It’s an exciting time, especially for scientists, when Nobel Prize announcements are made — when the world comes together to celebrate scientific achievements aimed at helping humankind and moving medicine forward.
Imagine the utter joy when a project you worked on receives such recognition. That’s what happened for Michael Caterina as he started his day reading the news that David Julius, Ph.D., at the University of California, San Francisco (UCSF), won the Nobel Prize in Physiology or Medicine.
Caterina was a postdoctoral fellow in Julius’ lab when the discoveries recognized by the Norwegian Nobel Committee were made. He was the first author of a 1997 paper in Nature that identified transient receptor potential vanilloid-1 (TRPV1), an ion channel in neurons and a receptor activated by heat-related pain.
Biological chemist Craig Montell, Ph.D., formerly on the Johns Hopkins University School of Medicine faculty, cloned the first TRP channel in flies.
Caterina is the Solomon H. Snyder Professor of Neurosurgery, director of the Department of Biological Chemistry and director of the Neurosurgery Pain Research Institute at Johns Hopkins.
I sat down with Caterina soon after the Nobel Prize announcement to talk about working in Julius’ lab and how the experience shaped medicine and his career. The following are his reflections, edited for brevity and clarity.
How did you learn that the 2021 Nobel Prize in Physiology or Medicine was awarded to your former lab director David Julius and Ardem Patapoutian?
Caterina: I woke up and got my iPad to casually look at news and saw the announcement on CNN. So, I sprung out of bed and figured I was going to have a busy morning.
Tell me about working in David Julius’ lab at the time of the discoveries during the 1990s.
Caterina: I joined David Julius’ lab because I wanted to enter the field of neuroscience and signal transduction [the biological process of sending signals from cell to cell].
Julius had pioneered a method known as expression cloning, which is a way of identifying cell receptors [like a radio receiver] for neurotransmitters [signals sent by neurons] by introducing cDNA libraries, or gene fragments, into cells that don’t have those receptors. Then, a functional screen identifies which cells respond to the stimulus that you are studying.
He had created this system and, initially, used it to identify receptors for serotonin and ATP [a compound that provides energy to cells]. I thought that this was exciting, and so I went to his lab for my postdoctoral fellowship. Originally, it was with the intent of identifying receptors for neurotransmitters like GABA [which blocks electrical impulses between brain cells], which scientists had experienced difficulty in locating at the time.
I spent a year trying to [find these receptors] and set up an assay that, at David’s suggestion, had involved visualizing calcium signals in cells using fluorescent dyes. The assay was finely tuned, but unfortunately, I wasn’t able to identify the GABA receptor. But, another research team eventually did find it.
However, because of the unique aspects of the GABA receptor, we never would have found it with this assay anyway.
Since we had this assay in place, and it was well-honed, David suggested applying it to what had been a long-standing question in his lab, which was whether we could find the receptor to capsaicin [the active ingredient in hot chili peppers].
We shifted our approach to look for the capsaicin receptor and, pulling together all of the cDNA libraries and doing the necessary experiments, within about a month, we had the first hint that we might have it.
Why search for capsaicin receptors? What’s their significance in the research world?
Caterina: Capsaicin has long been recognized as causing pain. It’s a fundamental compound in hot chili peppers and other spicy foods.
Other laboratories had recognized that capsaicin can activate ionic currents in neurons [brain cells] that initiate pain sensation. In addition, pharmacologist Peter Blumberg and pathologist Arpad Szallasi used biochemical methods to discover a location in sensory neuron tissues that capsaicin could bind to selectively. It was called the vanilloid binding site, because the chemical structure is similar to the structure for vanilla.
David’s lab had been testing other approaches to find this capsaicin receptor, which hadn’t worked. So, when we developed this calcium imaging-based assay, it seemed like a logical way to identify the receptor.
What followed after publishing the 1997 paper on TRPV1?
Caterina: In 1998, we published a paper that showed that this capsaicin receptor could integrate capsaicin-related heat and acid signals together. These integrated signals were capable of responding, in a coordinated way, to multiple stimuli.
Then, in 1999, we published a paper that described a related ion channel that’s now called TRPV2 — originally called vanilloid receptor like 1, or VRL1 — which also responds to heat and is also expressed in sensory neurons.
Finally, in 2000, we published research on a knockout [genetically modified] mouse that lacked TRPV1 receptors, and showed that the mouse lacked sensitivity to capsaicin and, in part, heat.
So, what does this tell us about heat and pain sensitivity, and are there ways to use this knowledge to treat related conditions?
Caterina: These findings provide an explanation for how capsaicin produces pain in the skin or tongue.
Also, there is a paradoxical finding that evolved from our discoveries and what we’ve observed for thousands of years: that people who consume lots of spicy foods can become tolerant to them. That’s because when TRPV1 gets activated again and again, it will lead to degeneration of the pain-sensing nerve terminals. So, doctors can treat some cases of chronic pain with repeated exposure to capsaicin, using prescription-strength capsaicin patches.
Another direction of research has been to stimulate the TRPV1 channel to diminish pain. In addition, drug companies are trying to develop blockers to inhibit the activity of the channel, but there have been challenges to this approach.
For scientists in this field, these molecules provide a molecular flag for the subpopulation of neurons that trigger pain sensation. With this knowledge, scientists have developed specific tools to manipulate the function of those sensory neurons and understand what comprises these neurons, the genes they express, and change the neurons’ function. So, there has been a trove of scientific tools that have emerged as a result of having this molecular flag.
Julius’ lab and collaborators at UCSF also worked to pioneer a new iteration to cryoelectron microscopy [use of ultrasensitive microscopes that visualize molecules] that made the ability to see structures at an atomic scale more powerful and informative.
How have you taken your experience working in Julius’ lab and applied it to your own research?
Caterina: My lab continued to study TRPV1 and other related ion channels. There is a lot to explore in the function and biology of these channels. That work led us to expand our focus to study the roles of cells other than neurons in the process of sensation, to understand how neurons and non-neuronal cells contribute to our sensory experience, notably pain.
What has made the work from David’s lab so impactful is that he’s willing to tackle long-standing problems in a field and apply fresh approaches and ideas to solve those problems. He’s not afraid to tackle a scientific question, even if it’s been lingering for a while. He has a gift for defining the questions and coming up with effective solutions to solve the problem.
What’s next for the frontier of touch research?
Caterina: How many days do you have to talk about this in depth? I’m going to need more coffee.
The frontier ahead is to figure out how these molecules that synthesize environmental stimuli, such as touch and temperature, work as part of a coordinated system in a sensory neuron to give us the normal experience of pain, under healthy conditions, and what changes in that system as a result of injury or inflammation to give us pathological pain. By understanding how that system works, we can figure out the areas of vulnerability to target with drugs or other approaches to interrupt pain.