The burning pain of a hot red chili pepper, the feeling of warmth in the sun, or the chill when we dive into the water are something we have long experienced. But no one really understood how temperature translates into electrical nerve signals the brain can interpret, until the discovery that was Nobel Prize awarded in 2021.
"I got interested in the whole biology of natural products and captivated by stories of people who used them to uncover important signaling pathways in our bodies. I wanted to find out more about how drugs work on a molecular level. Hallucinogens, magic mushrooms like psilocybin – I really wanted to understand how they work," says David Julius, Professor in Physiology at University of California San Francisco.
He turned to nature's own products for the answer, and above all to capsaicin. The substance is found in chili peppers and leads to the feeling of heat that food seasoned with chili peppers can produce.
“There is a stimulus you can link to a behavior that starts at the periphery and goes into the brain. This offered an opportunity to understand the molecular mechanisms behind the sensory experiences," explains David Julius.
Simply described, David Julius and his research team produced a library of tiny DNA fragments from neurons known to respond to temperature and pain. By then allowing cultured cells, which do not normally react to capsaicin, to express proteins from different parts of this library, it was possible to find the right gene that encodes an ion channel, TRPV1, in the cell membrane (see picture) and that also responds to painful heat above 43 degrees.
Illustration of the ion channels TRPV1 (chili pepper receptor) and TRPM8 (menthol receptor) that open when the temperature is higher than 43 Celsius degrees (TRPV1) and lower than 27 Celsius degrees (TRPM8). Then sodium and calcium ions are released into the nerve cell and form an electrical signal that when it reaches the brain makes us feel heat and cold. Illustration: Peter Zygmunt
"Initially, we didn't know what we were going to find, but we were sure that if we could figure out how capsaicin works, we would learn something interesting.
Using the same strategy, but with menthol as a tool, David Julius was soon thereafter able to identify the receptor (TRPM8) that is activated by cold. Today we know of several similar temperature sensors that are part of the TRP channels family and that together cover different temperatures, ranging from painful cold to painful heat.
New strategies for pain
The hope now is that the research results can eventually contribute to treatments for chronic pain. New strategies and treatments are desperately needed in this field.
"We believe that these ion channels can be affected by inflammatory substances produced in acute tissue damage, but which, when the system is pushed too hard, can lead to persistent or chronic pain.
Pain is a warning system. When we burn ourselves in the sun, we become sensitive to heat or pressure because inflammatory substances affect the capsaicin receptor and other receptors. It increases our sensitivity so that we are going to protect the burned area.
“But that can become more chronic, and an example would be an arthritic knee pain. Inflammation is also involved in knee pain caused by arthritis, where they increase the sensitivity of nerve endings. But somewhere, there must be changes in the central nervous system that contribute to that longer term persistent pain.”
Now many scientists are working to understand why that is. David Julius' research group investigates inflammation molecules at the atomic level and wants to understand more about how different cell types contribute to chronic pain and has primarily been interested in internal pain, which can be experienced, for example, in the intestinal disease IBS.
“We chose something that we know many people suffer from, that is interesting from a mechanistic perspective and that we can attack from several different angles. Depending on who you ask, IBS is between 2-5 times more common in women.
His wife Holly Ingraham, who is a professor of cellular and molecular pharmacology and a pediatrician specializing in gastro, is also working on the project.
If you could choose one question that you could get the answer to in research, which one would it be?
“Difficult. It's not how research works, it's instead about an ongoing process. But it is clear, to find out what controls the alternation between the acute and the chronic pain, it would have been valuable to know”.
Sometimes we use the word pain a little carelessly, much like we do with the word cancer, says David Julius:
"If you ask a cancer researcher, it's clear that they want to understand what causes cancer. But there can be different factors behind it, depending on whether it is melanoma or osteosarcoma. Probably, there are several mechanisms that contribute to different kinds of chronic pain. I think knee pain in osteoarthritis may have some similarities to migraine pain, but I also think there are differences.
Thought the Nobel call was a scam
David Julius may be used to receiving prizes, but someone calling in the middle of the night to announce the news hadn't happened before. He thought it was a scam, though he was often suggested in advance.
It has now been just over a year since the famous phone call. The pandemic put a spanner in the works for the Nobel festivities in 2021, but in December David Julius will celebrate in Stockholm. It will be a record number of laureates on hand, since the Nobel Foundation has invited laureates from 2020 and 2021.
"I have visited Lund before and have friends there with whom I have collaborated, including Peter Zygmunt.
How has the Nobel Prize affected your everyday life?
"I still go to the lab during the day and talk research with my colleagues. Two weeks after the announcement, I ran into a colleague with an office in the same corridor. She said it was an honor to share a corridor with me. I replied, ´But we've been sharing a corridor for two years, and not much has really changed.
With the attention that a Nobel Prize leads to, comes a responsibility and a lot of requests. The wow-factor that some people experiences meeting a Nobel Prize winner, is something one must get used to.
“My mother wonders how this could happen - and I answer: "Hard work, mom". I now have a reserved parking space at the university, it's big!” he says, laughing.
In May next year, he will visit Lund, when he will be conferred an honorary doctorate at the Faculty of Medicine, Lund University.
Free curiosity research
The discovery of TRP channels as temperature sensors is yet another example of how basic research is awarded a Nobel Prize. And when David Julius was in college, he’s interest in basic research started. At the time, he had a hard time sitting still in the classroom and needed something to do during breaks. He applied to the lab that offered a break from the monotonous.
“It started as a hobby, but it grew. You get data that you need to think about, and then you try to understand what's going on in something you can't even see with the naked eye. In those days, that was the case. Now we have electron microscopes and other things that allow us to see the cells. But back then it was like you were imagining something and then you tested this in the lab with different methods.”
Research is erratic and offers no guarantees. David Julius remembers speaking with a student who was hesitating between whether he should become a scientist or a doctor. Both professions, says David Julius, are worth pursuing, but fundamentally different. Those who study to become doctors follow a clear path where you know that on the other side of the tunnel a good profession awaits.
"Research lacks such guardrails. It offers greater freedom, yes, but also a freedom to fail. For some, this is annoying. There are no guarantees as to whether one will succeed. But if you are passionate and driven by either the issues or the technology/methods, and if you are persistent despite failures, then you will achieve something.
David Julius likes to and often talks about being a researcher both a mentor to others and having role models himself. Being a mentor is like discovery in that they are both very fulfilling – and he believes that the two are often connected. Two researchers he himself worked with have also received Nobel Prizes, Randy Schekman in 2013 and Richard Axel who shared the Nobel Prize in Medicine in 2004 with Linda B. Buck.
"When I talk to young people, I usually stress that you don't have to come from an academic family to succeed as a researcher. What you need is curiosity, and the drive to dare. I always tell my students, especially when they're in the doldrums – that persistence pays off. So if you're just interested in what you're doing, go ahead. Most of what you do will probably fail, but that's part of the process. In the end, you come across something, and suddenly it happens!