Every year since 1901, the Nobel Prize ceremonies show us the incredible discoveries at the cutting edge of science, and remind us of the nonstop movement of scientific progress. Just last year the awards were given for the revolutionary gene-editing technology known as CRISPR, and for proving the existence of black holes! This year, two scientists, Sykuro Manabe and Klaus Hasselman, were awarded the prize in physics for their looks into the future predicting global warming. Another physics prize went to Georgio Parisi, for his research in quantum physics that covers the interplay of everything from atoms to planets. In Chemistry, Benjamin List and David Macmillan won the prize for their work in “organocatalysis,” an elegant, precise new way to build organic molecules, thus making the work of chemists all over the world much easier and cheaper. However, in Medicine and Physiology, David Julius and Ardem Patapoutian won for the kind of discovery that represents one of the best aspects of science: its persistence. Julius and Patapoutian have given the world an amazing discovery that was built on literally thousands of years of inquiry, and passed from generation to generation until at last, the solution was found.
Imagine walking barefoot into a cool stream on a hot day, feeling river pebbles press into the bottom your cool, submerged feet as the hot sun warms the top of your head. For centuries, humans have tried to understand just what it is that allows us to have such magnificent, multilayered experiences of touch and sensation. How is it that we feel heat, and cold? How is it that we can touch, and feel? This year, Julius and Patapoutian have cracked the secret, and discovered the exact way that temperature and mechanical stimuli are converted into electrical impulses in our nervous system.
The ability to sense hot, cold, and pressure are absolutely integral to human survival, and truly one of medicine’s most enduring questions. In the 4th century B.C., no less than Aristotle theorized that nerves were controlled by and connected to the heart. In the Middle Ages, Muslim doctors such as Ibn Sina fully described the physical appearance of nerves throughout the body. In the 17th century, Rene Descartes theorized the tiny threads leading from the skin to the brain somehow relayed signals. But what exactly did they relay, and how? By the 18th century physiologists were beginning to make connections between nerves and the conduction of electrical signals. In 1944, another pair of researchers, Joseph Erlanger and Herbert Gasser, received the Nobel Prize for their discovery of different types of nerve fibers that react to specific types of stimuli, such as painful or non-painful stimuli. After centuries of inquiry, it was understood that nerve cells are highly specialized for detecting different types of stimuli, allowing us to feel the many sensations that are such an essential part of being alive.
Building on the previous generation’s discovery that nerve cells were specific and specialized, the opportunity finally emerged to understand exactly how specific nerve cells worked. Julius saw a potential for discovery in the compound Capsaicin, the compound responsible for the burning, spicy sensation of chili peppers. In the 1990’s, when his research began, no one understood how this compound actually worked to cause sensation. It was a riddle that eventually became the gateway to the 2021 Nobel Prize. By collecting a library of millions of DNA fragments that corresponded to sensory neurons responsible for pain, touch, and heat, Julius and his team made a big bet one of the DNA fragments would contain the gene that encoded the protein capable of reacting to capsaicin, and they found it! Dr. Julius was able to carefully test the specific capsaicin receptor, named TRPV1. Experiments revealed that the sensory receptor TRPV1 was an ion channel that opened in conditions hotter than 109 degrees F, and conducted a sensation of painful heat to the brain.
Working together, Julius and Patapoutian then used the compound Menthol to discover another such specific ion channel that relays the sensation of cold, TRPM8. The function of these ion channels was definitively proven when experimental mice with the TRPM8 gene deleted displayed drastically less sensitivity to cold! As this research continued over years, Dr. Patapoutian was able to tackle the mystery of the sensation of touch, discovering a previously unknown ion channel in called PIEZO2, that opens when pressure is applied to the skin, and relays the signal to the brain. Again, experimental mice with the PIEZO2 gene deleted displayed much less sensitivity to touch.
Thanks to this monumental research, it is now understood that TRP channels and PIEZO2 channels are the reason that we can sense temperature, heat pain, and touch. Many functions in the body rely on these channels for our daily function, including things like urination, respiration, core body temperature, and protective reflexes. What will the next generation of scientists find when they take up this inquiry? The future looks very bright: this discovery may open the doors for new and effective ways to stop pain in its tracks, at its source. Thank you to David Julius and Ardem Patapoutian, and thank you to all of the Nobel Laureates for adding new links to the great chain of inquiry that is science.
Sources and Further Reading:
A layman’s explanation of Julius and Patapoutian’s discovery: https://edition.cnn.com/2021/10/04/health/nobel-prize-medicine-physiology-winner-2021/index.html
A scientific explanation: https://www.nobelprize.org/prizes/medicine/2021/advanced-information/
All 2021 Nobel Winners: https://www.nobelprize.org/all-nobel-prizes-2021/
2021 Medicine and Physiology Nobel Laureate Lecture: https://www.youtube.com/watch?v=4TkmSJnhcFo
The Long History of Nerve Science: http://web.stanford.edu/class/history13/earlysciencelab/body/nervespages/nerves.html