested in these receptors through his curiosity about psilocybin research. In 1997, his group at the University of California, San Francisco published seminal work in Nature describing the discovery of an ion channel responsive to painful thermal stimuli. To discover the channel, the group investigated capsaicin, a naturally-occurring compound in capsicum peppers responsible for their spicy or “hot” flavor. Before Julius’s research, it was known that exposure to capsaicin excited certain neurons, leading to nociceptive experiences (experiences that often result in the perception of pain), however the underlying molecular mechanism was unknown. In order to identify the mechanism, the group cloned the genes encoding the receptor.
The researchers set out to express genes encoding receptors in cells that do not normally respond to capsaicin. They first created a library of complementary DNA (cDNA) from messenger RNA derived from dorsal root ganglion neurons. The clones of the DNA were then transfected into cells from the kidney. These kidney cells were examined for changes to intracellular calcium (indicative of cell activation) in response to capsaicin. By repeating the process for pools of cloned DNA the researchers eventually discovered a 3-kilobase clone of cDNA that made kidney cells sensitive to capsaicin. They named the receptor “transient receptor potential vanilloid type 1”, or TRPV1 because a main structural component of capsaicin is known as a vanilloid. TRPV1 responds not only to capsaicin but also noxious heat, which is why the sensation of eating spicy food feels like “burning”.
Explaining mechanosensation
In addition to probing temperature sensory signals, research teams worldwide were investigating how mechanical stimuli, such as pressure, could be converted to neuronal signals. A similar hunt for the receptor responsible for mechanical stimuli responses was underway.
Dr. Patapoutian was born and raised in Beirut, Lebanon. After moving to the United States, he completed degrees at the University of California, Los Angeles and California Institute of Technology, followed by a postdoctoral fellowship at the University of California, San Francisco. His research on nociception led to the investigation of the receptors responsible for sensitivity to mechanical stimuli that underlie processes like touch and pain sensation, hearing, and blood pressure regulation.
Researchers first established that a line of mouse neuroblastoma (Neuro2A [N2A] cancer cells) responded to physical pressure. Next, they generated a list of genes that encoded ion channels and were enriched in the N2A cells and systematically knocked-down (removed the function of) the candidate genes one by one. After each gene was knocked down, they tested the cells to see if they still responded to pressure. This process allowed them to identify a gene that controlled pressure sensitivity, which they named Piezo1 after the Greek word for pressure (pίesi). Piezo1 is present in many species, from slime mold to humans, but vertebrates also have a second member, Piezo2. Using similar methods to Dr. Julius, Dr. Patapoutian extended the work on thermosensation to mechanosensation. Independently of one another, both researchers also used menthol (the chemical responsible for the taste of mint) to identify a channel that responds to cold temperatures, TRPM8.
What’s the impact?
The contributions of Drs. Julius and Patapoutian to neuroscience provide an important puzzle piece for neuroscientists to understand how the external world is translated into signals perceptible to individuals. These advances in such fundamental elements of our perception changed the scientific understanding of how our brains recognize and interpret the surrounding world. By understanding the mechanisms underlying such environmental experiences, future scientists may also be able to better conceptualize what is happening when perception differs from expected, in the case of chronic pain or the lack of sensation.
There is still much unknown about the channels responsible for our perception of heat, cold, and pressure. Future studies may focus on interactions between the receptors and the surrounding cell environment, further explaining methods of activation responsible for our sensations.
