Michael Burton, PhD, is the Eugene McDermott Assistant Professor in Neuroscience and the principal investigator of the Neuroimmunology and Behavior Lab at the University of Texas at Dallas, US. His research focuses on how age, sex, and neuroimmune interactions influence chronic pain and comorbidities, such as depression and anxiety. He has been recognized as an early-career award winner by several institutions, including the American Pain Society and the Rita Allen Foundation.
Here, Michael chats with Yarim De la Luz-Cuellar, a PhD candidate at the Center for Research and Advanced Studies, South Campus, Mexico, and a PRF correspondent, about his journey to the field of pain research, his current work, and the translation of basic science research to clinical applications. Below is an edited transcript of their conversation.
How did you become a pain researcher?
It was actually by accident. My PhD was focused on immune function and cognition, and my initial postdoc at the University of Texas Southwestern, was focused on endocrinology, obesity, diabetes, and inflammation. I started my postdoc in 2012, and in 2013 a paper from Clifford Woolf’s laboratory was published. The paper stated that TLR2 (toll-like receptor 2) on sensory neurons is important for mediating pain, and that FPRs (formyl peptide receptors) were just as important (Chiu et al., 2013).
We ended up having a great project looking at how peripheral neurons control diet, obesity, and other endocrine functionality, and then we used these mice that selectively knocked TLR4 out of sensory and DRG [dorsal root ganglia] neurons. After doing some experiments that were obesity and metabolism based, we thought there might be something going on regarding pain. That did not work out very well because I was working with a bunch of endocrinologists, and I did not have any pain experts around me at the time.
In 2014, Ted Price had moved his lab from the University of Arizona, [US], to the University of Texas at Dallas [UT Dallas, US], and Robert Dantzer (my mentor at MD Anderson Cancer Center, Houston [US]) told me, "There is a guy really well known in the pain field. You should talk to him about how to get your models going.” So I came over to UT Dallas to meet Ted, and I told him about my idea. He said, "That's a great idea. Why don't you just become faculty? We're hiring people." It was my third year as a postdoc, and I said, "I need more time to develop as a pain person if I'm going to do this." Ted replied, "Fine. You can come and be my postdoc if you want to." We got funding for two years to work with Ted and Greg Dussor. I quickly learned a lot from Ted, and everybody in his lab at the time, about chronic pain biology.
I knew a ton about neuroanatomy from my previous postdoc experience, and that really helped everything fuse together. I'm lucky that my lab is not just about pain, but also behavior. We can do cognition, and then depression, so some of our experiments are looking at comorbidities. Long-term chronic pain and how that influences depression, or how that influences cognition. It has just been a fantastic experience.
So this transition was a huge step in your career.
Absolutely. I was a third-year postdoc thinking, "Do I make this decision to be in the pain field, when I should be making the decision to start my own lab, or should I try to find a job?" I just took a leap of faith. Ted Price has always been a positive person, and that is what I needed. “You'll be fine. You can come in…." I also needed about six months to really get into everything.
What is the overall aim of your current research?
We are interested in the conversation between the peripheral nervous system and the peripheral immune system, and how it mediates pain. But the research is not just pain; it’s also about comorbidities such as depression, cognition, and anything that can be transcribed within the brain. I like what we do because it is very broad. It goes from understanding what's happening in the periphery to how that can change the central compartment.
We are doing experiments to modulate sensory neurons in the periphery, but then looking deep into the dorsal horn of the spinal cord – or even in the anterior cingulate cortex, or the periaqueductal grey – to understand how that nociceptive input is controlling or changing input/output in more “affective” areas in the brain. We think this is more translatable to humans because nociception is a little bit, obviously different, depending on the animal type or species type. We are really interested in how various stimuli like age, obesity, sex, injury, or surgery can influence the immune system or the peripheral nervous system to mediate pain. We have some amazing projects where we are looking at how diet influences pain, independent of a pain state, and how an injury can change things if you are on a diet.
This gives us an understanding of how nociceptive inputs, going from acute to chronic, become more of a problem because we are understanding the basis of the mechanisms that are happening first. We are also looking at how the immune system – either the peripheral immune system or microglia/astrocytes – is changing across various situations in human tissue from donors who have passed away, or live patient samples. Then we can try to trace it back to mice and rats.
Why is it important to understand this communication between the immune and nervous systems?
For a long time, most neuroscientists interested in pain have been trying to understand these systems. Understanding how the neurons work is just as important as understanding the interaction and the conversation between the neurons and the non-neuronal cells – immune cells. I think we are missing key elements and a mechanistic kind of flow that we can take advantage of. It is not just giving someone a blocker to inhibit their nerve impulse, but also about telling the immune system to quiet down first, and then giving the block. This depends on how things work, because inflammation has a direct influence and input on pain and nociception itself.
