Editor’s Note: The first-ever North American Pain School (NAPS) took place June 26-30, 2016, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP); Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); and the Quebec Pain Research Network (QPRN), NAPS brought together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided first-hand reporting from the event, including summaries of scientific sessions and interviews with NAPS’ six visiting faculty members, along with coverage on social media. This is the fourth installment of interviews from the Correspondents, whose work is featured on PRF and on RELIEF, PRF’s new sister site for the general public. See previous interviews here.
Robert Gereau, IV, PhD, is the Dr. Seymour and Rose T. Brown Professor of Anesthesiology at Washington University in Saint Louis, Missouri, US, and director of the Washington University Pain Center. He is also a cofounder of NeuroLux, a company that develops wireless implantable optogenetic devices as neuroscience research tools. His main research interests are in understanding the signaling pathways responsible for the nervous system plasticity underlying pain sensitization. Gereau sat down with PRF-NAPS Correspondent Nathan Fried, a postdoctoral fellow at the University of Pennsylvania, to discuss his path to pain research, the promise of optogenetics, and what it was like to co-found a company. Below is an edited transcript of their conversation.
What was your path to science?
I come from a family of scientists. My grandfather was a microbiologist, and he had a lab in his house, so my mom and her sisters would work with my grandfather. My aunt and uncle are neuroscientists.
I was always one of those outdoorsy kids who loved being in nature, and I liked scuba diving in the ocean—typical for a kid from Missouri, right?—so I fancied that I would be a marine biologist. As I started looking at what programs were available, I realized there were only two or three of those in the whole world, and so maybe it wasn't the greatest career move. Marine biology is now a hobby for me instead.
I started wondering if I could work in a laboratory, and looked for opportunities at my undergraduate university. I talked to my aunt about working in her lab over the summer, and she said yes. My aunt's and uncle's labs were related to Parkinson's disease. They helped me create a summer research project, and I applied for a little funding from the Parkinson's Disease Foundation, which was awarded to me. I thought I would be in the lab and realize that it's not for me—I've got to be outside instead, I thought—but I just loved it. I had a nice, tractable research project taking neurons from fetal rats and helping them survive in vitro to promote neurite outgrowth. I saw some really interesting things there and got a publication out of it.
I then went to Emory University for my PhD in neuroscience, where I started working with Jeff Conn on G protein-coupled glutamate receptors, the metabotropic glutamate receptors (mGluRs). My projects involved identifying the role of specific receptor subtypes and how they regulated hippocampal function in learning and memory. I was really interested in this concept of synaptic plasticity, and how a momentary change in activity can change the function of a synapse for a lifetime, and how that might underlie memory.
How did you become interested specifically in pain?
I was going to Society for Neuroscience meetings and realized there were many people working on the hippocampus. I wondered if there was really a need for more of us working in that area. I happened to be in a class where I wrote a paper about phantom limb pain. As I was reading the literature, I started to understand that many of the problems of chronic pain are really problems of maladaptive plasticity in the brain. Here was something I could really get behind; chronic pain is a very important, understudied clinical problem that involves this fascinating phenomenon of synaptic plasticity in the brain.
I then looked for a postdoc in a pain lab where I could learn molecular biology tools, but at that time, that really didn't exist. I found a postdoc position with Steve Heinemann at the Salk Institute, who was one of the leaders in molecular neuroscience. I continued to study glutamate receptors, but focused on receptor structure-function studies and learned how to make knockout animals to study behavior.
I thought I should probably do another postdoc, in a pain lab, to get my feet wet in that field, but the realities of life caught up with me; I had a young child at the time and I figured it was time to get an actual job. I applied for jobs where I proposed to have two branches of research. One was to continue my line of investigation about metabotropic glutamate receptor modulation and how it regulates learning and memory in the hippocampus, and the other was to study how these receptors function in pain circuits and mediate plasticity in those pathways.
I got my first job doing that at Baylor College of Medicine. While I was there, my first grant was on the role of mGluR5 regulation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) and how that might be related to different types of learning. As we were starting to work on that, Houston got hit by Tropical Storm Allison, and the basement where my animal colony was became flooded, so I lost all of my animals.
What happened next?
At that time I had to stop the work I was doing, and I thought about what I could do next. I had some ideas about pain experiments, so we started working on very straightforward experiments, using the same tool set I already had, asking what metabotropic glutamate receptors do to neural circuits. But instead of studying the hippocampus, I did that in cells and circuits involved in pain. That's been the guiding principle of my lab: What are the maladaptive processes in the nervous system that lead to the development of chronic pain, and how can we intervene?
That's my road from wishful marine biologist to pain neurobiologist. Really, the thing in neuroscience that got me excited was this idea that the brain is such a powerful tool for plasticity. One way I conceptualize it that has colored a lot of the research we did, certainly initially, is that pain is really a memory of sorts. It's not a memory in the sense that we think of, but your past has changed your nervous system and colors everything in the future. It just does so in a bad way.
You said at NAPS that the best way to go about running a lab is to balance multiple projects. What are your main directions at the moment?
As I said, the overarching goal is to understand how the nervous system changes in the context of chronic pain and how we can intervene in a dysfunctioning nervous system to improve that process. It started with the glutamate receptors, which are important in neuromodulation but hadn’t been studied much in pain, so that's where my strengths are.
One set of experiments is focusing on mGluR5, which belongs to one of the excitatory groups of metabotropic glutamate receptors, and another set concentrates on mGluR2, on the inhibitory side. These two sets of experiments are conceptually organized around both mGluRs and pain, but they are asking slightly different questions and are separate projects that run in parallel.
It's helpful to have conceptually linked projects, but also enough diversity. Many things can happen in science—a line of investigation can run its course and lead to a logical endpoint, or it can also end because you're no longer able to get external support to fund it. In that scenario, if you don't have another program ongoing, you have to try and do something else completely new, but if you have multiple things going on at the same time, you mitigate against those kinds of natural or imposed ends to projects.
You also have an interest in optogenetics and co-founded NeuroLux, a company that develops implantable wireless optogenetic devices for animals. Who else was involved in this process, and what was it like?
John Rogers, at the University of Illinois, got the process going; John, along with Michael Bruchas, my colleague at Washington University, and myself are the co-founders of the company. For Dr. Bruchas and me, it was like launching into entrepreneurship with training wheels, because Dr. Rogers had started several companies, many of which have been successful and are still going. We had not only his experience to go on, but also the experience of the intellectual property of people with whom he's worked for many years. It's been a real partnership between the University of Illinois team and our group at Washington University. It's been nice for me because we’ve had our hand held throughout the process, and it's gently helped us figure out how to do this sort of thing.
The impetus for starting this company was that we thought the devices would be really useful for the neuroscience community. Dr. Rogers’ lab is a materials science and engineering group, so their job is to constantly innovate. What we realized is that this is a point in time where we have technology that should be very broadly applicable and useful.
Do you think it's feasible to use optogenetics to treat patients with pain?
Yes, I do. Conceptually, it makes sense. We've shown that you can make human neurons in nociceptive pathways fire, or stop firing, so the concept is relatively straightforward in that it's just a refined version of a local anesthetic. You can turn on the firing of a neuron for a defined period of time, or you can dampen down the firing of a neuron, for the duration of the application of a light source.
One challenge is using gene therapy to deliver light-sensitive molecules to neurons. That's going to take a while, and it's possible that something better will come along before that happens. But for now, optogenetics seems like something we should really try because there are certain types of pain for which this treatment could be pretty useful. It's easy to tell where it will work by looking at where local anesthetics have an effect; optogenetics is a way to do that in a refined manner.
Optogenetics, arguably, activates neurons in a non-physiological manner. Is there anything we can do to produce more physiologically relevant activation patterns?
I think so. One way is to record natural firing patterns of neurons in the context of a certain behavior you're trying to study and then simply play that back into the system. You might hear people say that when they use optogenetically stimulated neurons, the cells don't fire the same way as they usually do in vivo. But the same thing is true when you patch a neuron with an electrode and depolarize it; it's not going to fire the way it does in response to regular stimuli.