Being able to understand what that conversation is, and then being able to try to figure out what controls what – or what influences what – is the answer to help in the clinic. There are failed clinical trials every month, and I think it is because we don't have the whole picture to address what is going on. We are not looking in the right place, either. We are looking too much into animals and not enough into humans. There is a potential to get human samples so that we can look and see what is really going on, and taking advantage of that is important.
How did you end up working with hormones and sex differences in pain?
I think it's because of my training. One of the first grants I wrote was how leptin influences AgRP (agouti-related peptide) neurons in the brain and what that does to metabolism. It was one of those things where I have always had this interest, but the sex differences paper from Jeffrey Mogil's lab changed everything for a lot of people, especially for me as a neurologist in 2015 (Sorge et al., 2015). That Nature Neuroscience paper clearly insinuated that immune cells are playing a huge role in pain on mechanical hypersensitivity. Not only that, but it depended on where the immune cells came from – if they were male or female driven. I think people are paying attention to hormones, but maybe they are paying too much attention to a couple of hormones. If you think about estrogen, for instance, there are 13 to 30 different estrogen types – estriol, estrogen, etc. – that could be the one hormone, or several hormones, responsible for the sex effect on different types of cells.
My previous experience in endocrinology has been helpful in the understanding of how hormones influence immune cells and neurons. I have a group of people in the lab that I am training and making sure they don't say, "Yeah, male is testosterone; female is estrogen."
Do you think your preclinical research can be fully translated to clinical research in the future?
That's definitely the hope. Will we ever only have humans in our studies? I will say it is potentially true, but the idea is to try to do the best and keep both worlds happy. We have translational research, and then back-translational research where we are using human data so we can translate it appropriately to animals. We can get into more mechanisms because there are just so many things you can do with animals that you can’t do with humans. However, as long as that is allowable, that is something we will be doing. What my lab could look like in 10 or 20 years is terrifying because it could be, "No more mice, no more rodents."
If you were able to meet your younger version, what advice would you give him about your career?
I would tell my younger version, “Don't be so afraid of taking a leap,” and that, “Not everybody has the right advice.” If you ask 10 people for one piece of advice about one topic, you will get 10 different answers, and you have to go with your gut and do what is right for yourself. I think listening to everybody else around you is important, but they have their own experience.
If I didn't do what was right for me, comfortably and confidently, then what am I doing? One of the biggest things was that becoming a pain researcher (because that was not what I was going to do) and being able to say that I have a full-blown pain and behavior lab is absolutely insane. You definitely embrace that. Embrace the change. Embrace all that life has to give because there is a ton to do, and there is a reason for everything.
Do you think this advice would change your current work?
Maybe a little bit. I think that if I was not so afraid, I would have been able to be just a little bit more productive. I was hesitant to do too much as a postdoc. I was doing my research, teaching in a community college, and trying to learn new techniques and whole new systems in the pain world. The first time I did a von Frey assay wasn’t until my second postdoc in 2015.
Is there anyone or anything that really inspired you to become a better researcher and scientist?
I would say several people have, but I think one of the most influential people – especially as an adult and as a pain researcher now – is my little brother. He was in the Marines for seven years, and he has developed this random, idiopathic neuropathy that is very painful, and we do not understand where it came from. It is a close reminder that this pain realm is real, people are dealing with this every day, and how they deal with it is different. Pain can change someone’s world in a very short period of time. This has motivated me to plan some experiments to find out how something can change your nociceptive system without necessarily changing the baseline thresholds. I think my brother has always inspired me to be a good person and to be a good role model. Now I think about his pain all the time, and how pain is so detrimental and devastating to people.
Work-life balance is very important for a busy scientist. Do you have any hobbies outside the lab?
I want to have more, but we do bird watching, hiking, off-roading…. I do “outdoorsy” things, but I also call myself a chef and do a lot of cooking, trying new techniques. Oh, and I love wine and whiskey. So a lot of finding a new distillery or winery to go to. Obviously travel. COVID has made a huge issue for traveling, but I think that would be the number one thing I would’ve said before the pandemic that I want to continue doing. Traveling, seeing parts of the world, and interacting with people I never have interacted with before.
Yarim De la Luz-Cuellar is a PhD candidate at the Center for Research and Advanced Studies (Cinvestav, South Campus) in Mexico City, Mexico. Twitter – @atarii_cuellar