With electrophysiology, people use dynamic clamp where they basically play back into the cell the firing pattern that they've seen before. The same can be done, in theory, with optogenetics; it just depends on the complexities of the firing pattern and whether you can reproduce that faithfully using whatever stimulation protocol you need. It comes down to what question you are asking by using optogenetics. It's a way, certainly, to test the necessity of a neural pathway because you can use light to turn on or off the pathway in the context of the behavior and see if it's altered.
It becomes more of a challenge when trying to understand if a pathway is sufficient to drive a behavior. If you want to activate a pathway, you need to know how that pathway is normally activated before you can play that back, in order to drive the pathway and see a behavior. But how you drive it is really critical. Many people do that blindly; I was guilty of that in my first days. We chose a firing frequency for neurons in the amygdala based on how they fire in the context of chronic pain, but we didn't take into account the stochastic nature of action potential jitter and things like that. That’s where the challenge is in terms of mimicking natural firing patterns.
What is your advice for undergraduates, graduate students, and postdocs who are interested in pain?
Techniques are important for answering a question, but the most important thing is to find the question you're passionate about—something that's going to drive you and give you ideas and excitement. I learned this from my postdoc advisor—ask the big questions, and even if it all sounds impossible, you could probably find a way to do it. You have to look at what techniques are available, and if they aren't sufficient, develop new techniques to make it happen.
You also want to find mentors who have been successful at mentoring and share your passion for what you want to work on; you need a good relationship with them. You can find good mentors at places like the North American Pain School, or at the American Pain Society annual meeting.
Speaking of techniques and tools, there was a debate at NAPS that asked the trainees to address the assertion that pain research, using the animal models we have, has not led to new pain treatments and should be deprioritized accordingly. What do you think about this?
It’s a provocative statement—and patently false. We have clear examples of effective translation from animals to people. If you need some kind of test of validity to show this, you can take all the animal models of pain that we use, and apply currently effective pain therapies in people to those animal models, and the therapies are effective. This means that something that is effective for treating pain in people can be demonstrated in the animal models, though it does not mean that the animal models are 100 percent predictive of efficacy in humans.
There are many reasons that drugs fail to make it to market. Many times it's a lack of efficacy, but many times it’s not—it's safety or the drug has off-target effects. This doesn't mean the target is not valid or that modulating the same target in people would not treat pain. So there are examples of translation from animal models to humans. Animal models are not perfect, but they are a safe way to begin the process, and we've certainly learned a whole lot about the neurobiology of pain through animal research.
If you hadn’t become a research scientist, what career would you have chosen?
I'd probably be in construction because that was my dad's business, and I had an affinity for it. I did have a music scholarship in college, so I guess I could have gone into music or music education.
I played French horn.
Thanks for taking the time to speak to PRF.
Always a pleasure.
Davidson S, Golden JP, Copits BA, Ray PR, Vogt SK, Valtcheva MV, Schmidt RE, Ghetti A, Price T, Gereau RW
Pain. 2016 Sep; 157(9):2081-8.
Copits BA, Pullen MY, Gereau RW
Pain. 2016 May 19. [Epub ahead of print]
Park S I, Brenner DS, Shin G, Morgan CD, Copits BA, Chung H U, Pullen MY, Noh K N, Davidson S, Oh S J, Yoon J, Jang K-I, Samineni VK, Norman M, Grajales-Reyes JG, Vogt SK, Sundaram SS, Wilson KM, Ha J S, Xu R, et al.
Nat Biotechnol. 2015 Dec; 33(12):1280-6.
Crock LW, Kolber BJ, Morgan CD, Sadler KE, Vogt SK, Bruchas MR, Gereau RW
J Neurosci. 2012 Oct 10; 32(41):14217-26.
Montana MC, Gereau RW
Curr Pharm Biotechnol. 2011 Oct; 12(10):1681-8.
Other Interviews with NAPS Faculty: